[{"id":"f1787191586104","cycle":206,"visit":2,"ts":"2026-08-20T02:06:26.104Z","cancer":{"key":"bloom syndrome","name":"Bloom syndrome","mondo":{"id":"MONDO:0008876","name":"Bloom syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"A nine-patient multicentre paediatric Bloom syndrome cancer series (PMID:40641635) documents routine dose reduction, prolonged aplasia/sepsis and one toxic death alongside five remissions, promoting the genotoxin-sparing treatment-architecture lead to CANDIDATE and adding PARP inhibitors to the pred","confidence":0.52,"notebook":"Visit 2 delivers the first real clinical dataset for this programme. P5 (PMID:40641635), a nine-patient national multicentre series of paediatric BS malignancy, converts L1 from expert-opinion inference into observed practice and outcome: six solid tumours, three haematological; six treated with polychemotherapy \"often with dose reductions\"; complications prolonged aplasia, sepsis, early discontinuation, one toxic death — yet five remissions. That is precisely the shape L1 predicted (disproportionate normal-tissue toxicity on a constitutively BLM-null host, tumours still curable), so L1 is promoted to CANDIDATE. It also answers OQ3 in part: dose reduction is already de facto standard, but the abstract gives no per-agent dosing, no conditioning detail, no comparison to sarcoma/AML standards — full text or registry follow-up needed.\n\nP1 and P2 independently corroborate the mirror programme (L3) with new chemical matter beyond FMD-108: berberine/coptisine displace pSTAT1 from a parallel G-quadruplex in the BLM promoter, suppressing BLM transcription in colon cancer and synergising with olaparib (PMID:42087785); LYY-34 competitively blocks BLM-mediated unfolding of the c-MYC promoter G4, lowering MYC and suppressing TNBC (PMID:41941995). L3 → CANDIDATE. Caveat: coptisine is reported as a pan-genomic G4 stabiliser, so it is a poor selectivity probe for phenocopy work; LYY-34, acting on the 3′ overhang/enzyme rather than G4 stabilisation, is the better probe. Critically, the olaparib synergy is a window argument against BS: if BLM suppression sensitises cells to PARP inhibition, then BLM-null normal tissue in BS patients is predicted hypersensitive to olaparib [INFERRED] — PARPi joins alkylators/topoisomerase poisons/radiation on L1's caution list, not its therapeutic list.\n\nThe immunology cluster (P6 PMID:42131344, P7, P10 PMID:40925926) reframes the checkpoint-blockade limb of L1: DNA-repair-disorder patients carry inborn errors of immunity with hypogammaglobulinaemia, immune dysregulation and lymphoid-malignancy risk, so \"genotoxin-sparing = PD-1 blockade\" cannot be assumed without measuring B/T-cell competence first. New lead L4 captures this. New lead L5 records the mechanistic corollary of P1/P2: BLM-null cells cannot resolve promoter/telomeric G4s, predicting altered MYC output and dependence on backup G4 resolvases (WRN, DHX36, PIF1, RECQL5) — testable, but with the same window problem (paralogue inhibition would hit BLM-null normal tissue too), so falsification in non-malignant BS cells comes first. L2 unchanged; no new evidence. Both trials named BLOOM are acronym noise (Fragile X; Mayo dosing feasibility) — not oncology, ignore.","leadChanges":[{"id":"L1","title":"Genotoxin-sparing treatment architecture for BS-associated malignancy (osteosarcoma, MDS/AML)","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.62},{"id":"L3","title":"Mirror programme: pharmacological BLM suppression in BLM-overexpressing sporadic tumours, and BLM lactylation as the switch","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.45},{"id":"L4","title":"BS as an inborn error of immunity: immune competence gates checkpoint blockade as the genotoxin-sparing modality","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L5","title":"Unresolved G-quadruplex burden and backup G4 resolvases as a candidate axis in BLM-null cells","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["What are the per-agent dose reductions, conditioning regimens and grade 3-5 toxicities in the nine-patient BS cohort (full text of PMID:40641635), and do the four relapses cluster with dose de-escalation rather than with tumour biology?","Is there any BS-specific evidence on PARP inhibitor exposure, given that BLM suppression synergises with olaparib and BS normal tissue is constitutively BLM-null?","Do BS-derived tumour lines show a dependency (G4 resolvase, ATR/CHK1, WEE1) absent from BS non-malignant BLM-null cells — i.e. does any therapeutic window exist in this syndrome?","What is the measured immune phenotype of BS patients with malignancy (immunoglobulins, memory B cells, TCR diversity) and the TMB/neoantigen load of BS tumours, before checkpoint blockade is proposed?","Which somatic co-lesions recur in BS tumours (ARID1A, TP53, MSI, ALT), and do the characteristic BS structural-variant signatures identify a rerouted checkpoint dependency?","Are WRN, RECQL4, RECQL5, DHX36 or PIF1 upregulated or functionally compensating in BLM-null human cells, making paralogue inhibition prohibitively toxic in BS?"],"nextQueries":["(\"Bloom syndrome\" OR BLM) AND (\"PARP inhibitor\" OR olaparib OR talazoparib) AND (sensitivity OR \"synthetic lethal\" OR toxicity) AND SRC:MED","\"Bloom syndrome\" AND (immunodeficiency OR hypogammaglobulinemia OR \"T cell repertoire\" OR \"tumor mutational burden\" OR immunotherapy) AND SRC:MED","(BLM OR \"Bloom syndrome\") AND (\"G-quadruplex\" OR DHX36 OR PIF1 OR RECQL5 OR WRN) AND (CRISPR OR \"dependency\" OR \"synthetic lethal\") AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42087785","doi":"10.1093/nar/gkag383","year":2026,"isNew":true,"title":"A small molecule disrupts G4-STAT1 interaction and synergizes with olaparib to drive cancer cell death"},{"pmid":"41941995","doi":"10.1016/j.bcp.2026.117945","year":2026,"isNew":true,"title":"Fangchinoline derivative LYY-34 suppresses TNBC by inhibiting BLM DNA helicase from unfolding of c-MYC promoter G-quadruplex DNA"},{"pmid":"42599232","doi":"10.7868/s3034555326030053","year":2026,"isNew":true,"title":"[WRN and Other RecQ Helicases in Life Cycles of Viruses]"},{"pmid":"42389213","doi":"10.1159/000552262","year":2026,"isNew":true,"title":"Broken and Reassembled: The Molecular Mechanisms and Clinical Consequences of Structural Genomic Variation"},{"pmid":"40641635","doi":"10.1155/humu/7065233","year":2025,"isNew":true,"title":"Management of Paediatric Cancers Associated With Bloom Syndrome"},{"pmid":"42131344","doi":"10.3389/fimmu.2026.1815028","year":2026,"isNew":true,"title":"Inborn errors of immunity with DNA repair disorders: at the interface of immune deficiency, immune dysregulation, and malignancy"},{"pmid":"42104472","doi":"10.1186/s13223-025-01009-7","year":2026,"isNew":true,"title":"Navigating primary and secondary immunodeficiency intersections: how to find IEI hidden within SID"},{"pmid":"41096539","doi":"10.3390/ijms26199269","year":2025,"isNew":true,"title":"A Novel Approach to Prognostic Factors and Risk Stratification in Pediatric AML: Case Report and Literature Review"},{"pmid":"40452851","doi":"10.3389/fonc.2025.1580494","year":2025,"isNew":true,"title":"Synchronous childhood T-lymphoblastic lymphoma and B-cell precursor acute lymphoblastic leukemia associated with constitutional MMR deficiency syndrome -a case report"},{"pmid":"40925926","doi":"10.1038/s41375-025-02750-z","year":2025,"isNew":true,"title":"Insights into germline predisposition to pediatric lymphoid malignancies"}],"trialsShown":[{"nct":"NCT07209462","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Study of MRM-3379 in Male Participants With Fragile X Syndrome (BLOOM)"},{"nct":"NCT07287332","phase":"NA","status":"RECRUITING","isNew":false,"title":"BLOOM: Pragmatic Feasibility Trial"}],"usage":{"input":9391,"output":6445},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"Bloom syndrome\" OR \"BLM helicase\") AND (\"synthetic lethal\" OR \"synthetic lethality\" OR \"paralog\" OR WRN OR RECQL4) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"Bloom syndrome\" AND (chemotherapy OR radiotherapy OR \"reduced intensity conditioning\" OR transplantation OR toxicity OR leukemia OR lymphoma) AND SRC:MED"],"evidenceIds":["PMID:42087785","PMID:41941995","PMID:42599232","PMID:42389213","PMID:40641635","PMID:42131344","PMID:42104472","PMID:41096539","PMID:40452851","PMID:40925926","NCT07209462","NCT07287332"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787191378925","cycle":205,"visit":2,"ts":"2026-08-20T02:02:58.925Z","cancer":{"key":"xeroderma pigmentosum","name":"xeroderma pigmentosum","mondo":{"id":"MONDO:0019600","name":"xeroderma pigmentosum"}},"control":false,"modelLabel":"SCIENCE","summary":"Somatic XPA-variant cisplatin sensitisation (PMID:38500596) does not transfer to constitutional XP — retire platinum/NER synthetic lethality in germline XP — while XPG-TFIIH interface dependence (PMID:41641700) narrows the window for XPB-directed Minnelide in XP hosts.","confidence":0.42,"notebook":"This visit's pack was largely off-target: the checkpoint query returned nothing in XP (only mCRPC ICI meta-analysis, PMID:41672480, and unrelated pan-cancer surveys), and the gene-therapy query returned no XPC/XPA epidermal graft, keratinocyte-stem-cell or base-editing work at all. Two null searches are themselves informative and both cut against my leads.\n\nThe one substantive gain answers open question 6, and it answers it negatively. P1 (PMID:38500596) shows that *somatic* XPA missense variants (Y148D: destabilised protein, weak DNA binding, failed damage recruitment) sensitise cells to cisplatin, consistent with the ERCC1/ERCC2-mutant bladder precedent. That is a tumour-restricted vulnerability created against an NER-proficient host. In germline biallelic XP the host shares the defect, so the differential collapses and the expected result is host toxicity, not tumour selectivity [INFERRED]. I am recording platinum (and by extension NER-loss-based) synthetic lethality in constitutional XP as a retired dead end so the desk stops re-proposing it; the generic cisplatin-resistance review (PMID:41869709) adds nothing XP-specific. Corollary for the future: the same logic makes tumour-only somatic NER-loss (including ARID1A-driven transcriptional NER repression plus NQO1-mediated carcinogen bioactivation, PMID:41133886) a different disease from XP, and I will not import those results.\n\nP4 (PMID:41641700) forces a downgrade of L3. It shows XPG's spacer must engage TFIIH via p62-PH and XPD to assemble a catalytically competent complex and license ERCC1-XPF 5′ incision — i.e. TFIIH interfaces are load-bearing for the *residual* repair XP patients still have (TC-NER in XP-C, GG-NER in XP-E). Minnelide/triptolide engages XPB inside that same complex, so the normal-tissue window in a patient already running on partial NER is narrower than I assumed, not merely unknown. L3 drops to 0.14 and now requires XPB-occupancy-versus-NER-inhibition dose separation in XP-patient fibroblasts before any model work.\n\nL2 weakens on absence: the enabling XP-specific ex vivo correction data I hypothesised does not exist in the 2020–2026 literature; the lead is still mechanistically sound but rests entirely on the DCLRE1C analogue (NCT05071222).\n\nNew low-weight lead: P3 (PMID:42006004) shows Mn²⁺-potentiated cGAS-STING plus ATM/PRMT5 inhibition converts DNA damage into innate immune activation in osteosarcoma. XP tumours carry unrepaired lesions and cytosolic DNA constitutively; STING amplification *without* the ATM inhibitor may exploit that without adding genotoxicity — the ATM arm is explicitly contraindicated in a repair-deficient host [SPECULATIVE]. T1 (NCT05484570) gives a real DNA-repair-disorder natural-history cohort in which to nest RT-tolerance and second-primary endpoints for L4.","leadChanges":[{"id":"L1","title":"PD-1/PD-L1 blockade for XP-associated cutaneous SCC (repair-deficiency-driven adaptive immune resistance)","level":"LEAD","status":"WEAKENED","confidence":0.55},{"id":"L2","title":"Ex vivo lentiviral correction of epidermal stem cells for XPC/XPA chemoprevention (not AAV dermal delivery)","level":"LEAD","status":"WEAKENED","confidence":0.26},{"id":"L3","title":"XPB(ERCC3)-directed transcription inhibition (Minnelide) for chemo-refractory XP-associated internal sarcomas","level":"LEAD","status":"WEAKENED","confidence":0.14},{"id":"L5","title":"STING-pathway amplification (Mn2+-potentiated cGAS-STING) without ATM inhibition, as immunotherapy sensitiser in XP-associated sarcoma and SCC","level":"LEAD","status":"NEW","confidence":0.15}],"unverifiedCitations":0,"openQuestions":["Is there ANY published XP-specific checkpoint-inhibitor outcome beyond single cases (response rate, new-primary rate, irAE profile), and does XP-SCC TMB/UV-signature load exceed sporadic cutaneous SCC?","Do XP tumours show baseline cGAS-STING activation or, conversely, STING/IFN silencing - i.e. is innate-sensing amplification a real opportunity or already saturated?","Can XPB/TFIIH-directed agents be dosed to degrade RPB1 without inhibiting residual TC-NER in XP-patient fibroblasts, and at what fold separation?","Which epidermal compartment (interfollicular basal versus follicular bulge) must be corrected for durable XP chemoprevention, and does any unpublished/preprint XPC or XPA keratinocyte-graft or base-editing dataset exist?","Is there genotype-stratified evidence on radiotherapy tolerance by complementation group (XP-A/C/D vs XP-B/TTD) beyond single-case anecdote, and can NCT05484570's cohort supply second-tumour-in-field denominators?","What is the somatic driver landscape of XPC-null internal sarcomas (beta-catenin/CTNNB1, SWI/SNF, TP53), given that NER-low carcinogen-driven tumours can be beta-catenin dependent?"],"nextQueries":["(\"xeroderma pigmentosum\") AND (cemiplimab OR pembrolizumab OR nivolumab OR \"checkpoint\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(XPC OR XPA OR \"nucleotide excision repair\") AND (STING OR cGAS OR \"type I interferon\" OR \"innate immune\") AND SRC:MED AND PUB_YEAR:[2019 TO 2026]","(\"xeroderma pigmentosum\") AND (sarcoma OR \"internal malignancy\" OR \"exome\" OR \"mutational signature\") AND SRC:MED AND PUB_YEAR:[2015 TO 2026]"],"papersShown":[{"pmid":"38500596","doi":"10.1093/narcan/zcae013","year":2024,"isNew":true,"title":"XPA tumor variant leads to defects in NER that sensitize cells to cisplatin"},{"pmid":"41869709","doi":"10.1080/07853890.2025.2601401","year":2026,"isNew":true,"title":"Application and mechanistic research of novel therapeutic strategies in cisplatin-resistant small cell lung cancer"},{"pmid":"42006004","doi":"10.1016/j.bioactmat.2026.03.032","year":2026,"isNew":true,"title":"Manganese-potentiated cGAS-STING activation with ATM/PRMT5 inhibition remodels the immunosuppressive microenvironment in osteosarcoma &lt;i&gt;via&lt;/i&gt; bone-targeted delivery"},{"pmid":"41641700","doi":"10.1093/nar/gkag078","year":2026,"isNew":true,"title":"The interaction of XPG with TFIIH through p62 and XPD is required for the completion of nucleotide excision repair"},{"pmid":"41133886","doi":"10.1002/advs.202513981","year":2026,"isNew":true,"title":"Arid1a Deficiency Drives Aristolochic Acid-Induced Liver Tumorigenesis through Ctnnb1 Mutation and Defective Nucleotide Excision Repair"},{"pmid":"42286837","doi":"10.1080/19490976.2026.2679197","year":2026,"isNew":true,"title":"Recent advances and clinical relevance of microbiome dynamics in health and disease"},{"pmid":"41672480","doi":"10.1080/21645515.2026.2626084","year":2026,"isNew":true,"title":"The efficacy of immune checkpoint inhibitors in metastatic castration-resistant prostate cancer: A meta-analysis and reconstructed individual patient data analysis"},{"pmid":"41395847","doi":"10.1080/14756366.2025.2598478","year":2026,"isNew":true,"title":"Antitumor activity and structure-activity relationship of poly (ADP-ribose) polymerase (PARP)-based dual inhibitors"},{"pmid":"42292701","doi":"10.1016/j.bbrep.2026.102649","year":2026,"isNew":true,"title":"Pan-cancer expression, methylation, and prognostic significance of α7 nicotinic acetylcholine receptor in tumor immunology"},{"pmid":"42246161","doi":"10.3892/mmr.2026.13924","year":2026,"isNew":true,"title":"Beyond the primary site: Molecular insights and clinical implications of cancer metastatic overlap between lung and urological organ cancers (Review)"}],"trialsShown":[{"nct":"NCT05484570","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Natural History Study for DNA Repair Disorders"},{"nct":"NCT05071222","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Safety and Efficacy Study of Transplantation of Autologous CD34+ Cells Transduced With the G2ARTE Lentiviral Vector Expressing the DCLRE1C c"},{"nct":"NCT06330324","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Reproductive Options in Inherited Skin Diseases"}],"usage":{"input":10281,"output":6982},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"xeroderma pigmentosum\" OR \"nucleotide excision repair\") AND (cemiplimab OR pembrolizumab OR nivolumab OR \"PD-1\" OR \"PD-L1\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(XPC OR XPA OR ERCC2 OR ERCC3) AND (\"gene therapy\" OR \"base editing\" OR \"keratinocyte stem cell\" OR \"epidermal graft\" OR lentiviral) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"evidenceIds":["PMID:38500596","PMID:41869709","PMID:42006004","PMID:41641700","PMID:41133886","PMID:42286837","PMID:41672480","PMID:41395847","PMID:42292701","PMID:42246161","NCT05484570","NCT05071222","NCT06330324"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787191160795","cycle":204,"visit":20,"ts":"2026-08-20T01:59:20.795Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Retire FBXO3–DUSP9 (third empty pass plus direction-discordant DUSP9-pro-stemness biology), keep the a3/asciminib conformational programme as the priority with nanopore adaptive-sampling junction typing (PMID:41254115) as its enabling assay, and open a blast-phase lead anchored on the ELN-BP prognos","confidence":0.62,"notebook":"This visit's pack answers open question 1 only obliquely and kills a lead outright.\n\nThe a3-transcript query returned no CML series and no isogenic pharmacology, but two Ph+ acute-leukaemia case reports in which a3-architecture disease responded to ATP-site inhibition: e13a3 MPAL entering remission on VCD/venetoclax/dasatinib before early relapse (PMID:41366999) and e1a3 ALL controlled by allo-HSCT plus dasatinib (PMID:42064782). [INFERRED] Consistent with the structural argument in L18 — an incomplete SH3 clamp should be irrelevant to agents binding the ATP cleft — but these are lymphoid/mixed-phenotype cases with confounding chemotherapy, so the a2-versus-a3 selectivity of asciminib remains unproven in CML and the isogenic panel is still the decisive experiment. Two methodological additions matter more. Targeted nanopore adaptive sampling resolved typical and atypical BCR::ABL1 genomic junctions patient-specifically in <72 h (PMID:41254115), making L18's \"junction-resolved typing before asciminib\" arm and L5's STIM1-style DNA-breakpoint relapse-clonality tracking operational with one assay. And a FISH-positive, repeatedly RT-qPCR-negative CML that progressed to lymphoid blast phase and then responded to asciminib (PMID:41869197) is precisely the monitoring blind spot L18 predicts: molecular silence from primer non-coverage, not absent disease — with preserved asciminib sensitivity arguing the junction was not a3. L18 strengthened, still DOSSIER.\n\nThe FBXO3/DUSP9 query, its third dedicated pass, returned zero leukaemia data and direction-discordant biology: DUSP9 is pro-stemness in HCC via ERK–FOXO3 and via an ERK1/2–PPARG–SCD lipid axis (PMID:41508037, PMID:41383134), and is transcriptionally induced by EZH2 in hepatoblastoma (PMID:41731536, PMID:42574564). L16 requires DUSP9 to be a tumour-suppressive MAPK brake whose FBXO3-mediated loss drives LSC persistence; the only independent DUSP9 literature says the opposite in solid tissue. Prespecified retirement fires. Recorded so the desk never re-proposes F-box/DUSP9 targeting in CML without primary CD34+ data.\n\nL7 gains a second, independent guideline endorsing dose optimisation by efficacy and safety, individualised milestone interpretation and revised TFR/fertility criteria (PMID:41486652) — still no randomised dose-reduction trial, so the rise is small; question 4 stays open.\n\nNew: the ELN Blast Phase Registry score (275 patients; blast %, platelets, age, immunophenotype, extramedullary disease, prior CML history; median OS 97 vs 22 vs 9 months) finally supplies a stratification backbone for the phase where CML mortality concentrates (PMID:41714405). Opens a lead pairing lymphoid-BP immunophenotype with chemotherapy-sparing ponatinib+blinatumomab (NCT03147612) versus early transplant.\n\nCalibration: the programme's centre of gravity remains ATP-site plus allosteric BCR::ABL1 inhibition, as the 2025 Chinese guideline reaffirms.","leadChanges":[{"id":"L18","title":"Transcript-architecture triage: atypical and insertion-bearing BCR::ABL1 fusions as a distinct resistance class and a blind spot in molecular monitoring","level":"DOSSIER","status":"STRENGTHENED","confidence":0.66},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"DOSSIER","status":"STRENGTHENED","confidence":0.81},{"id":"L16","title":"FBXO3-mediated DUSP9 degradation sustains MAPK output in the persistent CML LSC: FBXO3 inhibition plus ATP-site TKI","level":"LEAD","status":"RETIRED","confidence":0.06},{"id":"L19","title":"Immunophenotype- and score-stratified blast-phase CML: chemotherapy-sparing ponatinib+blinatumomab for lymphoid BP versus early transplant for myeloid/high-risk","level":"LEAD","status":"NEW","confidence":0.32}],"unverifiedCitations":0,"openQuestions":["Do isogenic e13a3/e14a3 CML models retain full imatinib/ponatinib/olverembatinib sensitivity while losing asciminib potency, confirming a3 as a selectively allosteric liability rather than a general resistance class?","Can targeted nanopore adaptive sampling (PMID:41254115) be validated as a diagnostic gate before asciminib and as a patient-specific genomic-breakpoint MRD assay in FISH-positive/RT-qPCR-negative CML?","Which of the 279 asciminib-resistance mutations lie in SH3/non-kinase regions and remain ponatinib- or olverembatinib-sensitive, i.e. can the mutation-to-agent matrix be published from the DMS atlas?","Does the ELN-BP prognostic score interact with treatment modality (ponatinib+blinatumomab versus early allograft) in lymphoid versus myeloid blast phase, and has it been externally validated?","Does any randomised or prospective dose-reduction/TDM trial in chronic-phase CML exist, and do the ELN 2025 or China 2025 guidelines supply quantitative reduction schedules usable as a comparator arm?","Is the ABL1 E255V neoepitope presented on primary CML cells, and does NCT06904066 admit CML kinase-domain point mutations as participant-specific neoantigens (final pass for L17)?"],"nextQueries":["(\"BCR::ABL1\" OR \"BCR-ABL1\") AND (e13a3 OR e14a3 OR \"exon 3\" OR \"SH3 domain\") AND (asciminib OR allosteric OR Ba/F3 OR isogenic) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"chronic myeloid leukemia\" OR CML) AND (\"blast phase\" OR \"blast crisis\") AND (blinatumomab OR ponatinib OR olverembatinib OR transplantation) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(asciminib AND (resistance OR mutation) AND (ponatinib OR olverembatinib OR \"kinase domain\" OR NGS)) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]"],"papersShown":[{"pmid":"41254115","doi":"10.1038/s41375-025-02801-5","year":2026,"isNew":true,"title":"Long read nanopore DNA sequencing with adaptive sampling to identify tyrosine kinase fusion genes"},{"pmid":"41508037","doi":"10.1186/s12967-025-07630-9","year":2026,"isNew":true,"title":"Single-cell multi-omics reveals DUSP9 as a key regulator of cancer stemness and a potential therapeutic target in hepatocellular carcinoma"},{"pmid":"41383134","doi":"10.1002/ctm2.70550","year":2025,"isNew":true,"title":"Oncofetal dual‑specificity phosphatase 9 drives stem-like properties through ERK1/2-PPARG-SCD axis-mediated lipid metabolism in hepatocellular carcinoma"},{"pmid":"42064782","doi":"10.1097/bs9.0000000000000293","year":2026,"isNew":true,"title":"Allogeneic hematopoietic stem cell transplantation combined with dasatinib successfully treated adult acute lymphoblastic leukemia with &lt;i&gt;e1a3 BCR-ABL1&lt;/i&gt; fusion gene"},{"pmid":"41714405","doi":"10.1038/s41375-026-02875-9","year":2026,"isNew":true,"title":"Development of a prognostic scoring system for chronic myeloid leukemia in blast phase"},{"pmid":"41869197","doi":"10.7759/cureus.103856","year":2026,"isNew":true,"title":"From Molecular Silence to Lymphoid Blast Phase: Diagnostic and Therapeutic Challenges in a Young Female Patient With Chronic Myeloid Leukemia"},{"pmid":"41486652","doi":"10.3760/cma.j.cn121090-20250923-00437","year":2025,"isNew":true,"title":"[Guideline for the diagnosis and treatment of chronic myeloid leukemia in China (2025)]"},{"pmid":"41366999","doi":"10.1097/md.0000000000046329","year":2025,"isNew":true,"title":"A case report of mixed-phenotype acute leukemia with atypical BCR::ABL1 e13a3 fusion gene"},{"pmid":"42574564","doi":"10.1002/mc.70155","year":2026,"isNew":true,"title":"DUSP9 Regulates Hepatoblastoma Progression With Implications for Diagnosis and Targeted Therapy"},{"pmid":"41731536","doi":"10.1186/s12943-025-02474-9","year":2026,"isNew":true,"title":"EZH2 is a key prognostic marker and therapeutic target in aggressive and proliferative hepatoblastoma"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":16587,"output":7966},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"BCR::ABL1\" OR \"BCR-ABL\") AND (e13a3 OR e14a3 OR \"a3 transcript\" OR \"atypical transcript\") AND (ponatinib OR olverembatinib OR imatinib OR response) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(FBXO3 OR DUSP9) AND (leukemia OR \"stem cell\" OR MAPK) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:41254115","PMID:41508037","PMID:41383134","PMID:42064782","PMID:41714405","PMID:41869197","PMID:41486652","PMID:41366999","PMID:42574564","PMID:41731536","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787190939595","cycle":203,"visit":2,"ts":"2026-08-20T01:55:39.595Z","cancer":{"key":"rhabdoid tumor predisposition syndrome","name":"rhabdoid tumor predisposition syndrome","mondo":{"id":"MONDO:0016473","name":"familial rhabdoid tumor"}},"control":false,"modelLabel":"SCIENCE","summary":"Reorient RTPS secondary-prevention work from tazemetostat-class EZH2 inhibition toward EZH2 degraders and DCAF5-mediated SWI/SNF restoration, per the 2026 rhabdoid Therapeutic Development Workshop consensus (PMID:41680284), while restricting paralog-dependency plans to tumours with proven SMARCA2 re","confidence":0.5,"notebook":"The pack's one substantive item is P5 (PMID:41680284), the paediatric Therapeutic Development Workshop consensus on rhabdoid tumours; the rest is adult SMARCA4-deficient case/review noise (P1, P2, P8, P10) plus off-target reviews (P4, P6, P7).\n\nP5 reframes L1 rather than merely confirming it. It endorses EZH2 as a priority target but states that **degraders may outperform catalytic inhibitors**, and nominates MDM2, DCAF5, FGFR/PDGFR (subgroup-restricted), and EZH2+MDM2+SINE combinations, while asserting that intracranial and extracranial RT should share one therapeutic strategy — which directly supports my genotype-driven, site-agnostic maintenance design. Mechanistically the degrader argument matters: tazemetostat-class inhibitors block H3K27me3 catalysis but leave non-canonical, scaffolding PRC2/EZH2 functions intact, and EZH1 compensates [KNOWN]; P3 independently documents dual EZH1/2 agents (valemetostat, tulmimetostat) moving clinically in another PRC2-dependent, BAP1-loss context. L1 therefore promotes to CANDIDATE but its arm 2 is rewritten as a three-way pharmacology question (selective EZH2i vs dual EZH1/2i vs EZH2 degrader), with the chronic-dosing infant window as the gating unknown — and a degrader is *worse* on window grounds than a reversible inhibitor, since it removes non-catalytic EZH2 needed in cortical neurogenesis [INFERRED].\n\nL2 weakens. P8 reports SMARCA4-deficient small-intestinal carcinomas in which several cases also lost SMARCA2 — dual-ATPase-null tumours cannot depend on SMARCA2, so paralog-directed therapy needs SMARCA2 protein/genotype confirmation as an inclusion assay, not inference from SMARCA4 loss. P9 shifts emphasis for SMARCA4-deficient disease toward ICI (high TMB, MMR defects) and EZH2/HDAC rather than paralog synthetic lethality; that is adult-tumour biology and RT are immunologically cold with low TMB [KNOWN], so I do not import the ICI claim into RTPS. Confidence 0.35→0.28.\n\nTwo new leads from P5. L4: DCAF5 as a degradation-dependency — DCAF5 is the CUL4 substrate receptor that clears misassembled SMARCB1-deficient BAF, so DCAF5 loss/binders restore residual SWI/SNF activity and kill SMARCB1-null cells [KNOWN]; this is the only proposal in the pack that is *restorative* rather than suppressive and is genotype-matched to RTPS-1. L5: MDM2 inhibition in the near-uniformly TP53-wild-type RT genome, combined with EZH2 blockade and nuclear-export inhibition.\n\nL3 (porcine RTPS-1) unchanged — penetrance still unreported; no new data.","leadChanges":[{"id":"L1","title":"Epigenetic maintenance/secondary prevention in RTPS carriers after first remission","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55},{"id":"L2","title":"Residual SWI/SNF ATPase paralog dependency: SMARCA4 degradation in SMARCB1-null, SMARCA2 in SMARCA4-deficient rhabdoid tumours","level":"LEAD","status":"WEAKENED","confidence":0.28},{"id":"L4","title":"DCAF5 degradation-dependency: restoring residual SWI/SNF function in SMARCB1-null rhabdoid tumours","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L5","title":"MDM2 inhibition in TP53-wild-type rhabdoid tumours, combined with EZH2 blockade and nuclear-export inhibition","level":"LEAD","status":"NEW","confidence":0.38}],"unverifiedCitations":0,"openQuestions":["Is there any published RT-specific preclinical comparison of EZH2 degraders vs catalytic inhibitors (H3K27me3 kinetics, non-catalytic PRC2 loss, CNS exposure), and does the degrader advantage in PMID:41680284 rest on data or expert opinion?","What is the RT-relevant DCAF5 evidence base — are there published DCAF5 binders/degraders, structural data, and dependency-map evidence on DCAF5 essentiality in normal neural and haematopoietic tissue?","What fraction of germline SMARCA4 (RTPS2) tumours retain SMARCA2 protein, given the co-loss reported in SMARCA4-deficient carcinomas (PMID:41744871) — does this leave a real eligible population?","Is TP53 genuinely wild-type across ATRT/MRT subgroups (SHH/TYR/MYC), and does MDM2 amplification or p53-pathway dosage vary by subgroup?","Does the porcine RTPS-1 line (PMID:42352415) develop ATRT/MRT, at what penetrance and latency, and can it support years-long chronic dosing with neurodevelopmental endpoints?","Any human experience — case series or registry — of EZH2-directed therapy or metronomic maintenance in RTPS carriers in remission, with second-tumour rates and infant toxicity?"],"nextQueries":["(\"DCAF5\" OR \"DDB1-CUL4\") AND (SMARCB1 OR rhabdoid OR \"SWI/SNF\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"EZH2 degrader\" OR \"PRC2 degrader\" OR valemetostat OR tulmimetostat) AND (rhabdoid OR \"atypical teratoid\" OR SMARCB1) AND SRC:MED","(\"rhabdoid tumor predisposition\" OR \"germline SMARCB1\" OR \"germline SMARCA4\") AND (surveillance OR penetrance OR \"second primary\" OR metachronous) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"40421964","doi":"10.1093/oncolo/oyaf121","year":2025,"isNew":true,"title":"Thoracic SMARCA4-deficient undifferentiated tumor: diagnostic characteristics, molecular insights, and treatment approaches"},{"pmid":"42279597","doi":"10.3390/diagnostics16111732","year":2026,"isNew":true,"title":"Peri-Implant Gingival Undifferentiated SWI/SNF Complex-Deficient Tumor with Molecularly Confirmed Biallelic SMARCA4 Inactivation: Diagnostic Pitfalls and Genomic Characterization"},{"pmid":"42257802","doi":"10.1007/s11912-026-01754-x","year":2026,"isNew":true,"title":"The Role of EZH2 ın Malıgnant Pleural Mesothelıoma and Beyond: Current Practıce and Future Perspectıves"},{"pmid":"42254188","doi":"10.1097/ms9.0000000000004853","year":2026,"isNew":true,"title":"Molecular regulators of thromboinflammation and angiogenesis in pediatric cancer: emerging roles of noncoding RNAs, epigenetics, and extracellular vesicles - narrative review"},{"pmid":"41680284","doi":"10.1038/s41416-026-03348-7","year":2026,"isNew":true,"title":"Paediatric Therapeutic Development Workshop on rhabdoid tumours"},{"pmid":"42278411","doi":"10.3390/ijms27114880","year":2026,"isNew":true,"title":"Brain Cancer: Molecular Alterations and Emerging Trends in Neuropharmacology"},{"pmid":"42186167","doi":"10.2340/actadv.v106.adv-2025-0120","year":2026,"isNew":true,"title":"Swelling of the Left Upper Limb with Red Papules, Necrosis and Crusting: A Quiz"},{"pmid":"41744871","doi":"10.3390/curroncol33020107","year":2026,"isNew":true,"title":"SMARCA4-Deficient Carcinomas of the Small Intestine: A Systematic Review"},{"pmid":"41367953","doi":"10.1177/17588359251399031","year":2025,"isNew":true,"title":"Tumor-agnostic therapy: a potential therapeutic approach for SMARCA4-deficient malignancies"},{"pmid":"41814084","doi":"10.1007/s12672-026-04780-0","year":2026,"isNew":true,"title":"Implications for clinical prognosis and target discovery of the SWI/SNF complex in genitourinary tumors"}],"trialsShown":[{"nct":"NCT01238250","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":9346,"output":6636},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(tazemetostat OR \"EZH2 inhibitor\") AND (\"rhabdoid\" OR \"atypical teratoid\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"SMARCA2\" OR \"BRM\" OR \"BRG1\") AND (degrader OR PROTAC OR \"synthetic lethal\") AND (SMARCB1 OR rhabdoid OR \"SMARCA4-deficient\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:40421964","PMID:42279597","PMID:42257802","PMID:42254188","PMID:41680284","PMID:42278411","PMID:42186167","PMID:41744871","PMID:41367953","PMID:41814084","NCT01238250","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787190732020","cycle":202,"visit":2,"ts":"2026-08-20T01:52:12.020Z","cancer":{"key":"dicer1 syndrome","name":"DICER1 syndrome","mondo":{"id":"MONDO:0100216","name":"DICER1-related tumor predisposition"}},"control":false,"modelLabel":"SCIENCE","summary":"HMGA2 protein is near-universally overexpressed in DICER1-variant lesions but absent in normal tissue (PMID:42583679), promoting the let-7-deficit axis to CANDIDATE and giving a tumour-restricted pharmacodynamic biomarker for miRNA-restoration agents such as enoxacin (PMID:41748289).","confidence":0.45,"notebook":"Visit 2 changed the programme in one important way: the let-7-deficit axis now has direct human-tissue evidence. PMID:42583679 scored HMGA2 immunohistochemistry across 78 lesions with confirmed DICER1 pathogenic variants — CNS spindle cell sarcoma, Sertoli-Leydig, PPB, cystic nephroma, cervical/ovarian eRMS, thyroid follicular nodular disease — and found nuclear HMGA2 in essentially every lesion type (thyroid only ~50%) with normal controls uniformly negative. That is exactly the pattern L1 predicted: a canonical let-7 target de-repressed at protein level in tumour but not in DICER1-heterozygous normal tissue. It supplies the therapeutic-window argument empirically rather than by inference, and it establishes HMGA2 IHC as a cheap pharmacodynamic readout for any agent claiming to restore 5p/let-7 output. Two caveats: HMGA2 positivity in benign cystic nephroma and thyroid nodular disease means it marks an early, possibly initiating event, not an aggressive-phenotype dependency (the abstract states this), and IHC is a surrogate — small-RNA-seq 5p:3p arm ratios in the same specimens remain unmeasured. L1 → CANDIDATE, confidence 0.55; the IGF arm is still weaker than the HMGA2 arm, with PMID:42113881 offering only a cross-syndrome analogy (convergent IGF2/IGF1R/IR-A competence in BWS-associated PPGL) that reinforces IR-A bypass as an expected resistance route.\n\nNew therapeutic handle: PMID:41748289 shows endothelial Dgcr8 deletion phenocopies Dicer1 loss to spontaneous angiosarcoma with global mature-miRNA loss, and that enoxacin — a repurposed fluoroquinolone that enhances TRBP-dependent miRNA processing [KNOWN] — reduces AS viability, migration and clonogenicity while raising tumour-suppressive miRNAs. This is a miRNA-restoration strategy in a miRNA-biogenesis-deficient tumour, i.e. mechanistically adjacent to DICER1 syndrome. The critical, cheap falsification test: enoxacin works through Dicer/TRBP, so a hotspot RNase IIIb missense Dicer may be uncorrectable by it, and 5p cleavage may not be rescued at all. Opened as L4 at LEAD/0.3 with that experiment as the gate; HMGA2 loss is the readout.\n\nL2 (KEAP1/NRF2) retired. Two visits, zero DICER1-tumour sequencing evidence for recurrent KEAP1/NFE2L2 alteration; the lead rested only on a Monarch correlation plus background. Recorded as a dead branch — do not re-propose without a somatic sequencing paper.\n\nL3 strengthened by two registry outputs: PMID:38807260 gives the outcome bar (2-year EFS 81.8% for stage I–II anaplastic sarcoma of kidney, with advanced-stage numbers truncated in the abstract — so targeted proposals must aim at stage III/IV and relapse, not localized disease), and PMID:42107965 shows 183/868 submitted thoracic tumours were misclassified, with hotspot variants found in discrepant cases — reflex molecular testing is justified. PMID:42230820 (miR-107 represses DICER1) is noted only as a possible sporadic phenocopy route.","leadChanges":[{"id":"L1","title":"let-7 5p-strand deficit as the actionable consequence of RNase IIIb hotspot hypomorphism: target IGF1R/IGF2BP1 downstream","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55},{"id":"L2","title":"Somatic KEAP1 loss / NRF2 hyperactivation as a co-driver dependency in DICER1-related tumours","level":"LEAD","status":"RETIRED","confidence":0.05},{"id":"L4","title":"Pharmacologic enhancement of miRNA biogenesis (enoxacin) as miRNA-restoration therapy — gated on whether hotspot Dicer is correctable","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L3","title":"Registry/natural-history network as the only available tissue and enrolment pipeline for DICER1 target validation","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55}],"unverifiedCitations":0,"openQuestions":["Do small-RNA-seq data from human hotspot-mutant DICER1 tumours actually show a selective 5p-arm deficit, or is HMGA2 protein overexpression (PMID:42583679) driven by something other than let-7 loss?","Is HMGA2 a maintenance dependency or only an initiation marker — does HMGA2 knockdown/degradation kill hotspot-mutant models but spare DICER1-wildtype ones?","Can enoxacin or any TRBP-directed agent restore 5p cleavage by hotspot-mutant Dicer in a biochemical assay, or is the hotspot allele pharmacologically uncorrectable?","What are the stage III/IV and relapsed outcomes and failure patterns in ASK, PPB type II/III and DICER1 sarcomas — the population any targeted agent would actually address?","Do DICER1 hotspot-mutant PDX, GEMM or organoid models exist, and has any agent been tested in them?","Does germline DICER1 heterozygosity impose a systemic toxicity constraint on global miRNA-biogenesis enhancement or IGF-axis blockade in children?"],"nextQueries":["(\"DICER1\" AND (\"small RNA sequencing\" OR \"miRNA profiling\" OR \"5p arm\" OR \"arm switching\")) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"HMGA2\" AND (\"knockdown\" OR \"dependency\" OR \"degrader\" OR \"synthetic lethal\") AND (sarcoma OR rhabdomyosarcoma OR blastoma)) AND SRC:MED","(\"DICER1\" AND (\"patient-derived xenograft\" OR organoid OR \"mouse model\" OR \"cell line\" OR \"hotspot\" AND \"E1705\" OR \"D1709\")) AND SRC:MED"],"papersShown":[{"pmid":"38807260","doi":"10.1002/pbc.31090","year":2024,"isNew":true,"title":"Anaplastic sarcoma of the kidney (DICER1-sarcoma of the kidney): A report from the International Pleuropulmonary Blastoma/DICER1 Registry"},{"pmid":"41693964","doi":"10.1016/j.ncrna.2026.01.010","year":2026,"isNew":true,"title":"The paradox of nuclear miRNAs: Mechanisms, therapeutic potential, and future directions"},{"pmid":"42192969","doi":"10.3390/cancers18101610","year":2026,"isNew":true,"title":"miRNA-lncRNA Cross-Regulation Landscape in Cancer: From Molecular Mechanisms to Therapeutic and Diagnostic Applications"},{"pmid":"42148803","doi":"10.1080/15384101.2026.2630878","year":2026,"isNew":true,"title":"Circular RNAs in tumorigenesis: an insight into recent research in biogenesis and targeted tumor therapy"},{"pmid":"42583679","doi":"10.1111/his.70255","year":2026,"isNew":true,"title":"HMGA2 is a highly sensitive marker for DICER1-related tumours"},{"pmid":"42230820","doi":"10.1038/s41417-026-01042-7","year":2026,"isNew":true,"title":"The paradox of miR-107 in oncology: dual roles as a tumor suppressor and oncomiR"},{"pmid":"42346035","doi":"10.3390/epigenomes10020040","year":2026,"isNew":true,"title":"The Role of Epigenetics in Corneal Fibrosis"},{"pmid":"42113881","doi":"10.1530/erc-26-0061","year":2026,"isNew":true,"title":"Convergent IGF2 overexpression in pheochromocytoma/paraganglioma: insights from Beckwith-Wiedemann syndrome"},{"pmid":"41748289","doi":"10.1261/rna.080706.125","year":2026,"isNew":true,"title":"Canonical microRNA loss drives tumor development, implicating therapeutic efficacy of enoxacin in angiosarcoma"},{"pmid":"42107965","doi":"10.5858/arpa.2024-0364-oa","year":2026,"isNew":true,"title":"Pleuropulmonary Blastoma and Diagnostic Pitfalls: A Report from the International Pleuropulmonary Blastoma/DICER1 Registry"}],"trialsShown":[{"nct":"NCT01247597","phase":"n/a","status":"RECRUITING","isNew":false,"title":"DICER1-related Pleuropulmonary Blastoma Cancer Predisposition Syndrome: A Natural History Study"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT03382158","phase":"n/a","status":"RECRUITING","isNew":false,"title":"International PPB/DICER1 Registry"},{"nct":"NCT06523582","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients"}],"usage":{"input":10083,"output":6269},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"DICER1\" AND (\"let-7\" OR \"LIN28\" OR \"IGF2BP\" OR \"HMGA2\" OR \"5p strand\" OR \"miRNA arm\")) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"pleuropulmonary blastoma\" OR \"DICER1 sarcoma\" OR \"anaplastic sarcoma of kidney\") AND (chemotherapy OR outcome OR xenograft OR \"patient-derived\" OR \"mouse model\") AND SRC:MED"],"evidenceIds":["PMID:38807260","PMID:41693964","PMID:42192969","PMID:42148803","PMID:42583679","PMID:42230820","PMID:42346035","PMID:42113881","PMID:41748289","PMID:42107965","NCT01247597","NCT03050268","NCT03382158","NCT06523582"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787190528343","cycle":201,"visit":2,"ts":"2026-08-20T01:48:48.343Z","cancer":{"key":"neurofibromatosis type 2","name":"neurofibromatosis type 2","mondo":{"id":"MONDO:0007039","name":"NF2-related schwannomatosis"}},"control":false,"modelLabel":"SCIENCE","summary":"TEAD inhibition now has functional merlin-null pharmacology (restores CAR-T sensitivity in NF2-loss mesothelioma) plus a newly predicted renal-tubular on-target toxicity, so the YAP/TAZ-TEAD lead is promoted to CANDIDATE and should be tested in NF2-conditional schwannoma models with tubular-injury m","confidence":0.55,"notebook":"Visit 2. The pack is largely off-target (oxalate nephropathy, cardiac ferroptosis, hepatocyte cadherins, a melatonin phase-separation manifesto, breast-cancer DepMap domain adaptation), but three items move the programme and one noise paper turns out to be a toxicity oracle.\n\nThe important paper is PMID:42208538: NF2 loss in diffuse pleural mesothelioma drives acquired resistance to CAR-T and anti-PD-1, acting through site-specific recruitment of CRIg+ immunosuppressive macrophages via tumour-secreted chemokines and retinoic acid — and pharmacologic TEAD inhibition restored CAR-T sensitivity. This is the first pharmacological TEAD-inhibitor readout in a merlin-null context anywhere in this programme, and it is functional, not review-level. It also supplies a mechanism I had not considered: merlin loss is not only cell-intrinsically proliferative but immunologically reorganising, and the effect was compartment-dependent (pleural, not subcutaneous) — [INFERRED] the intracranial/perineural niche of NF2-SWN may impose its own analogous macrophage programme, testable in NF2-conditional Schwann-cell models. Note the genotype caveat: the patient cohorts linked macrophage infiltration to NF2 copy-number loss, not point mutation; germline NF2-SWN second hits are frequently LOH [KNOWN], so the copy-loss phenotype is the relevant one [INFERRED]. PMID:42167578 (a second LATS1/2 autophosphorylation site, Ser872/Ser835, required for full YAP phosphorylation) adds independent mechanistic depth to the LATS→YAP axis downstream of merlin. L2 therefore moves to CANDIDATE.\n\nThe therapeutic-window argument for TEAD inhibition sharpens unexpectedly: PMID:41833934 shows YAP1/TEAD1 directly drives SLC7A5 transcription in renal tubule, and its loss triggers leucine/mTOR collapse and tubular ferroptosis. So beyond the expected GI/hepatic regeneration liability, I now predict renal tubular injury as an on-target TEAD-inhibitor toxicity — a monitorable endpoint (urinary KIM-1, tubular proteinuria) and a hazard in combination with bevacizumab, which is itself nephrotoxic [KNOWN].\n\nPMID:40956079 answers part of Q3 from the other end: salvage microsurgery after bevacizumab failure in 21 NF2-SWN patients (mean 33.7 months of treatment, 10.2 mg/kg monthly, stopped mean 5.8 months pre-op) with intraoperative bleeding judged notable in only a minority — bevacizumab failure is a defined clinical state with a viable surgical exit, so L1 is strengthened as a backbone but its progression phenotype needs formal definition.\n\nPMID:41898726 names two agents I had no lead for: brigatinib and a brain-penetrant HDAC inhibitor, plus a TβR1–RKIP pathogenic axis. Two new leads opened, both low confidence (review abstract only). No new NF2-relevant trials; NCT02523014's NF2 arm remains unreported, so L3 and L4 stand unchanged.","leadChanges":[{"id":"L2","title":"YAP/TAZ-TEAD transcriptional dependency as the most merlin-proximal druggable node in NF2-SWN","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.6},{"id":"L1","title":"Bevacizumab (anti-VEGF) as the systemic backbone and comparator arm for NF2-SWN vestibular schwannoma","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.78},{"id":"L5","title":"Brigatinib as repurposed multi-kinase therapy in NF2-SWN","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L6","title":"Brain-penetrant HDAC inhibition and the TbetaR1-RKIP axis as non-Hippo mechanisms in NF2-SWN","level":"LEAD","status":"NEW","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["Does the NF2-loss/CRIg+ macrophage/retinoic-acid immunosuppressive programme (PMID:42208538) occur in merlin-null schwannoma and meningioma tissue, and is it copy-loss-specific rather than mutation-specific?","Which TEAD palmitoylation inhibitors have been dosed in vivo in NF2-null models, at what exposure, and do published toxicology data show renal tubular injury consistent with the YAP1/TEAD1-SLC7A5 axis (PMID:41833934)?","What are the primary NF2-SWN data behind brigatinib and the brain-penetrant HDAC inhibitor cited in PMID:41898726 — response rates, hearing endpoints, tumour type?","What defines progression on bevacizumab in NF2-SWN mechanistically (angiogenic switch markers, volume vs oedema, WRS trajectory), and can the 6-8 week preoperative washout be shortened given the bleeding data in PMID:40956079?","Has the NF2-mutant arm of NCT02523014 (GSK2256098 FAK, capivasertib, abemaciclib) reported, and is FAK dependency validated in primary merlin-null schwannoma cells?","Do merlin-loss synthetic-lethal screens outside the Hippo axis (CDK4/6, AXL, dual mTORC1/2, SLC7A5/leucine or glutamine metabolism) show NF2-null selectivity in published DepMap-type data?"],"nextQueries":["(\"NF2\" OR merlin) AND (\"TEAD inhibitor\" OR VT3989 OR IK-930 OR \"palmitoylation inhibitor\") AND (schwannoma OR meningioma OR mesothelioma) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"NF2-related schwannomatosis\" OR \"vestibular schwannoma\") AND (brigatinib OR \"HDAC inhibitor\" OR RKIP OR \"TGF-beta receptor\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"NF2\" OR merlin) AND (\"synthetic lethal\" OR CRISPR OR DepMap OR \"dependency screen\") AND (SLC7A5 OR AXL OR CDK4 OR mTOR OR glutamine) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"papersShown":[{"pmid":"41833934","doi":"10.1080/13510002.2026.2643967","year":2026,"isNew":true,"title":"The hippo-YAP1/TEAD1-SLC7A5 axis: uncovering a novel therapeutic target for oxalate-induced renal tubular ferroptosis"},{"pmid":"42246156","doi":"10.3892/mmr.2026.13931","year":2026,"isNew":true,"title":"Molecular mechanisms of iron metabolism and ferroptosis in cardiovascular diseases and intervention strategies targeting natural products (Review)"},{"pmid":"42201352","doi":"10.1083/jcb.202509170","year":2026,"isNew":true,"title":"E- and N-cadherin drive hepatic polarity and lumen elongation via opposing effects on RhoA activity"},{"pmid":"41815350","doi":"10.1016/j.bioactmat.2026.03.009","year":2026,"isNew":true,"title":"Targeting VEGFR2 inhibition within a spatially-confined conduit promotes nerve self-resolution and alleviates mechanical allodynia"},{"pmid":"42339999","doi":"10.1002/gepi.70044","year":2026,"isNew":true,"title":"Deep Unsupervised Domain Adaptation for Translating Cancer Dependency Maps From Cell Lines to Breast Cancer Tumor Genomics"},{"pmid":"42306984","doi":"10.1111/jpi.70156","year":2026,"isNew":true,"title":"Multiaxial Biophysical Control of Oncogenic Phase Separation by Indoleamines: A Proof-of-Concept Synthesis of Landscape-Level Regulation"},{"pmid":"42208538","doi":"10.1016/j.medj.2026.101149","year":2026,"isNew":true,"title":"Loss of tumor suppressor NF2 mediates resistance to CAR T cell and anti-PD-1 therapy: Strategies to restore immunotherapy sensitivity"},{"pmid":"42167578","doi":"10.1016/j.jbc.2026.113177","year":2026,"isNew":true,"title":"LATS kinase activity and tumor suppressor function are regulated by a second autophosphorylation site"},{"pmid":"41898726","doi":"10.3390/ijms27062867","year":2026,"isNew":true,"title":"Emerging Molecular Insights and Therapeutic Directions in Neurofibromatosis Type 1 and NF2-Related Schwannomatosis"},{"pmid":"40956079","doi":"10.1227/neu.0000000000003728","year":2026,"isNew":true,"title":"Salvage Microsurgery After Failed Bevacizumab Treatment for NF2-Related Schwannomatosis Vestibular Schwannoma: A Multicentric Retrospective Study"}],"trialsShown":[{"nct":"NCT04166409","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma"},{"nct":"NCT02407405","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibroma"},{"nct":"NCT06175637","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Observational Study to Evaluate the Effect and Safety of Selumetinib in Pediatric Patients With NF1-PNs"},{"nct":"NCT00598351","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Natural History Study of Patients With Neurofibromatosis Type 2"},{"nct":"NCT02523014","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Vismodegib, FAK Inhibitor GSK2256098, Capivasertib, and Abemaciclib in Treating Patients With Progressive Meningiomas"},{"nct":"NCT06541847","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2, Open-Label Study to Evaluate the Safety and Effects of HLX-1502 in Patients With Neurofibromatosis Type 1"},{"nct":"NCT03190915","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia"},{"nct":"NCT03962543","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas"}],"usage":{"input":11158,"output":6832},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"NF2\" OR \"merlin\") AND (\"TEAD\" OR \"YAP\" OR \"TAZ\" OR \"Hippo\") AND (inhibitor OR palmitoylation OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"NF2-related schwannomatosis\" OR \"vestibular schwannoma\" OR meningioma) AND (bevacizumab) AND (resistance OR \"hearing outcome\" OR discontinuation OR rebound) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"evidenceIds":["PMID:41833934","PMID:42246156","PMID:42201352","PMID:41815350","PMID:42339999","PMID:42306984","PMID:42208538","PMID:42167578","PMID:41898726","PMID:40956079","NCT04166409","NCT02407405","NCT06175637","NCT00598351","NCT02523014","NCT06541847","NCT03190915","NCT03962543"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787190320560","cycle":200,"visit":2,"ts":"2026-08-20T01:45:20.560Z","cancer":{"key":"neurofibromatosis type 1","name":"neurofibromatosis type 1","mondo":{"id":"MONDO:0018975","name":"neurofibromatosis type 1"}},"control":false,"modelLabel":"SCIENCE","summary":"The 2025 NF1 PNST consensus (PMID:39500722) makes CDKN2A/B, SUZ12/EED/TP53 and aneuploidy routine diagnostic strata, promoting the abemaciclib/ANNUBP interception lead to CANDIDATE and opening an H3K27me3-negative (PRC2-loss) MPNST stratum for BET-inhibitor testing.","confidence":0.55,"notebook":"This visit's pack was largely off-target: liposarcoma systemic therapy (PMID:42279279), chest-wall PEEK reconstruction (PMID:42309817), free functional muscle transfer (PMID:42206261), a pan-cancer proteasome dependency screen (PMID:42280256) and an unrelated case report (PMID:42256972) carry no NF1 content. Three items matter.\n\nFirst, PMID:39500722 (consensus/WHO-aligned integrated diagnostic framework) is the most consequential: it formalises CDKN2A/B inactivation as the molecular definition of ANNUBP and SUZ12, EED or TP53 inactivation *or significant aneuploidy* as MPNST-defining. This does two things for the programme. It converts L2's stratification variable from an aspiration into standard-of-care molecular pathology — CDKN2A/B status will be available on the biopsies feeding NCT04750928, so a CDKN2A/B-stratified response analysis is now executable rather than hypothetical. L2 therefore moves to CANDIDATE. It also embeds L1's premise (aneuploidy as the malignant-transformation signature) into the diagnostic criteria, which raises prior prevalence for chr8-gain strata — but note this is indirect: the consensus does not name PTK2 or chr8. My targeted query for MPNST/FAK/PTK2/chromosome-8 2022–2026 returned no new mechanistic corroboration, so L1 stays at LEAD (no promotion) and I log the null result: one FAK paper (PMID:42579369) still carries the whole hypothesis. The proposed renaming of \"low-grade MPNST\" to ANNUBP-with-in-situ-transformation will shift trial eligibility boundaries and must be tracked before designing an interception arm.\n\nSecond, the same consensus surfaces a stratum the desk had not addressed: PRC2 core loss (SUZ12/EED). [KNOWN] SUZ12/EED loss ablates H3K27me3, and H3K27me3 IHC is already a routine surrogate; [KNOWN] PRC2 loss amplifies RAS-driven transcriptional output through enhancer reprogramming and BRD4 dependency. New lead L5: BET inhibition ± MEKi in H3K27me3-negative MPNST, with H3K27me3 IHC as a ready-made, no-cost patient selector. Speculative on the therapeutic side, hence low confidence.\n\nThird, PMID:39847441 (spatial transcriptomics of PNSTs, FFPE-compatible) gives the assay to answer open question 4: it resolves niche-level heterogeneity and differentiation states in archival tissue, so post-selumetinib resistant regions can be profiled without fresh biopsies. Attached to L3 as methodology, not as efficacy support.\n\nRecorded as a caution, not a lead: soft-tissue sarcoma is characterised as predominantly immune-cold with inconsistent checkpoint responses (PMID:42172443), and fmTLS in STS predicts better survival but *higher* local recurrence (PMID:42279277) — do not propose single-agent ICI in MPNST. PNST-on-a-chip (PMID:42158533) is a platform review only.","leadChanges":[{"id":"L1","title":"FAK/PTK2 + RAF-MEK co-inhibition in chr8-gain MPNST","level":"LEAD","status":"STRENGTHENED","confidence":0.58},{"id":"L2","title":"CDK4/6 inhibition in CDKN2A/B-deleted atypical neurofibromatous neoplasms (ANNUBP) as MPNST interception","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55},{"id":"L3","title":"MEK inhibition as the NF1 therapeutic backbone: pain/function endpoints and combination scaffold","level":"LEAD","status":"STRENGTHENED","confidence":0.7},{"id":"L5","title":"PRC2-loss (SUZ12/EED, H3K27me3-negative) MPNST as a BET-dependent stratum","level":"LEAD","status":"NEW","confidence":0.32}],"unverifiedCitations":0,"openQuestions":["Is H3K27me3-negative (SUZ12/EED-null) MPNST actually BET-inhibitor sensitive in NF1 PDX, and is that sensitivity separable from generic MYC dependence?","Do chr8 gain and PTK2 expression/amplification track independently within the 'significant aneuploidy' MPNST class, and does either predict FAKi+MEKi synergy?","In NCT04750928, does abemaciclib response track with biallelic CDKN2A/B loss, and does it reduce conversion to MPNST rather than only stabilise volume?","How does the proposed reclassification of 'low-grade MPNST' to ANNUBP-with-in-situ-transformation change eligibility and endpoint definitions for interception trials?","Are the brigatinib, bevacizumab and TbR1-RKIP claims in PMID:41898726 NF1-specific or NF2-SWN-specific? Still unresolved and still blocking any lead built on them.","Do MEK inhibitors help or harm NF1 skeletal outcomes (BMD, pseudarthrosis healing) in children on chronic therapy?"],"nextQueries":["(\"malignant peripheral nerve sheath tumor\" OR MPNST) AND (SUZ12 OR EED OR PRC2 OR H3K27me3 OR BRD4 OR \"bromodomain\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(neurofibromatosis AND (selumetinib OR mirdametinib) AND (resistance OR biopsy OR \"single-cell\" OR relapse OR progression)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(neurofibromatosis type 1 AND (\"bone mineral density\" OR pseudarthrosis OR tibia OR osteoblast) AND (MEK OR selumetinib OR trametinib)) AND SRC:MED"],"papersShown":[{"pmid":"39500722","doi":"10.1093/neuonc/noae235","year":2025,"isNew":true,"title":"Consensus recommendations for an integrated diagnostic approach to peripheral nerve sheath tumors arising in the setting of Neurofibromatosis Type 1"},{"pmid":"39847441","doi":"10.1093/neuonc/noaf016","year":2025,"isNew":true,"title":"Spatially resolved transcriptomics of benign and malignant peripheral nerve sheath tumors"},{"pmid":"42172443","doi":"10.1080/21645515.2026.2674185","year":2026,"isNew":true,"title":"The promise of immunotherapy in the treatment of sarcoma: A state-of-the-art review of practice changing research and future directions"},{"pmid":"42206261","doi":"10.1016/j.jpra.2026.04.022","year":2026,"isNew":true,"title":"Free functional muscle transfer after oncologic extremity reconstruction: A systematic review"},{"pmid":"42309817","doi":"10.1111/1759-7714.70323","year":2026,"isNew":true,"title":"The Long-Term Quality of Life Study for Patients Received Chest Wall Reconstruction by Using 3D-Printed PEEK Implants"},{"pmid":"42280256","doi":"10.3390/molecules31111954","year":2026,"isNew":true,"title":"Integrative Pan-Cancer Mapping of Proteasome Dependency Prioritizes PSMB5 and PSMB6 as Context-Dependent Vulnerability Biomarkers Linked to Immune Context"},{"pmid":"42256972","doi":"10.1002/ccr3.72743","year":2026,"isNew":true,"title":"Right Upper Lobe Pulmonary Spindle Cell Neoplasm With Rhabdoid Differentiation and Spinal Canal Invasion in a 19-Year-Old Female: A Case Report"},{"pmid":"42158533","doi":"10.1016/j.mtadv.2026.100770","year":2026,"isNew":true,"title":"Peripheral nerve sheath tumors-on-a-chip: Next-generation platforms for mechanistic and therapeutic studies"},{"pmid":"42279279","doi":"10.3390/cancers18111694","year":2026,"isNew":true,"title":"The Evolving Landscape of Systemic Therapy for Liposarcoma"},{"pmid":"42279277","doi":"10.3390/cancers18111685","year":2026,"isNew":true,"title":"Beyond Surgical Margins: Fully Mature Tertiary Lymphoid Structures (fmTLSs) Are Predictive Biomarkers for Local Recurrence in Primary Soft-Tissue Sarcomas"}],"trialsShown":[{"nct":"NCT04166409","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma"},{"nct":"NCT04590235","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of Selumetinib in Chinese Paediatric and Adult Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas ("},{"nct":"NCT04750928","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type I (NF1) Related Atypical Neurofibromas"},{"nct":"NCT06880991","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Development of Patient-Reported Outcome Measures Assessing Tumor Visibility and Appearance Concerns in Neurofibromatosis Type 1: A Qualitati"},{"nct":"NCT05361811","phase":"NA","status":"RECRUITING","isNew":false,"title":"Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized "},{"nct":"NCT05309668","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Pharmacokinetics, Safety and Efficacy of the Selumetinib Granule Formulation in Children Aged ≥1 to <7 Years With NF1-related Symptomatic, I"},{"nct":"NCT02407405","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibroma"},{"nct":"NCT06175637","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Observational Study to Evaluate the Effect and Safety of Selumetinib in Pediatric Patients With NF1-PNs"}],"usage":{"input":10267,"output":6467},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"malignant peripheral nerve sheath tumor\" AND (resistance OR \"focal adhesion kinase\" OR PTK2 OR \"chromosome 8\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"atypical neurofibroma\" OR ANNUBP OR \"plexiform neurofibroma\") AND (CDKN2A OR CDK4 OR \"CDK4/6\" OR abemaciclib OR ribociclib) AND SRC:MED"],"evidenceIds":["PMID:39500722","PMID:39847441","PMID:42172443","PMID:42206261","PMID:42309817","PMID:42280256","PMID:42256972","PMID:42158533","PMID:42279279","PMID:42279277","NCT04166409","NCT04590235","NCT04750928","NCT06880991","NCT05361811","NCT05309668","NCT02407405","NCT06175637"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787190114229","cycle":199,"visit":2,"ts":"2026-08-20T01:41:54.229Z","cancer":{"key":"von hippel-lindau disease","name":"von Hippel-Lindau disease","mondo":{"id":"MONDO:0008667","name":"von Hippel-Lindau disease"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise ETS1 degradation (cc-885-class glues) plus belzutifan as a cofactor-directed escape-proofing combination in VHL-null ccRCC, and test systemic belzutifan or cabozantinib as first-line therapy for retinal capillary hemangioblastoma with local anti-VEGF/laser reserved for salvage.","confidence":0.62,"notebook":"Visit 2 turned over one lead, retired one, and opened a genuinely new mechanistic axis; it did not answer my central resistance question.\n\nThe strongest new item is P7 (PMID:42089431): the CRBN molecular glue cc-885 degrades ETS1 (p51/p42 isoforms) selectively killing VHL-deficient ccRCC, ETS1 acting as an EPAS1/HIF-2α transcriptional partner, and the cc-885 + belzutifan combination was superadditive. This is mechanistically orthogonal to the ARNT dimerization interface — it removes a required cofactor rather than the dimer — so it is the first pack evidence for a co-factor-directed escape-proofing strategy and it plausibly retains activity against EPAS1 gatekeeper mutants [INFERRED]. Caveats stated plainly: cc-885 is a promiscuous CRBN glue with GSPT1 degradation and known preclinical toxicity, and ETS1 is required for T/NK lineage development and endothelial function [KNOWN] — the window, not the potency, is the problem. New lead L6.\n\nTwo independent ophthalmic case reports invert L3's premise. P8 (PMID:42494590) documents RCH regression with decreased perfusion four months after systemic belzutifan, and P10 (PMID:42111285) reports complete, three-year-durable regression of a juxtapapillary hemangioblastoma refractory to intravitreal anti-VEGF, vitrectomy and laser after cabozantinib started for ccRCC. Systemic agents therefore reach the retinal compartment adequately; the \"drug-sequestered eye requiring local ligand neutralisation\" framing is weakened, and local anti-VEGF moves to salvage/adjunct. L3 reframed and strengthened, but held at LEAD: n=2 case reports, no prospective ocular endpoint.\n\nP9 (PMID:42313274) consolidates L1 (regulatory approvals across the lesion spectrum) and, importantly, states that pVHL has functions beyond HIF degradation whose loss may contribute to tumorigenesis — my open question 3 now has a literature home but no named substrate in the abstract. P6 (PMID:42406187) positions belzutifan as post-ICI/TKI with earlier-line testing, consistent with L1's combination arm logic. P4 (PMID:42481355) is a multistakeholder call showing that belzutifan's PPGL approval rests on no published genomic correlates — this sharpens rather than resolves L4's sequencing question against 177Lu-DOTATATE.\n\nL5 (CCND1/CDK4-6) is retired as pre-committed: nothing in this pack links cyclin D1 to HIF-2α-inhibitor resistance. Parked, not promoted: FAM120A→SREBP1 lipogenic dependency in ccRCC (PMID:42469889) — attractive as a HIF-independent metabolic node but the tool compound is a natural product with no VHL-genotype comparison; mitochondrial reductive stress/PTM routing (PMID:42150423) is too abstract to act on. Off-programme: ticagrelor/EGFR (PMID:41741334), CRP-albumin ratio (PMID:41566198).\n\nStill unanswered after two visits: no clinical EPAS1 gatekeeper frequency data, no CNS hemangioblastoma cyst-volume data.","leadChanges":[{"id":"L1","title":"HIF-2α–ARNT dimerization blockade (belzutifan) as systemic backbone across the VHL lesion spectrum","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.82},{"id":"L6","title":"ETS1 degradation as a cofactor-directed adjunct to HIF-2α blockade in VHL-null ccRCC","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"Compartment-directed therapy for retinal capillary hemangioblastoma: intravitreal anti-VEGF plus focal laser as adjunct or alternative to systemic HIF-2α blocka","level":"LEAD","status":"STRENGTHENED","confidence":0.5},{"id":"L4","title":"SSTR-directed theranostics for VHL pseudohypoxic pNET and pheochromocytoma/paraganglioma","level":"LEAD","status":"STRENGTHENED","confidence":0.42},{"id":"L5","title":"CCND1/CDK4-6 as a downstream node after HIF-2α escape","level":"LEAD","status":"RETIRED","confidence":0.08}],"unverifiedCitations":0,"openQuestions":["What is the published frequency and spectrum of acquired belzutifan resistance mechanisms (EPAS1 gatekeeper substitutions, ARNT alterations, HIF-1α or ETS1-dependent persistence) in VHL disease and sporadic ccRCC — still unanswered after tw","Which HIF-independent pVHL functions are named in the recent literature (non-canonical substrates, ubiquitin-ligase-independent activities), and are any lesion-type specific and druggable?","Can ETS1 be degraded with a therapeutic window — i.e. does any CRBN glue/PROTAC degrade ETS1 without GSPT1 co-degradation, and does ETS1 loss spare T/NK and endothelial compartments in vivo?","Is systemic belzutifan or cabozantinib activity in retinal and CNS/spinal hemangioblastoma durable and cyst-penetrating enough to defer resection — what quantitative lesion- and cyst-volume data exist?","Do belzutifan PPGL/pNET responses segregate by genotype or SSTR expression, and how should 177Lu-DOTATATE be sequenced against HIF-2α blockade under renal dosimetric constraint?","Is the FAM120A/SREBP1 lipogenic axis a VHL-genotype-selective dependency in ccRCC, or a general lipid phenotype of the histology?"],"nextQueries":["(\"ETS1\" OR \"molecular glue\" OR \"cereblon\") AND (\"renal cell carcinoma\" OR \"VHL\" OR \"HIF-2\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"von Hippel-Lindau\" OR pVHL) AND (\"HIF-independent\" OR \"non-canonical substrate\" OR \"ubiquitin ligase independent\" OR \"genotype-phenotype\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(belzutifan OR \"MK-6482\" OR cabozantinib) AND (hemangioblastoma OR \"retinal capillary\" OR \"spinal cord\" OR cyst) AND (volume OR response OR durability) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42150423","doi":"10.1016/j.redox.2026.104224","year":2026,"isNew":true,"title":"Impact of mitochondrial reductive stress due to respiratory chain limitation on cancer via posttranslational modifications"},{"pmid":"41741334","doi":"10.1080/07853890.2026.2635268","year":2026,"isNew":true,"title":"Drug repurposing of ticagrelor suppresses renal cell carcinoma growth by blockading the EGFR/PI3K/AKT axis"},{"pmid":"41566198","doi":"10.1080/07853890.2026.2618431","year":2026,"isNew":true,"title":"Elevated C-reactive protein to albumin ratio is a promising predictive biomarker for prognosis in patients with renal cell carcinoma"},{"pmid":"42481355","doi":"10.1016/j.tem.2026.06.007","year":2026,"isNew":true,"title":"A multistakeholder call for belzutifan biomarker data in advanced pheochromocytoma and paraganglioma"},{"pmid":"42469889","doi":"10.1186/s13046-026-03788-2","year":2026,"isNew":true,"title":"Soulangianolide A targets FAM120A to disrupt SREBP1-driven lipid metabolic reprogramming and suppress clear cell renal cell carcinoma"},{"pmid":"42406187","doi":"10.1007/s11912-026-01809-z","year":2026,"isNew":true,"title":"Next-Generation Checkpoint Combinations: Optimizing PD-(L)1-Based Therapy Across the Advanced, Adjuvant, and Neoadjuvant Settings"},{"pmid":"42089431","doi":"10.1002/advs.202520237","year":2026,"isNew":true,"title":"Molecular Glue cc-885 Inhibits VHL-Deficient Clear Cell Renal Cell Carcinoma via ETS1 Degradation"},{"pmid":"42494590","doi":"10.3389/fonc.2026.1870341","year":2026,"isNew":true,"title":"Regression of retinal capillary hemangioblastoma with systemic belzutifan in von Hippel-Lindau disease: a case report"},{"pmid":"42313274","doi":"10.1007/s10689-026-00579-8","year":2026,"isNew":true,"title":"Von Hippel-Lindau disease: pathophysiological and clinical advances"},{"pmid":"42111285","doi":"10.1016/j.ajoc.2026.102591","year":2026,"isNew":true,"title":"Juxtapapillary retinal hemangioblastoma remission in a von Hippel-Lindau patient treated with cabozantinib"}],"trialsShown":[{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT07405164","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Extension Study for Participants in Studies That Include Belzutifan (MK-6482-043/LITESPARK-043)"},{"nct":"NCT00005902","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of Brain and Spinal Cord Tumor Growth and Cyst Development in Patients With Von Hippel Lindau Disease"},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT00102544","phase":"NA","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Use of Tracking Devices to Locate Abnormalities During Invasive Procedures"},{"nct":"NCT01496625","phase":"n/a","status":"RECRUITING","isNew":false,"title":"National Eye Institute Biorepository for Retinal Diseases"},{"nct":"NCT05955014","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Data Collection Protocol for Patients With Von Hippel Lindau Disease"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":10787,"output":7402},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"belzutifan\" OR \"MK-6482\") AND (resistance OR \"EPAS1\" OR \"HIF-2alpha mutation\" OR biomarker) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"von Hippel-Lindau\" OR \"VHL disease\") AND (hemangioblastoma) AND (belzutifan OR \"HIF-2\" OR systemic therapy OR response) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:42150423","PMID:41741334","PMID:41566198","PMID:42481355","PMID:42469889","PMID:42406187","PMID:42089431","PMID:42494590","PMID:42313274","PMID:42111285","NCT00001238","NCT07405164","NCT00005902","NCT04924075","NCT00102544","NCT01496625","NCT05955014","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787189898358","cycle":198,"visit":2,"ts":"2026-08-20T01:38:18.358Z","cancer":{"key":"hereditary pheochromocytoma-paraganglioma","name":"hereditary pheochromocytoma-paraganglioma","mondo":{"id":"MONDO:0017366","name":"hereditary pheochromocytoma-paraganglioma"}},"control":false,"modelLabel":"SCIENCE","summary":"Belzutifan now has phase 2 efficacy in advanced PPGL (ORR 26%, DCR 85%) but no genotype correlates, while SDH-deficient GIST supplies two immediately testable repurposing hypotheses for SDHx PPGL — pan-FGFR inhibition (rogaratinib, ORR 41.7%, mPFS 31 mo) and MGMT-methylation-guided alkylator therapy","confidence":0.62,"notebook":"Belzutifan moved from hypothesis to fact. PMID:42573142 reports LITESPARK-015 in advanced PPGL: DCR 85%, ORR 26%, with blood-pressure and QoL benefit and mechanism-based grade 1–3 anaemia as dominant toxicity (EPO suppression is the on-target window cost) [KNOWN]; PMID:42503916 confirms regulatory approval and cluster-1 framing. But PMID:42481355 is a multistakeholder demand for exactly the datum L1 was built to interrogate — genomic correlates of response. So L1 is promoted to CANDIDATE on efficacy, while open question 1 (SDHx-succinate/PHD2 versus VHL-null dependence) is *un*answered and now the field's stated priority, not just mine. Perioperative implications of belzutifan (PMID:42468809) flag a management interface worth tracking.\n\nTwo transferable findings arrive via SDH-deficient GIST, which shares the succinate→TET inhibition→genome-wide hypermethylation state with SDHx PPGL [KNOWN]; PMID:42150423 gives the broader ETC-limitation→dioxygenase/PTM-routing rationale. PMID:42191879: rogaratinib, pan-FGFR, ORR 41.7% and median PFS 31.0 months in SDH-deficient GIST, mechanism being hypermethylation-driven insulator disruption releasing FGF3/FGF4 and an autocrine FGFR1 loop. If the same insulator loss occurs at the FGF3/FGF4 locus in SDHx chromaffin tumours, this is an off-the-shelf oral drug for a genotype we can already identify — new lead L6, contingent on measuring FGF3/FGF4/FGFR1 in SDHx PPGL, which the pack does not do. PMID:40629847 finds MGMT promoter methylation in 11/30 SDH-deficient GISTs plus MDM4 gain in 7 — a mechanistic footing for the long-standing empirical temozolomide signal in SDHB-mutant disease (new lead L7) and a second, p53-axis handle; note CVD chemotherapy remains the guideline comparator (PMID:42454639).\n\nPMID:42181244 answers the functional-screen gap directly, though for SDHB not MAX: unbiased CRISPR in Sdhb-null immortalised mouse chromaffin cells nominates neddylation, with UBE2F (not UBE2M) loss selectively suppressing Sdhb-deficient growth and pevonedistat/HA-9104 recapitulating it. New lead L5; window argument rests on UBE2F/CRL5 selectivity over pan-NAE1 (myelosuppression, hepatotoxicity) [KNOWN].\n\nL3 (MAX/MEN5 synthetic lethality) retires as promised: a genuine chromaffin CRISPR screen landed this visit and contained no MAX arm and no MYC-network dependency; I will not carry an unfunded lead. L4 persists unchanged as the enrolment funnel — now more load-bearing, since biomarker-stratified belzutifan analysis requires correctly classified genotypes.\n\nNext I need FGF3/FGF4/FGFR1 and MGMT methylation data in SDHx PPGL specifically, HIF2A/HIF1A/EGLN1 sequencing at belzutifan progression, and any SDHB-restricted 177Lu-DOTATATE response data (L2 still imaging-only).","leadChanges":[{"id":"L1","title":"HIF-2α inhibition (belzutifan) in cluster-1 pseudohypoxic hereditary PPGL","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.72},{"id":"L5","title":"Neddylation (UBE2F/NAE) inhibition as an SDHB-selective vulnerability in PPGL","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L6","title":"FGFR1 autocrine loop from succinate-driven hypermethylation: rogaratinib repurposing in SDHx PPGL","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L7","title":"MGMT-methylation-stratified alkylator therapy (and MDM4-p53 axis) in SDHx metastatic PPGL","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L3","title":"MAX-null (MEN5) PPGL: synthetic-lethal dependencies downstream of lost MXD repression","level":"LEAD","status":"RETIRED","confidence":0.12}],"unverifiedCitations":0,"openQuestions":["Do SDHx-mutant PPGL show the same insulator-loss-driven FGF3/FGF4 derepression and FGFR1 phosphorylation as SDH-deficient GIST, and what fraction carry MGMT promoter methylation?","Within LITESPARK-015 / NCT04924075, does belzutifan response (ORR, PFS) segregate by SDHx vs VHL vs FH vs sporadic genotype, and what genomic correlates emerge in response to PMID:42481355?","What acquired-resistance mechanisms occur on belzutifan in PPGL specifically (HIF2A PAS-B/dimerisation mutations, HIF1A switching, EGLN1 or VHL restoration), and are ctDNA assays able to detect them?","Is the UBE2F/neddylation dependency reproducible in human SDHB-mutant PPGL cells or PDX in vivo, and which CRL5 substrate mediates it?","Is there any 177Lu-DOTATATE response or SSTR2 expression data restricted to SDHx-mutant metastatic PPGL, as opposed to imaging avidity alone?","Does SDH/FH loss cause a bona fide homologous-recombination defect, or is alkylator sensitivity purely MGMT-methylation-driven?"],"nextQueries":["(pheochromocytoma OR paraganglioma OR SDHB OR SDHD) AND (FGF3 OR FGF4 OR FGFR1 OR insulator OR \"methylation classifier\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(pheochromocytoma OR paraganglioma) AND (belzutifan OR \"HIF-2alpha\") AND (resistance OR biomarker OR genotype OR ctDNA OR \"LITESPARK-015\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(SDHB OR SDHx OR paraganglioma) AND (MGMT OR temozolomide OR \"177Lu-DOTATATE\" OR neddylation OR pevonedistat OR UBE2F) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42150423","doi":"10.1016/j.redox.2026.104224","year":2026,"isNew":true,"title":"Impact of mitochondrial reductive stress due to respiratory chain limitation on cancer via posttranslational modifications"},{"pmid":"42191879","doi":"10.1038/s41591-026-04376-9","year":2026,"isNew":true,"title":"Fibroblast growth factor receptor inhibition for succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 2 trial"},{"pmid":"42181244","doi":"10.1016/j.isci.2026.115885","year":2026,"isNew":true,"title":"Unbiased CRISPR synthetic lethal screening for genetic vulnerabilities in a succinate dehydrogenase-loss model of paraganglioma"},{"pmid":"40629847","doi":"10.1097/pas.0000000000002444","year":2025,"isNew":true,"title":"DNA Methylation Profiling Separates SDH-Deficient GISTs From KIT-PDGFRA-Driven GISTs and Identifies Predictive Biomarkers for Targeted Therapy"},{"pmid":"42573142","doi":"10.1210/clinem/dgag324","year":2026,"isNew":true,"title":"Belzutifan, A Hypoxia-Inducible Factor 2-Alpha Inhibitor, for Patients with Advanced Pheochromocytoma and Paraganglioma"},{"pmid":"42444448","doi":"10.1080/14656566.2026.2704873","year":2026,"isNew":true,"title":"Selecting optimal therapy in the evolving therapeutic landscape of metastatic pheochromocytoma and paraganglioma"},{"pmid":"42503916","doi":"10.3760/cma.j.cn112137-20260228-00568","year":2026,"isNew":true,"title":"[Pheochromocytoma and paraganglioma in the era of precision medicine: from molecular clusters to clinical decision-making]"},{"pmid":"42481355","doi":"10.1016/j.tem.2026.06.007","year":2026,"isNew":true,"title":"A multistakeholder call for belzutifan biomarker data in advanced pheochromocytoma and paraganglioma"},{"pmid":"42468809","doi":"10.1016/j.eprac.2026.07.009","year":2026,"isNew":true,"title":"Response to Letter \"Perioperative Implications of Belzutifan Therapy in HIF2A-Related Pheochromocytoma and Paraganglioma\""},{"pmid":"42454639","doi":"10.1530/ec-26-0334","year":2026,"isNew":true,"title":"Systemic management of adrenal malignancies: adrenocortical carcinoma and pheochromocytoma/paraganglioma"}],"trialsShown":[{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT04284774","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Trea"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT06573723","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Institutional Registry of Rare Diseases"},{"nct":"NCT07316075","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Multicenter Study on Cardiovascular and Metabolic Complications in Patients With Biochemically Silent Pheochromocytomas and Paragangliomas"},{"nct":"NCT03160274","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Genetic Analysis of Pheochromocytomas, Paragangliomas and Associated Conditions"},{"nct":"NCT07167329","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Real-World Effectiveness and Pharmacogenetics of Belzutifan in VHL Syndrome: The BELIEVE-VHL Trial"}],"usage":{"input":9958,"output":6698},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(belzutifan OR \"HIF-2alpha\" OR \"HIF2A inhibitor\") AND (pheochromocytoma OR paraganglioma OR SDHB) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(SDHB OR SDHD OR \"succinate dehydrogenase\") AND (\"synthetic lethal\" OR PARP OR temozolomide OR \"homologous recombination\" OR \"DNA methylation\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:42150423","PMID:42191879","PMID:42181244","PMID:40629847","PMID:42573142","PMID:42444448","PMID:42503916","PMID:42481355","PMID:42468809","PMID:42454639","NCT00001238","NCT04924075","NCT04284774","NCT03050268","NCT06573723","NCT07316075","NCT03160274","NCT07167329"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787189692296","cycle":197,"visit":2,"ts":"2026-08-20T01:34:52.296Z","cancer":{"key":"juvenile polyposis syndrome","name":"juvenile polyposis syndrome","mondo":{"id":"MONDO:0017380","name":"juvenile polyposis syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Visit 2 was an evidentiary null: a directed sirolimus/everolimus-in-JPS query returned no cohort or series data, so the rapalog lead (L1) is weakened rather than promoted, and future queries must be disease-phrase-anchored because bare 'SMAD4' floods the pack with fibrosis and animal-nutrition liter","confidence":0.24,"notebook":"This visit produced no usable JPS evidence. Both queries were well-formed but returned a pack that is off-target in substance: mitochondrial quality control in diabetic kidney disease (PMID:41633353), sirtuins in renal fibrosis (PMID:42135894), circRNAs in IBD (PMID:42290604), ncRNA glycolysis in PDAC (PMID:42262932), ferroptosis in prostate cancer (PMID:42233093), and three animal-nutrition/comparative-physiology papers whose only link to the target is incidental *smad3/smad4/tgf-β1* transcript readouts in carp muscle and scallop CR transcriptomes (PMID:42179907, PMID:42087881, PMID:42603517). None of these bear on SMAD4/BMPR1A polyposis and none are citable in support of any lead. The trial slot returned only NCT03050268, already attached to L1.\n\nThe informative content is negative. A query explicitly built around (\"juvenile polyposis\" OR SMAD4 OR BMPR1A) AND (sirolimus OR everolimus OR rapamycin OR mTOR) surfaced zero rapalog-in-JPS records — no cohort, no series, no PTEN-hamartoma phenocopy polyp data. Open question 1 therefore remains unanswered after a directed attempt, and L1 still rests on a single case-report sentence (PMID:42110114). I am marking L1 WEAKENED (0.35→0.29): not because contradicting data appeared, but because a search designed to find the corroboration required for promotion found none, which shifts the prior toward \"this evidence does not exist in the indexed literature\" rather than \"not yet retrieved.\" Next visit should reframe the query around the phenocopy (PTEN hamartoma tumour syndrome, Peutz–Jeghers, rapalog + polyp burden) and around gastric polyposis/gastrectomy series, since SMAD4-JPS morbidity is increasingly gastric.\n\nThe stroma/immune query returned two generic reviews — CAF biology as a therapeutic vulnerability (PMID:42082461 is PDAC-wide; PMID:41902481 is the CAF review) — neither of which mentions SMAD4 in the abstract. I am logging a deliberately low-confidence scaffolding lead (L4, 0.15) so that open question 4 has a docket entry, with the explicit caveat that these citations establish only that CAF/TGF-β-axis stromal programmes are being drugged in SMAD4-frequently-null tumour types [KNOWN for PDAC SMAD4 deletion], not that SMAD4 loss drives them. L4 cannot be promoted on this material; it needs a paper linking SMAD4 genotype to a stromal or immune-exclusion phenotype in GI epithelium.\n\nL2 and L3 are unchanged and carry forward untouched. Notebook flag for the desk: do not re-run broad \"SMAD4 AND TGF-beta AND stroma\" style queries — the term SMAD4 is too promiscuous across fibrosis, nutrition and non-mammalian transcriptomics and floods the pack. Use disease-anchored phrase queries (\"juvenile polyposis\", \"hamartomatous polyp\", \"BMPR1A\") joined to therapy or somatic-genetics terms instead.","leadChanges":[{"id":"L1","title":"Rapalog (sirolimus/everolimus) suppression of hamartomatous polyp burden in SMAD4/BMPR1A-germline JPS","level":"LEAD","status":"WEAKENED","confidence":0.29},{"id":"L4","title":"SMAD4-loss-associated stromal/CAF and immune-exclusion programme as the polyp-to-carcinoma engine in JPS (scaffolding lead)","level":"LEAD","status":"NEW","confidence":0.15}],"unverifiedCitations":0,"openQuestions":["Does any human cohort or case series report polyp burden change on sirolimus/everolimus in a hamartomatous polyposis syndrome (PHTS, Peutz-Jeghers, Cowden) that could serve as the phenocopy benchmark for JPS?","In JPS polyps that progress to dysplasia, is the second hit (SMAD4/BMPR1A LOH, KRAS, APC, TGFBR2) in the epithelium or the stroma, and is there compartment-resolved sequencing anywhere in the literature?","Is SMAD4-JPS gastric polyposis (and prophylactic gastrectomy series) a better-documented endpoint substrate than colonic polyp count for a within-patient pre/post trial design?","Can any Ipsl1-3 candidate (STAM2, PSMD6, NAMPT, CACNB4) be tied to polyp burden in genotype-matched human SMAD4 carriers?","Does BMP9/10-ALK1-ENG-SMAD4 endothelial pharmacology (pazopanib, bevacizumab, thalidomide) have transfusion-requirement data in SMAD4-JPS/HHT overlap specifically, as opposed to HHT1/HHT2?"],"nextQueries":["(\"juvenile polyposis\" OR \"hamartomatous polyp*\" OR \"BMPR1A\") AND (sirolimus OR everolimus OR rapamycin) AND SRC:MED","(\"juvenile polyposis\" OR \"BMPR1A\") AND (\"loss of heterozygosity\" OR \"second hit\" OR somatic OR dysplasia OR carcinoma) AND SRC:MED","(\"SMAD4\" AND \"hereditary hemorrhagic telangiectasia\") AND (bevacizumab OR pazopanib OR thalidomide OR transfusion) AND SRC:MED"],"papersShown":[{"pmid":"41633353","doi":"10.1080/0886022x.2026.2620218","year":2026,"isNew":true,"title":"Targeting mitochondrial quality control in diabetic kidney disease: emerging therapeutic opportunities"},{"pmid":"41902481","doi":"10.1002/advs.202510043","year":2026,"isNew":true,"title":"Cancer-Associated Fibroblasts Functions as Multifunctional Architects of the Tumor Stroma and Represent Emerging Therapeutic Vulnerabilities"},{"pmid":"42290604","doi":"10.1080/15476286.2026.2684781","year":2026,"isNew":true,"title":"Crosstalk between circRNAs and the classic signaling pathways in IBD"},{"pmid":"42262932","doi":"10.1080/07853890.2026.2672785","year":2026,"isNew":true,"title":"The regulatory roles of non-coding RNAs in aerobic glycolysis and therapeutic potential in pancreatic ductal adenocarcinoma"},{"pmid":"42135894","doi":"10.1080/0886022x.2026.2667561","year":2026,"isNew":true,"title":"A review of the sirtuins family: pivotal regulators and emerging therapeutic targets in renal fibrosis"},{"pmid":"42233093","doi":"10.1016/j.gendis.2025.101967","year":2026,"isNew":true,"title":"Ferroptosis and prostate cancer: A translational path from molecular mechanisms to precision therapy"},{"pmid":"42179907","doi":"10.1016/j.aninu.2025.12.011","year":2026,"isNew":true,"title":"Dietary coated sodium selenite enhances muscle growth associated with mitochondrial function in sub-adult grass carp (&lt;i&gt;Ctenopharyngodon idellus&lt;/i&gt;)"},{"pmid":"42087881","doi":"10.1016/j.aninu.2026.01.003","year":2026,"isNew":true,"title":"Guanidinoacetic acid improves flesh quality associated with collagen synthesis and nucleotide metabolism in gibel carp CAS V (&lt;i&gt;Carassius gibelio&lt;/i&gt;, CAS V)"},{"pmid":"42603517","doi":"10.1016/j.cbd.2026.101972","year":2026,"isNew":true,"title":"Transcriptomics reveals species-specific adaptive strategies to calorie restriction in two Argopecten scallops with distinct lifespans"},{"pmid":"42082461","doi":"10.1038/s41392-026-02705-5","year":2026,"isNew":true,"title":"Pancreatic ductal adenocarcinoma: integrating molecular insights for targeted interventions"}],"trialsShown":[{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":10051,"output":4510},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"juvenile polyposis\" OR \"SMAD4\" OR \"BMPR1A\") AND (sirolimus OR everolimus OR rapamycin OR mTOR) AND SRC:MED","(\"SMAD4\" AND (\"loss\" OR \"deficient\")) AND (\"immune evasion\" OR \"TGF-beta\" OR \"checkpoint\" OR \"stroma\") AND PUB_YEAR:[2022 TO 2026] AND SRC:MED"],"evidenceIds":["PMID:41633353","PMID:41902481","PMID:42290604","PMID:42262932","PMID:42135894","PMID:42233093","PMID:42179907","PMID:42087881","PMID:42603517","PMID:42082461","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787189509845","cycle":196,"visit":2,"ts":"2026-08-20T01:31:49.845Z","cancer":{"key":"peutz-jeghers syndrome","name":"Peutz-Jeghers syndrome","mondo":{"id":"MONDO:0008280","name":"Peutz-Jeghers syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"CoREST/HDAC1 inhibition (TNG260) plus anti-PD-1 is now the leading mechanism-backed strategy for STK11-null PJS-associated carcinomas, while metformin-style AMPK-directed chemoprevention is mechanistically suspect because LKB1 loss uncouples the AMPK arm it depends on.","confidence":0.45,"notebook":"Fresh pack shifts the programme away from cell-autonomous synthetic lethality and toward epigenetic immune re-sensitisation. P1 (PMID:40882030) is the highest-value item: an in vivo CRISPR screen nominates HDAC1 as the node reversing anti-PD-1 resistance under STK11 loss [SOMATIC in NSCLC], and TNG260, a CoREST-complex inhibitor, produced immune-mediated stasis/regression with anti-PD-1 in STK11-deficient syngeneic and autochthonous models, with paired human tumour PD (rising histone acetylation, PD-L1 TPS, T-cell infiltration) in NCT05887492. This directly corroborates L3's negative-design core (no PD-1 monotherapy in LKB1-null disease) while replacing its speculative MEK+STING partner with a validated, clinically dosed priming mechanism; L3 moves to CANDIDATE (two evidence-bearing visits, two citations). Scope discipline: this applies to PJS-associated *carcinomas* [SOMATIC/second-hit], not to hamartomatous polyps, whose stromal-epithelial biology is not an immune-evasion problem [INFERRED].\n\nL4 weakens. The pack's CRISPR-screen arm returned an off-target hit (P3, STK11 as a sialic-acid-cluster regulator for influenza attachment in porcine trachea cells — irrelevant to oncology but worth recording so the desk stops treating \"STK11 + CRISPR screen\" as an oncology query) and a generic KRAS review (P4). No partner gene, drug or isogenic replication emerged for PMID:42286854. Notably, the one genuine STK11-LoF dependency in this pack (HDAC1) is immune-contextual, not cell-intrinsic — evidence that cell-line pharmacoprofiling may be the wrong assay for this genotype. Confidence 0.2→0.12; kill next visit unless a full-text partner emerges.\n\nMetformin: the targeted rapamycin/metformin/polyp query yielded no Lkb1+/- or PJS interventional data at all — Q1 remains unanswered and the absence is itself informative. What arrived is indirect: drug-target MR (P5) validating PRKAG1 (AMPK γ1) proxies for reduced CRC risk (OR 0.74, HbA1c-independent), observational meta-analysis favouring metformin over other antidiabetics for pancreatic cancer risk (P8), and an endometrial-cancer review (P6) — both PJS-relevant organ sites. Critical caveat for a new lead: LKB1 is the obligate upstream kinase for AMPK activation [KNOWN], so germline STK11 loss should blunt precisely the AMPK arm that P5's genetic instrument implicates; metformin in PJS must therefore be justified on complex-I/AMPK-independent grounds or abandoned. New lead L5 records this as a testable pharmacodynamic contradiction rather than a repurposing recommendation.\n\nL2 gains a design template from the Danish Polyposis Register (P10): five decades of registry-linked lifelong endoscopic surveillance in FAP as the infrastructure model for longitudinal PJS polyp-burden endpoints; P2 additionally frames low-dose aspirin as the cross-syndrome chemoprevention comparator for L1.","leadChanges":[{"id":"L3","title":"LKB1-null / KRAS co-mutant PJS-spectrum tumours: avoid PD-1 monotherapy, prioritise MEK-plus-immune-priming combinations","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55},{"id":"L4","title":"STK11 loss-of-function as a synthetic-lethal drug-response biomarker","level":"LEAD","status":"WEAKENED","confidence":0.12},{"id":"L5","title":"Metformin/AMPK-axis chemoprevention in PJS is mechanistically self-defeating — test complex-I-dependent, AMPK-independent readouts before any PJS trial","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L2","title":"Size-stratified endoscopic polyp burden as the primary efficacy endpoint for PJS drug trials","level":"LEAD","status":"STRENGTHENED","confidence":0.5}],"unverifiedCitations":1,"openQuestions":["Does NCT05887492 (TNG260 + pembrolizumab) enrol or permit germline STK11 carriers, and what were the objective response and PD data in the STK11-deficient cohort beyond acetylation/PD-L1 changes?","Is there any Lkb1+/- murine or human PJS evidence for rapalog (rapamycin/everolimus) effects on polyp burden, and does it outperform celecoxib — the visit-2 query found none?","Can AMPK-T172 phosphorylation be induced by metformin or phenformin in STK11-null intestinal epithelium/hamartoma organoids, or is the AMPK arm truly uncoupled?","Do PJS hamartomas versus PJS-associated carcinomas differ in HDAC1/CoREST-dependent immunomodulatory gene programmes and T-cell exclusion, i.e. is epigenetic priming carcinoma-restricted?","What inter-operator reproducibility and paediatric bleeding rates have been published for size-stratified small-bowel polyp burden, and can a PJS registry replicate the Danish FAP model?","In STK11-mutant gynaecologic mucinous and SMMN-FGT lesions, what fraction of STK11 mutations are germline versus somatic, and does KRAS co-mutation stratify outcome or immune contexture?"],"nextQueries":["(TNG260 OR \"CoREST\" OR \"HDAC1\") AND (STK11 OR LKB1) AND (immunotherapy OR \"PD-1\") AND SRC:MED","(\"Peutz-Jeghers\" OR \"Lkb1+/-\" OR \"Stk11 heterozygous\") AND (rapamycin OR sirolimus OR everolimus OR \"mTORC1\") AND (polyp OR hamartoma) AND SRC:MED","(STK11 OR LKB1) AND (AMPK OR PRKAA1 OR \"complex I\") AND (metformin OR phenformin) AND (organoid OR intestin*) AND PUB_YEAR:[2020 TO 2026] AND SRC:MED"],"papersShown":[{"pmid":"40882030","doi":"10.1158/0008-5472.can-25-0998","year":2025,"isNew":true,"title":"TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes STK11-Mutant Tumors to Anti-PD-1 Immunotherapy"},{"pmid":"41017554","doi":"10.5946/ce.2025.189","year":2026,"isNew":true,"title":"Epidemiology of colonic adenoma and cancer"},{"pmid":"41061927","doi":"10.1016/j.jare.2025.09.059","year":2026,"isNew":true,"title":"Genome-wide CRISPR screen identifies STK11 as a critical regulator of sialic acid clusters important for influenza A virus attachment"},{"pmid":"38275900","doi":"10.3390/cancers16020460","year":2024,"isNew":true,"title":"CRISPRing <i>KRAS</i>: A Winding Road with a Bright Future in Basic and Translational Cancer Research"},{"pmid":"41755790","doi":"10.1111/dom.70598","year":2026,"isNew":true,"title":"Evaluating the Impact of Putative Metformin Targets on Cancer Outcomes: A Drug-Target Mendelian Randomization Study"},{"pmid":"42384117","doi":"10.1007/s12672-026-05531-x","year":2026,"isNew":true,"title":"Metformin in endometrial cancer from metabolic regulation to precision therapeutics"},{"pmid":"42280217","doi":"10.3390/molecules31111914","year":2026,"isNew":true,"title":"From Berry to Bedside: Translational Potential of Berry-Derived Phytochemicals in HNSCC"},{"pmid":"42196179","doi":"10.3390/ijms27104195","year":2026,"isNew":true,"title":"Do We Have Enough Evidence That Metformin Is Superior to Other Antidiabetic Drugs in Pancreatic Cancer Risk Reduction?"},{"pmid":"42121939","doi":"10.3390/cells15090838","year":2026,"isNew":true,"title":"Beyond ATP: Lipid-Driven Plasticity and the Immunometabolism of ILC2s"},{"pmid":"42101961","doi":"10.1111/apm.70191","year":2026,"isNew":true,"title":"Familial Adenomatous Polyposis-Risk of Cancer, Cancer Prevention, and Long-Term Consequences: Learnings from Five Decades with the Danish Polyposis Register"}],"trialsShown":[{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT05692596","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"The Pancreas Interception Center (PIC) for Early Detection, Prevention, and Novel Therapeutics"},{"nct":"NCT02775461","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Pancreas Registry and High Risk Registry"},{"nct":"NCT02000089","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"The Cancer of the Pancreas Screening-5 CAPS5)Study"},{"nct":"NCT06722534","phase":"NA","status":"RECRUITING","isNew":false,"title":"Celecoxib for Prevention of Progression in Peutz-Jeghers Syndrome"},{"nct":"NCT04095195","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Registry of Subjects at Risk of Pancreatic Cancer"}],"usage":{"input":10012,"output":7084},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"Peutz-Jeghers\" OR \"Lkb1\" OR \"STK11\") AND (rapamycin OR sirolimus OR everolimus OR metformin OR celecoxib) AND (polyp OR polyposis OR chemoprevention) AND SRC:MED","STK11 AND (\"synthetic lethal\" OR \"CRISPR screen\" OR \"salt-inducible kinase\" OR SIK) AND PUB_YEAR:[2022 TO 2026] AND SRC:MED"],"evidenceIds":["PMID:40882030","PMID:41017554","PMID:41061927","PMID:38275900","PMID:41755790","PMID:42384117","PMID:42280217","PMID:42196179","PMID:42121939","PMID:42101961","NCT03050268","NCT05692596","NCT02775461","NCT02000089","NCT06722534","NCT04095195"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787189292481","cycle":195,"visit":2,"ts":"2026-08-20T01:28:12.481Z","cancer":{"key":"birt-hogg-dube syndrome","name":"Birt-Hogg-Dube syndrome","mondo":{"id":"MONDO:0800444","name":"Birt-Hogg-Dube syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Three new FLCN-mutant renal series show morphologic promiscuity but transcriptional convergence on a TFEB/TFE3-GPNMB program (including one tumour reaching it via TFEB amplification), making GPNMB a sensitive-but-not-specific pharmacodynamic readout and TFEB-axis dependency the priority screen; the ","confidence":0.42,"notebook":"Fresh pack is almost entirely renal pathology, and it reshapes the diagnostic scaffold more than the therapeutic one. Three independent series now define the FLCN-mutant renal phenotype: seven tumours with unclassified/translocation-like, papillary and ESC-like morphology, recurrent loss of 1p/15q/17p/14q and gain of 17q, diffuse TFE3 and uniformly diffuse GPNMB (PMID:42000053); eleven histiocyte-rich renal epithelial neoplasms of which 5/11 carried FLCN mutations, three with occult BHD (PMID:42423092); and eighteen low-grade eosinophilic tumours, 12 in confirmed BHD, spanning mosaic HOCT, ChRCC-like, SDH-like and \"histiocytic lake\" patterns (PMID:42379850). Mechanistically this is one message: biallelic FLCN loss produces a morphologically promiscuous but transcriptionally convergent TFEB/TFE3 lysosomal program, and one case reaches it instead via TFEB locus amplification in a germline-FLCN clear cell RCC (PMID:42000053) — genetic convergence on the same node, which is exactly what a dependency screen should exploit. L3 strengthens on that convergence plus 17p loss corroborating the two-hit state; NCT00033137 is the obvious tissue source for isogenic and organoid work.\n\nGPNMB earns its own lead. It is a canonical TFEB target [KNOWN], diffusely positive in every FLCN-mutant tumour across both series, and therefore the best available pharmacodynamic readout of pathway activity — answering part of Q6. But P8 explicitly reports 3/6 FLCN-wild-type morphologic mimics also GPNMB-positive, so it is sensitive, not specific: usable as a PD endpoint, not as a genotyping surrogate. That same surface abundance makes GPNMB-directed ADC/CAR worth a look, with the caveat that glembatumumab vedotin failed in TNBC and GPNMB is expressed on melanocytes, osteoclasts and macrophages [KNOWN] — a narrow window in an indolent population.\n\nL1 must move down, not up. The only new immunotherapy datum (PMID:40707936) is a BHD sarcomatoid RCC in which first-line axitinib + toripalimab *failed*, with partial response only after switching to anlotinib + the same PD-1 antibody. The simplest reading is that the anti-angiogenic backbone, not checkpoint blockade, drove the response; PD-1 exposure was continuous across failure and response. That undercuts the checkpoint-centric framing of L1. I record it as a near-negative for ICI-as-driver and weaken to 0.3. The co-occurring BRCA2 variant with a single olaparib cycle is uninterpretable.\n\nNew extra-renal axis: FLCN alterations in 1.1% of thyroid carcinomas, enriched in oncocytic morphology, 2% of sporadic versus 23% of anaplastic TC, with homozygous deletion in genomically unstable tumours (PMID:40277780, PMID:40658617). Oncocytic morphology in kidney and thyroid alike implies mitochondrial mass expansion — a candidate OXPHOS/complex I dependency [SPECULATIVE], and a surveillance question for BHD carriers.","leadChanges":[{"id":"L1","title":"Dual immune checkpoint blockade (ipilimumab + nivolumab) in FLCN-null renal neoplasia, including epithelioid angiomyolipoma","level":"LEAD","status":"WEAKENED","confidence":0.3},{"id":"L3","title":"Two-hit FLCN inactivation as the maintenance state to attack by synthetic lethality","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.42},{"id":"L4","title":"GPNMB as pharmacodynamic biomarker — and conditional surface target — of the FLCN/TFEB program","level":"LEAD","status":"NEW","confidence":0.38},{"id":"L5","title":"Pan-organ oncocytic phenotype of FLCN loss (kidney and thyroid) as a shared mitochondrial/OXPHOS vulnerability","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["In FLCN-mutant renal tumours treated with ICI+TKI, can VEGFR-TKI effect be separated from checkpoint effect — is there any case of response to single-agent PD-1/CTLA-4 blockade, and what are TMB/PD-L1/CD8 values?","Does TFEB amplification in a germline-FLCN clear cell RCC (PMID:42000053) behave as a dependency, i.e. does TFEB degradation or knockdown kill FLCN-null renal cells more than WT?","What is the quantitative dynamic range of GPNMB IHC/transcript between FLCN-null and FLCN-WT oncocytic tumours, and can it move measurably on drug to serve as a trial endpoint?","Do FLCN-null renal and thyroid oncocytic cells show a measurable complex I / OXPHOS dependency, and is any approved agent (biguanide) active in isogenic models?","What is the natural history of the newly defined histiocyte-rich and unclassified FLCN-mutant morphologies — metastatic rate versus classic HOCT — since only aggressive subsets can justify systemic toxicity?","Is stromal senescence in fibrofolliculoma (L2) reproducible in genetically confirmed BHD carriers only, and do senolytics clear PAS+ dermal glycogenosis ex vivo?"],"nextQueries":["(FLCN OR folliculin) AND (\"synthetic lethal\" OR \"CRISPR screen\" OR dependency OR \"complex I\" OR OXPHOS OR mitochondrial) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]","(TFEB OR TFE3) AND (amplification OR degrader OR \"transcription factor inhibitor\") AND (\"renal cell carcinoma\" OR kidney) AND SRC:MED","(GPNMB OR \"glycoprotein nonmetastatic B\" OR glembatumumab) AND (biomarker OR immunohistochemistry OR \"antibody-drug conjugate\") AND SRC:MED"],"papersShown":[{"pmid":"41280159","doi":"10.1016/j.euros.2025.10.009","year":2025,"isNew":true,"title":"Genetic Testing and Counselling for Hereditary Renal Carcinoma: What Do Clinicians Need to Know?"},{"pmid":"42000053","doi":"10.1016/j.humpath.2026.106122","year":2026,"isNew":true,"title":"Renal tumors harboring FLCN mutations: Case series from clinical practice"},{"pmid":"40707936","doi":"10.1186/s12957-025-03941-9","year":2025,"isNew":true,"title":"Successful treatment of advanced Birt-Hogg-Dubé syndrome-associated renal cell carcinoma with sarcomatoid dedifferentiation using anlotinib combined with PD-1 inhibitor after first"},{"pmid":"40658617","doi":"10.1089/thy.2024.0641","year":2025,"isNew":true,"title":"Thyroid Carcinoma in Birt-Hogg-Dubé Syndrome: Case Series and Review of Literature"},{"pmid":"40015928","doi":"10.1111/cup.14799","year":2025,"isNew":true,"title":"A Case of Hybrid Cellular Neurothekeoma and Perineurioma With a Folliculin Gene Mutation"},{"pmid":"40277780","doi":"10.3390/curroncol32040224","year":2025,"isNew":true,"title":"&lt;i&gt;Folliculin&lt;/i&gt; (&lt;i&gt;FLCN&lt;/i&gt;) in Thyroid Tumors: Incidence, Significance, and Role as a Driver Gene and Secondary Alteration"},{"pmid":"42272253","doi":"10.3892/ijmm.2026.5887","year":2026,"isNew":true,"title":"Spatial architecture of immunometabolism: Mitochondrial‑organelle interfaces in immune signaling (Review)"},{"pmid":"42423092","doi":"10.1097/pas.0000000000002587","year":2026,"isNew":true,"title":"Histiocyte-Rich Renal Epithelial Neoplasm: A Morphology Associated With Folliculin Mutations and Birt-Hogg-Dubé Syndrome"},{"pmid":"42379850","doi":"10.3760/cma.j.cn112151-20251210-00816","year":2026,"isNew":true,"title":"[Clinicopathological features of low-grade eosinophilic renal tumor associated with FLCN mutation: an analysis of eighteen cases]"},{"pmid":"42156139","doi":"10.1101/gad.353584.125","year":2026,"isNew":true,"title":"Mechanisms coordinating exit from the stem cell state in mammals"}],"trialsShown":[{"nct":"NCT00033137","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Genetic Analysis of Birt Hogg-Dube Syndrome and Characterization of Predisposition to Kidney Cancer"},{"nct":"NCT06330350","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling"},{"nct":"NCT06330324","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Reproductive Options in Inherited Skin Diseases"},{"nct":"NCT03749980","phase":"n/a","status":"RECRUITING","isNew":false,"title":"MyVHL: Patient Natural History Study"}],"usage":{"input":10600,"output":6686},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(FLCN OR folliculin) AND (TFEB OR TFE3 OR \"RagC\" OR \"synthetic lethal\" OR \"CRISPR screen\" OR dependency) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(FLCN OR \"Birt-Hogg-Dube\") AND (\"immune checkpoint\" OR nivolumab OR ipilimumab OR \"tumor microenvironment\" OR \"tumor mutational burden\") AND SRC:MED"],"evidenceIds":["PMID:41280159","PMID:42000053","PMID:40707936","PMID:40658617","PMID:40015928","PMID:40277780","PMID:42272253","PMID:42423092","PMID:42379850","PMID:42156139","NCT00033137","NCT06330350","NCT06330324","NCT03749980"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787189083201","cycle":194,"visit":2,"ts":"2026-08-20T01:24:43.201Z","cancer":{"key":"gorlin syndrome","name":"Gorlin syndrome","mondo":{"id":"MONDO:0007187","name":"nevoid basal cell carcinoma syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Patidegib topical gel now has Gorlin-specific randomised phase IIA support (PMID:39545486) alongside the ongoing phase 3 NCT06050122, promoting skin-compartment-restricted SMO inhibition to CANDIDATE, while oral itraconazole monotherapy (1 mm median shrinkage, PMID:42101092) is banked as a near-nega","confidence":0.55,"notebook":"**Visit 2 notebook.** The pack's single high-value item is P1 (PMID:39545486), a UK two-site randomised double-blind phase IIA of patidegib topical gel 2%/4% applied twice daily to the whole face for 6 months in Gorlin syndrome, designed explicitly around the compartmentalisation question L1 was built on: can follicular drug levels be tumoricidal while plasma stays below the threshold for cramps/dysgeusia/alopecia. The abstract is truncated and the positive efficacy statement is *post hoc* (\"suggested… reduced the number of\"), so I record this as supportive but not confirmatory; no numeric new-lesion rate, no plasma pharmacokinetics visible. It is nonetheless new, independent, Gorlin-specific clinical evidence for the exact intervention in L1, corroborated by an editorial (PMID:39969481) and by two independent reviews listing patidegib among viable Hh agents (PMID:40262619, PMID:39796697). L1 → CANDIDATE, confidence 0.65, with a standing caveat I must not let slide: the earlier Sol-Gel patidegib gel 2% phase 3 missed its primary endpoint [KNOWN], so NCT06050122 is a re-test, and any positive phase IIA post hoc signal must be reconciled against that failure (vehicle, follicular penetration, endpoint definition).\n\nNegative/near-negative to bank: perioperative oral itraconazole (PMID:42101092) shrank low-risk BCC from a median 14 mm to 13 mm over 60 days — statistically significant, clinically trivial, with the mechanistic read-out being CD105 (angiogenesis) rather than GLI targets. Itraconazole monotherapy cytoreduction is not a route this desk should re-propose in Gorlin; at most an anti-angiogenic add-on. Also banked: the resistance-focused query returned only reviews (P2, P3) and no primary paired-biopsy genotyping series, i.e. the SMO-mutant vs GLI2/CCND1-amplified split in *germline PTCH1* skin remains unmeasured. L4 weakened to 0.35 on that literature void — the lead is still the right instrument, but the field has not generated the data.\n\nNew lead L5 (Gorlin SHH-medulloblastoma, radiotherapy-sparing): a 10-year ongoing complete response to first-line vismodegib in adult metastatic medulloblastoma (PMID:42109078) is single-patient but shows durable SMO-dependence without radiotherapy; paired with compartmentalised GLI1 targeting via phenformin-loaded niosomes achieving cerebellar tumour accumulation with reduced hepatic exposure and Gli1/Ptch1 knockdown in vivo (PMID:42117983), this gives a delivery-restricted route around the two blockers in children — growth-plate fusion from systemic HHi and lactic acidosis from free phenformin. New lead L6: neoadjuvant/combination Hh-plus-checkpoint strategies flagged in PMID:39796697 as the emerging axis for advanced BCC, relevant as post-HHi salvage given BCC's UV-driven mutational burden [KNOWN]; Gorlin-specific data absent.","leadChanges":[{"id":"L1","title":"Skin-compartment-restricted SMO inhibition (topical patidegib) as chemoprevention in germline PTCH1 Gorlin syndrome","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.65},{"id":"L4","title":"Resistance-genotype mapping of Hedgehog-inhibitor failure in Gorlin BCC via prospective registries","level":"LEAD","status":"WEAKENED","confidence":0.35},{"id":"L5","title":"Delivery-restricted SMO/GLI inhibition as a radiotherapy-sparing strategy in Gorlin-associated SHH medulloblastoma","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L6","title":"Immune-checkpoint blockade as post-HHi salvage and Hh/checkpoint combination in Gorlin BCC","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does NCT06050122 replicate the phase IIA signal, and why did the earlier patidegib gel 2% phase 3 fail — vehicle/follicular penetration, dosing area, or new-lesion endpoint definition?","Are there measured plasma patidegib concentrations and lesional GLI1/PTCH1 transcript changes proving true skin compartmentalisation rather than inferring it from absent toxicity?","What is the somatic genotype spectrum at HHi progression in Gorlin BCC (SMO binding-site mutants vs GLI2/CCND1 amplification vs somatic SUFU loss), and does germline PTCH1 vs SUFU status change it?","Does intermittent/pulsed oral HHi dosing preserve the 84% ORR while cutting the 90% adverse-effect burden, and does it delay or accelerate resistance?","Is there any Gorlin- or BCC-specific evidence for checkpoint blockade after HHi failure, or for GLI-direct agents (arsenic trioxide, BET/BRD4, phenformin) in PTCH1-null keratinocytes?","Can SMO or GLI inhibition permit radiotherapy avoidance in Gorlin medulloblastoma, and what is the measured growth-plate risk under intermittent or delivery-restricted dosing in children?"],"nextQueries":["(patidegib) AND (\"basal cell carcinoma\" OR Gorlin) AND (pharmacokinetic* OR plasma OR \"phase 3\" OR \"phase III\") AND SRC:MED","(\"basal cell carcinoma\") AND (vismodegib OR sonidegib) AND (\"paired biops*\" OR \"whole exome\" OR sequencing) AND (progression OR resistance) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"basal cell carcinoma\") AND (cemiplimab OR pembrolizumab OR \"immune checkpoint\") AND (\"hedgehog inhibitor\" OR vismodegib OR sonidegib OR Gorlin) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"39545486","doi":"10.1093/bjd/ljae444","year":2025,"isNew":true,"title":"Topical application of the Hedgehog inhibitor patidegib in patients with Gorlin syndrome: a phase II trial"},{"pmid":"39796697","doi":"10.3390/cancers17010068","year":2024,"isNew":true,"title":"Therapeutic Approaches for Advanced Basal Cell Carcinoma: A Comprehensive Review"},{"pmid":"40262619","doi":"10.1080/1061186x.2025.2496470","year":2025,"isNew":true,"title":"Hedgehog signalling pathway inhibitors in the treatment of basal cell carcinoma: an updated review"},{"pmid":"42101092","doi":"10.1111/exd.70264","year":2026,"isNew":true,"title":"A Phase II Trial of Perioperative Oral Itraconazole for the Management of Low-Risk Basal Cell Carcinoma"},{"pmid":"39969481","doi":"10.1093/bjd/ljae515","year":2025,"isNew":true,"title":"Patidegib: a novel, promising treatment for basal cell carcinoma lesions in patients with Gorlin syndrome"},{"pmid":"42240603","doi":"10.1158/2767-9764.crc-25-0163","year":2026,"isNew":true,"title":"Ldha Regulates Osteosarcoma Lung Metastasis through Hedgehog Signaling"},{"pmid":"41955967","doi":"10.1016/j.neo.2026.101306","year":2026,"isNew":true,"title":"Targeting tumor dormancy: the next frontier in gastrointestinal stromal tumor therapy"},{"pmid":"41680284","doi":"10.1038/s41416-026-03348-7","year":2026,"isNew":true,"title":"Paediatric Therapeutic Development Workshop on rhabdoid tumours"},{"pmid":"42117983","doi":"10.3390/nano16090566","year":2026,"isNew":true,"title":"Brain-Targeted Delivery of Phenformin Using Phospholipid and Non-Phospholipid Vesicles for SHH Medulloblastoma"},{"pmid":"42109078","doi":"10.2340/1651-226x.2026.45543","year":2026,"isNew":true,"title":"A 10-year-long ongoing complete response to vismodegib as first-line treatment in adult metastatic medulloblastoma"}],"trialsShown":[{"nct":"NCT06050122","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Efficacy and Safety of Patidegib Gel 2% for Preventing Basal Cell Carcinomas on the Face of Adults With Gorlin Syndrome"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT06623201","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Blue-Light Photodynamic Therapy and Sonidegib for Multiple Basal Cell Carcinomas"},{"nct":"NCT04569149","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Primordial Dwarfism Registry"},{"nct":"NCT06330350","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling"},{"nct":"NCT06330324","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Reproductive Options in Inherited Skin Diseases"},{"nct":"NCT05463757","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Oral Hedgehog Inhibitors in the Treatment of Basal Cell Carcinoma in the Netherlands: a Prospective Registration Study"}],"usage":{"input":9365,"output":6431},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"basal cell carcinoma\") AND (vismodegib OR sonidegib) AND (resistance) AND (SMO OR GLI2 OR SUFU) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(patidegib OR \"topical hedgehog inhibitor\") AND (\"basal cell carcinoma\" OR \"Gorlin\") AND SRC:MED"],"evidenceIds":["PMID:39545486","PMID:39796697","PMID:40262619","PMID:42101092","PMID:39969481","PMID:42240603","PMID:41955967","PMID:41680284","PMID:42117983","PMID:42109078","NCT06050122","NCT03050268","NCT06623201","NCT04569149","NCT06330350","NCT06330324","NCT05463757"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787188877407","cycle":193,"visit":2,"ts":"2026-08-20T01:21:17.407Z","cancer":{"key":"multiple endocrine neoplasia type 2","name":"multiple endocrine neoplasia type 2","mondo":{"id":"MONDO:0019003","name":"multiple endocrine neoplasia type 2"}},"control":false,"modelLabel":"SCIENCE","summary":"At RET-inhibitor progression in MEN2 MTC, split management by resistance genotype: solvent-front/gatekeeper RET mutations should go to next-generation RET inhibitors (zeteletinib, SYHA1815, BOS172738, SY-5007) rather than MEK combinations, which should be reserved for documented MAPK-reactivation/NF","confidence":0.5,"notebook":"This visit's pack was review-heavy and, importantly, my targeted query for MTC/MEN2 plus MEK-inhibitor/NF1 returned no primary human data — only generic combination-strategy reviews (PMID:41976235) and thyroid-genomics overviews (PMID:41595456, PMID:42070503, PMID:42279395). That silence is informative: NF1 loss and MAPK reflux remain, in humans, undocumented at RET-inhibitor progression. I therefore mark L1 WEAKENED rather than strengthened, and narrow it: MEK co-inhibition should be tested only in the MAPK-reactivation/NF1-loss/RAS-secondary genotype, not offered as a generic post-selpercatinib strategy.\n\nThe reason for narrowing is competitive, not just evidential. Two independent MTC-focused reviews now describe an actual next-generation RET pipeline aimed at gatekeeper (V804) and solvent-front (G810) mutations — zeteletinib and SYHA1815 (PMID:42520863), plus BOS172738 and SY-5007 with early activity (PMID:42525389). For G810S disease the rational answer is a structurally distinct RET inhibitor, not downstream MEK blockade, which addresses my open question 3 in the negative for the MEK route. PMID:42525389 also records pralsetinib's market withdrawal — a supply/access fact that reshapes sequencing and makes the second-generation agents strategically load-bearing rather than optional. New lead L4 captures this: genotype-directed sequencing at progression, with ctDNA-defined subsets (solvent-front → next-gen RET inhibitor; MAPK-reactivation → L1 combination; bypass/undefined → neither). PMID:41837125 supplies the operational scaffold — universal germline RET testing plus somatic profiling in advanced/progressive disease — which is exactly the infrastructure both leads need; NCT01660984 remains the plausible specimen source.\n\nNegative results to bank so the desk never re-proposes them: cytotoxic chemotherapy in metastatic MEN2A pheochromocytoma was ineffective in the newly reported case, which died 3y2m from primary surgery (PMID:41837230). That case also documents a biochemical phenotype shift (rising spot urine normetanephrine heralding peritoneal and distant spread), which upgrades metanephrine kinetics from response marker to surveillance trigger and modestly strengthens L2's endpoint logic. PMID:41809780 adds that adrenal-sparing surgery in bilateral MEN2 pheo preserves steroid independence — relevant because it defines the residual-tissue population in whom systemic/radioligand options will be needed. PRRT is now flagged as an emerging MTC modality (PMID:42525389), so L2's radioligand axis extends beyond pheo to C-cell disease. Still no HIF-2α transcriptional data in RET-driven pheo; belzutifan (NCT04924075) stays an eligibility observation only.\n\nL3 (GLP-1R in human C-cell neoplasia) received nothing this visit and persists unchanged.","leadChanges":[{"id":"L1","title":"Vertical RET+MEK blockade (selpercatinib + trametinib) for RET-inhibitor-resistant MEN2-associated MTC","level":"LEAD","status":"WEAKENED","confidence":0.45},{"id":"L4","title":"Genotype-directed sequencing to next-generation RET inhibitors for gatekeeper/solvent-front resistant MEN2-associated MTC","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L2","title":"Radioligand-plus-systemic control of MEN2A metastatic pheochromocytoma, with cluster-2 vs pseudohypoxia target triage","level":"LEAD","status":"STRENGTHENED","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["Are there any published human MTC biopsy or ctDNA series at selpercatinib/pralsetinib progression that report NF1 loss, RAS or MAP2K1 mutations, i.e. does the CRISPR-derived MAPK-reflux mechanism exist in patients at all?","What are the reported potencies, MTC-specific response data and trial identifiers for zeteletinib, SYHA1815, BOS172738 and SY-5007 against RET G810 solvent-front and V804 gatekeeper mutants?","Does SSTR2 expression in MEN2-associated MTC and pheochromocytoma support 177Lu-DOTATATE, and what response/biochemical endpoints have been reported for PRRT in MTC?","Are MET or EGFR bypass tracks documented in MTC (as opposed to RET-fusion lung cancer), and with what frequency relative to secondary RET mutations?","Do RET-driven MEN2 pheochromocytomas show any HIF-2alpha/EPAS1 target-gene activation that would justify belzutifan, or should they be managed purely as cluster-2 kinase-driven disease?","Is GLP-1R expressed in human MTC and C-cell hyperplasia from MEN2 carriers, and does GLP-1RA exposure alter calcitonin kinetics?"],"nextQueries":["(\"medullary thyroid\" OR \"RET\") AND (zeteletinib OR SYHA1815 OR BOS172738 OR \"SY-5007\" OR vepafestinib) AND SRC:MED","(\"medullary thyroid carcinoma\") AND (\"circulating tumor DNA\" OR ctDNA OR \"somatic profiling\") AND (progression OR resistance OR \"acquired\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"medullary thyroid carcinoma\" OR \"pheochromocytoma\") AND (\"177Lu-DOTATATE\" OR \"peptide receptor radionuclide\" OR SSTR2 OR MIBG) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"41976235","doi":"10.3390/molecules31071195","year":2026,"isNew":true,"title":"Molecularly Targeted Therapies in Oncology: Mechanisms, Resistance, and Combination Strategies"},{"pmid":"41595456","doi":"10.3390/genes17010036","year":2025,"isNew":true,"title":"Review of Genomic Drivers of Thyroid Cancer and Their Clinical Implications"},{"pmid":"42525389","doi":"10.1093/oncolo/oyag300","year":2026,"isNew":true,"title":"Targeted therapies in the management of advanced medullary thyroid cancer"},{"pmid":"42520863","doi":"10.1016/j.critrevonc.2026.105506","year":2026,"isNew":true,"title":"RET alterations in thyroid cancer: Molecular mechanisms, targeted therapies, and emerging resistance"},{"pmid":"42070503","doi":"10.1016/j.tranon.2026.102799","year":2026,"isNew":true,"title":"Multimodal strategies for diagnosing and treating thyroid cancer: Advances in basic and clinical research"},{"pmid":"42279395","doi":"10.3390/cancers18111814","year":2026,"isNew":true,"title":"The Role of Cytology, Histology and Molecular Pathology in the Diagnostic Process of Thyroid Nodules"},{"pmid":"42116529","doi":"10.3322/caac.70086","year":2026,"isNew":true,"title":"Medullary thyroid carcinoma and RET molecular testing: A virtual tumor board on clinical decision-making"},{"pmid":"41837230","doi":"10.1210/jcemcr/luag038","year":2026,"isNew":true,"title":"Advanced disease and biochemical phenotype shift in multiple endocrine neoplasia type 2A-related pheochromocytoma"},{"pmid":"41809780","doi":"10.21037/tau-2025-683","year":2026,"isNew":true,"title":"Bilateral pheochromocytoma: case series and review of treatment strategies based on genetic mutations"},{"pmid":"41837125","doi":"10.3389/fendo.2026.1794118","year":2026,"isNew":true,"title":"Precision management of medullary thyroid carcinoma: a dynamic framework integrating biomarkers, genotyping, and risk stratification"}],"trialsShown":[{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT07285044","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"The Cancer Connected Access and Remote Expertise Beyond Walls Program to Provide In-Home Cancer Treatment and Improve Treatment Satisfaction"},{"nct":"NCT07492680","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Study of BMS-986504 Monotherapy and in Combination With Other Agents in Participants With Advanced and/or Metastatic Solid Tumors With Hom"},{"nct":"NCT07303894","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Study of Isoquercetin in People With Ovarian Cancer"},{"nct":"NCT01660984","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Natural History Study of Children and Adults With Medullary Thyroid Cancer"},{"nct":"NCT05142189","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Clinical Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced No"},{"nct":"NCT02867592","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumor"},{"nct":"NCT03655223","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Early Check: Expanded Screening in Newborns"}],"usage":{"input":9902,"output":5879},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"medullary thyroid carcinoma\") AND (selpercatinib OR pralsetinib) AND (resistance OR \"G810\" OR \"acquired\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"medullary thyroid\" OR \"multiple endocrine neoplasia type 2\") AND (\"MEK inhibitor\" OR trametinib OR selumetinib OR NF1) AND SRC:MED"],"evidenceIds":["PMID:41976235","PMID:41595456","PMID:42525389","PMID:42520863","PMID:42070503","PMID:42279395","PMID:42116529","PMID:41837230","PMID:41809780","PMID:41837125","NCT04924075","NCT07285044","NCT07492680","NCT07303894","NCT01660984","NCT05142189","NCT02867592","NCT03655223"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787188679128","cycle":192,"visit":19,"ts":"2026-08-20T01:17:59.128Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"ABL1 exon-3 (a3) junctions abolish asciminib activity through an incomplete SH3 domain — proven by chimeric-SH3 rescue in NUP214::ABL1 — so junction-resolved transcript typing should gate asciminib selection and be paired with the new base-editing/DMS asciminib resistance atlas for variant triage.","confidence":0.62,"notebook":"Visit 19 delivers the first mechanistic close on the question I set myself. P1 (PMID:42485989) does two things: it states plainly that ABL1 exon-3 breakpoints (e13a3, e14a3) in BCR::ABL1 confer asciminib resistance through an incomplete SH3 domain, and it shows the converse experimentally — NUP214 exon 32 substitutes for the missing ABL1 exon 2, reconstituting a chimeric SH3 that restores asciminib sensitivity in Ba/F3 and in three NUP214::ABL1 PDX models (e31a2, e32a3, e34a3), with deletion series mapping the SH3 segment required for allosteric inhibition. That is exactly the isogenic/structural test L18 specified, done from the ALL side, and it converts my [INFERRED] a2-versus-a3 conformational argument into a mapped structural requirement: myristoyl-pocket inhibition needs the assembled SH3 clamp, and partner-gene architecture — not kinase-domain genotype — decides. L18 accordingly moves to DOSSIER; the clinical corollary is unchanged but now urgent: junction-resolved typing before any asciminib line, and re-genotyping of every NGS-negative asciminib failure for a3 junctions.\n\nP3 (PMID:42365381) supplies the orthogonal resistance atlas: base-editing plus deep mutational scanning yields 279 asciminib-resistance mutations with hotspots distributed *including the SH3 domain*, an edit-on-edit epistasis screen on the imatinib-resistant Y253H background, and a FRET conformational biosensor reading BCR::ABL1 autoinhibition state in live cells. This strengthens L8's two-axis taxonomy (kinase-domain plus architecture/conformation) and gives the mutation-to-agent matrix a pre-computed prior plus a functional assay to triage clinical variants of unknown significance. It also, notably, does not show a mutational blind spot that dual-site occupancy would uniquely close.\n\nL1 retires. Three visits of consistent non-endorsement (blast-phase reviews, ELN 2025 sequential framing) plus zero prospective concurrent-dosing data, and NCT03906292 remains a dead branch; P3's finding of broad, convergent, epistasis-permissive resistance argues the combination is not the guaranteed compound-mutant trap I posited. Recorded so the desk does not re-propose concurrent asciminib+ATP-site dosing without paired compound-mutant clinical data.\n\nL7 gains guideline-adjacent human tolerability data: ASC4FIRST post hoc (PMID:42389818) shows fewer difficult-to-tolerate AEs, fewer AEs prompting dose modification/discontinuation and shorter modification duration for asciminib versus imatinib and 2G TKIs — the therapeutic window is now demonstrably agent-dependent as well as dose-dependent. Still no randomised dose-reduction trial; open question 2 unanswered by this pack.\n\nL11 weakens again: no clinical-grade HDAC6 (ricolinostat/citarinostat) CML-LSC data anywhere; 7b remains a tool compound. One dedicated empty pass from retirement. L16 and L17 untouched this visit (no dedicated pass run); their prespecified retirement clocks stand.","leadChanges":[{"id":"L18","title":"Transcript-architecture triage: atypical and insertion-bearing BCR::ABL1 fusions as a distinct resistance class and a blind spot in molecular monitoring","level":"DOSSIER","status":"STRENGTHENED","confidence":0.62},{"id":"L8","title":"Sequential ATP-site to allosteric switch: asciminib as non-cross-resistant salvage after ponatinib and in T315I disease","level":"DOSSIER","status":"STRENGTHENED","confidence":0.82},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"DOSSIER","status":"STRENGTHENED","confidence":0.79},{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"RETIRED","confidence":0.1},{"id":"L11","title":"HDAC6-selective inhibition plus asciminib: autophagy blockade to maladaptive ISR, MCL-1 loss and BCL-xL-dependent apoptosis in CML","level":"CANDIDATE","status":"WEAKENED","confidence":0.32}],"unverifiedCitations":0,"openQuestions":["Do e13a3/e14a3 CML patients retain full sensitivity to ATP-site agents (imatinib, ponatinib, olverembatinib) in isogenic cells and case series, i.e. is a3 architecture selectively an allosteric-inhibitor liability?","Which of the 279 asciminib-resistance mutations (PMID:42365381) lie in SH3/non-kinase regions, and do they remain sensitive to ponatinib or olverembatinib — can a computable mutation-to-agent matrix be published from the atlas?","Can the FRET conformational biosensor classify clinically observed NGS-negative asciminib failures as conformational versus LSC-state resistance?","Does any randomised or prospective dose-reduction/TDM trial in chronic-phase CML exist, and does ELN 2025 give quantitative reduction schedules usable as a comparator arm?","Final passes: any independent replication of FBXO3-DUSP9 in primary CML CD34+ cells (L16), and any ricolinostat/citarinostat primary CML-LSC data (L11)?","Is the ABL1 E255V neoepitope presented on primary CML cells, and does NCT06904066 admit CML kinase-domain point mutations as participant-specific neoantigens (L17)?"],"nextQueries":["(\"BCR::ABL1\" OR \"BCR-ABL\") AND (e13a3 OR e14a3 OR \"a3 transcript\" OR \"atypical transcript\") AND (ponatinib OR olverembatinib OR imatinib OR response) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(FBXO3 OR DUSP9) AND (leukemia OR \"stem cell\" OR MAPK) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(ricolinostat OR citarinostat OR \"HDAC6 inhibitor\") AND (\"chronic myeloid leukemia\" OR \"leukemic stem cell\" OR CD34) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42485989","doi":"10.1016/j.neo.2026.101337","year":2026,"isNew":true,"title":"The partner gene modulates response to asciminib in ABL1-rearranged Acute Lymphoblastic Leukemia"},{"pmid":"42389818","doi":"10.3324/haematol.2025.300145","year":2026,"isNew":true,"title":"Favorable tolerability of asciminib &lt;i&gt;versus&lt;/i&gt; ATP-competitive tyrosine kinase inhibitors in the ASC4FIRST study of newly diagnosed patients with chronic-phase chron"},{"pmid":"42365381","doi":"10.1186/s13073-026-01679-x","year":2026,"isNew":true,"title":"Dual functional genomics reveals a broad and convergent landscape of asciminib resistance in BCR::ABL1"},{"pmid":"41877800","doi":"10.2147/blctt.s573070","year":2026,"isNew":true,"title":"Safety and Efficacy of Flumatinib in Patients with Chronic Phase Chronic Myeloid Leukemia: A Real-Life Cohort Observational Study"},{"pmid":"42284888","doi":"10.1016/j.biopha.2026.119652","year":2026,"isNew":false,"title":"Selective HDAC6 inhibition perturbs autophagy and enhances integrated stress response-mediated immunogenic apoptosis in chronic myeloid leukemia"},{"pmid":"42591375","doi":"10.21037/tcr-2026-1659","year":2026,"isNew":false,"title":"Matching-adjusted indirect comparison between asciminib and flumatinib as first-line treatment for chronic myeloid leukemia in China"},{"pmid":"42463944","doi":"10.1038/s41375-026-02972-9","year":2026,"isNew":false,"title":"Asciminib monotherapy in patients with BCR::ABL1 T315I-mutated chronic-phase chronic myeloid leukemia: phase 1 trial final results"},{"pmid":"42458108","doi":"10.1007/s44313-026-00153-2","year":2026,"isNew":false,"title":"Asciminib as first-line therapy in chronic myeloid leukemia: a systematic review"},{"pmid":"42412118","doi":"10.1007/s00280-026-04919-4","year":2026,"isNew":false,"title":"Pharmacokinetics of asciminib in a patient with chronic myeloid leukemia undergoing maintenance hemodialysis"},{"pmid":"41976356","doi":"10.3390/cancers18071133","year":2026,"isNew":false,"title":"A Current Overview of Quality-of-Life Research in Chronic Myeloid Leukemia (CML)"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":17819,"output":8330},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(asciminib) AND (\"a3\" OR e13a3 OR e14a3 OR e1a3 OR \"SH3 domain\" OR \"myristoyl pocket\" OR \"allosteric\") AND (\"BCR::ABL1\" OR \"BCR-ABL\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"chronic myeloid leukemia\") AND (\"dose reduction\" OR \"de-escalation\" OR \"low dose\") AND (randomi* OR \"phase 3\" OR \"phase III\" OR \"patient-reported\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:42485989","PMID:42389818","PMID:42365381","PMID:41877800","PMID:42284888","PMID:42591375","PMID:42463944","PMID:42458108","PMID:42412118","PMID:41976356","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787188451105","cycle":191,"visit":3,"ts":"2026-08-20T01:14:11.105Z","cancer":{"key":"multiple endocrine neoplasia type 1","name":"multiple endocrine neoplasia type 1","mondo":{"id":"MONDO:0007540","name":"multiple endocrine neoplasia type 1"}},"control":false,"modelLabel":"SCIENCE","summary":"With no published isogenic MEN1-null CDK4/6 or MEN1-specific spatial TME data existing, the desk should pivot near-term effort to a 68Ga-DOTATATE/SSTR2-stratified PRRT-plus-mTOR-inhibitor hypothesis in MEN1 duodenopancreatic NET while commissioning MEN1-null adult-pancreatic-cell organoid models, an","confidence":0.33,"notebook":"This visit's pack was largely off-target — taxanes, halogen chemistry, an IGF2BP3 inhibitor in B-ALL (PMID:41307127) — and both of my fielded queries returned informative nulls rather than data. That matters more than it looks.\n\nThe isogenic query for MEN1-null endocrine models tested against palbociclib/ribociclib/abemaciclib retrieved nothing. Combined with PMID:41238828, which states explicitly that NEN biology is impaired by \"paucity of models\" and that pancreatic NENs appear to arise from adult pancreatic cells rather than progenitors, this is a substantive negative: the CDK4/6 dependency in L2 remains untested because the reagents do not exist publicly. I am therefore weakening L2 (0.35 → 0.32) while keeping it at CANDIDATE — the mechanism is unrefuted, but the corroboration I asked for is absent, not merely unfound. The only new lateral support is PMID:40869136, which lists CDKN1B alongside MEN1/DAXX/ATRX as a recurrent panNET driver and re-anchors chromatin-remodelling and mTOR dysregulation; review-level, so it does not lift confidence.\n\nSimilarly, the MEN1-specific single-cell/spatial query yielded no MEN1 tumour microenvironment study. L3 drops to 0.20: after two visits the immune-exclusion hypothesis for MEN1 panNET still rests entirely on sporadic panNET and adrenocortical lateral data. PMID:41238828 endorses single-cell/spatial sequencing as the needed modality, which sharpens the experiment but supplies no result.\n\nThe pack does harden one thing decisively. Three independent 2026 reviews (PMID:42122138, PMID:41704185, PMID:41899095) restate that KMT2A-fusion leukaemogenesis *requires* menin as an obligate cofactor and that revumenib-class inhibitors work by disrupting that interaction, with resistance arising via MEN1 binding-site mutations. [INFERRED] In MEN1 tumours menin is biallelically lost — the drug target is already deleted; menin inhibition is mechanistically void here and the desk must never propose it. I mark L5 STRENGTHENED on that exclusion clause only, holding confidence at 0.20 since the positive chromatin-writer arm (EZH2/PRMT5/DOT1L) gained nothing.\n\nNew lead L6, repurposing-first: PMID:40869136 places SSTR2 as the dominant actionable axis in panNET, enabling 68Ga-DOTATATE-selected PRRT, with mTOR dysregulation as a parallel documented pathway — echoed in parathyroid carcinoma (PMID:42196524). A SUV-stratified PRRT-plus-mTOR-inhibitor sequencing hypothesis in MEN1 duodenopancreatic disease is the fastest translatable option and is orthogonal to the untested cell-cycle bet. L1 and L4 unchanged; NCT04969926 remains the only trial in the pack able to adjudicate the thymectomy hypoparathyroidism penalty.\n\nNext visit must attack the model gap directly: MEN1 conditional-knockout/organoid CRISPR screens, and PRRT combination data.","leadChanges":[{"id":"L2","title":"Menin-loss to p27/p18 G1 dysregulation as a CDK4/6-inhibitor dependency in MEN1 tumours","level":"CANDIDATE","status":"WEAKENED","confidence":0.32},{"id":"L3","title":"Stroma/immune-exclusion-directed combination rather than checkpoint monotherapy in MEN1 panNET","level":"LEAD","status":"WEAKENED","confidence":0.2},{"id":"L5","title":"Chromatin-writer dependency created by menin loss (PRC2/EZH2, PRMT5, DOT1L) — and explicit exclusion of menin-KMT2A inhibitors","level":"LEAD","status":"STRENGTHENED","confidence":0.2},{"id":"L6","title":"SSTR2-density-stratified PRRT with mTOR-pathway inhibition in MEN1 duodenopancreatic NET","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does any group hold MEN1-conditional-knockout or MEN1-null adult human islet/panNET organoids, and can a CDK4/6i IC50 shift with p27/p18 rescue be run in them (the decisive test L2 now depends on)?","Are MEN1-germline panNETs systematically SSTR2-higher (68Ga-DOTATATE SUVmax) than sporadic panNETs, and is there published PRRT outcome data specifically in MEN1 patients?","Does concurrent CDK4/6 or mTOR inhibition antagonise or radiosensitise 177Lu-DOTATATE cytotoxicity in neuroendocrine models?","Is there any single-cell or spatial dataset of MEN1-germline panNET/parathyroid tissue at all, published or in a repository, that can resolve CD8 topology, TAM polarisation and HLA copy number?","In MEN1 tumour archives, what is the frequency of RB1 loss, CDKN2A/p16 deletion and MTAP co-deletion — i.e. how large are the RB-intact CDK4/6-eligible and PRMT5-eligible fractions?","Can the cervical-thymectomy cure benefit be reproduced with surgeon volume and resection extent controlled, and what permanent hypoparathyroidism rate does a natural-history cohort such as NCT04969926 imply?"],"nextQueries":["(MEN1 OR menin) AND (\"conditional knockout\" OR organoid OR \"islet\" OR \"mouse model\") AND (CRISPR OR \"drug screen\" OR dependency) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]","(\"pancreatic neuroendocrine\" OR panNET) AND (\"177Lu-DOTATATE\" OR PRRT OR \"peptide receptor radionuclide\") AND (MEN1 OR \"multiple endocrine neoplasia\" OR everolimus) AND SRC:MED","(MEN1 OR \"multiple endocrine neoplasia type 1\") AND (parathyroid OR pancreatic OR pituitary) AND (\"single-cell RNA\" OR \"spatial transcriptomics\" OR \"tumor microenvironment\" OR HLA) AND SRC:MED"],"papersShown":[{"pmid":"40869136","doi":"10.3390/ijms26167814","year":2025,"isNew":true,"title":"Decoding Pancreatic Neuroendocrine Tumors: Molecular Profiles, Biomarkers, and Pathways to Personalized Therapy"},{"pmid":"41307127","doi":"10.3324/haematol.2025.288221","year":2026,"isNew":true,"title":"A small molecule inhibitor of RNA-binding protein IGF2BP3 shows anti-leukemic activity"},{"pmid":"41897316","doi":"10.3390/biom16030381","year":2026,"isNew":true,"title":"Halogen-Containing Drugs in 2025: A Record Year for the Therapeutic Use and Synthesis of FDA-Approved Small Molecules"},{"pmid":"41238828","doi":"10.1007/s00428-025-04311-2","year":2026,"isNew":true,"title":"Novel concepts of cell-of origin in neuroendocrine neoplasms"},{"pmid":"41214336","doi":"10.1038/s41585-025-01104-9","year":2026,"isNew":true,"title":"20 years of taxane therapy in prostate cancer - the past, present and future"},{"pmid":"42196524","doi":"10.3390/ijms27104549","year":2026,"isNew":true,"title":"Parathyroid Carcinoma: From Molecular Pathogenesis and Diagnostic Biomarkers to Targeted Therapeutics"},{"pmid":"42180980","doi":"10.21037/tcr-2025-1-2830","year":2026,"isNew":true,"title":"Targeting \"undruggable\" cancer proteins: pharmacological challenges and emerging strategies"},{"pmid":"42122138","doi":"10.3390/cancers18091341","year":2026,"isNew":true,"title":"Acute Myeloid Leukemias with Alterations of Lysine Methyltransferase 2A (KMT2A): Recent Therapeutic Developments"},{"pmid":"41704185","doi":"10.1111/febs.70460","year":2026,"isNew":true,"title":"Current perspectives on KMT2A fusion proteins and menin inhibition in paediatric acute myeloid leukaemia"},{"pmid":"41899095","doi":"10.3390/jcm15062171","year":2026,"isNew":true,"title":"Resistance to Targeted Therapy in AML: Current Challenges and Emerging Treatment Strategies"}],"trialsShown":[{"nct":"NCT06957691","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Proof-of-Concept Trial to Assess the Efficacy and Safety of Fezolinetant in Improving Vasomotor Symptoms in Men With Prostate Cancer Undergo"},{"nct":"NCT04969926","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Natural History Study of Parathyroid Disorders"},{"nct":"NCT06781983","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Safety and Tolerability of IPH4502 in Patients With Advanced Solid Tumors"},{"nct":"NCT05142189","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Clinical Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced No"},{"nct":"NCT05250284","phase":"n/a","status":"RECRUITING","isNew":false,"title":"The Intersection of Oncology Care and Worker Well-Being"},{"nct":"NCT06834204","phase":"NA","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Advancing Care Coordination Between Cancer and Primary Care Teams for Complex Cancer Survivors"},{"nct":"NCT03655223","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Early Check: Expanded Screening in Newborns"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":11628,"output":6999},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(MEN1 OR menin) AND (isogenic OR organoid OR \"cell line\" OR xenograft) AND (palbociclib OR ribociclib OR abemaciclib OR \"CDK4/6\") AND SRC:MED","(\"pancreatic neuroendocrine\" OR parathyroid OR \"pituitary adenoma\") AND (\"single-cell\" OR \"spatial transcriptomics\" OR \"tumour microenvironment\") AND MEN1 AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"evidenceIds":["PMID:40869136","PMID:41307127","PMID:41897316","PMID:41238828","PMID:41214336","PMID:42196524","PMID:42180980","PMID:42122138","PMID:41704185","PMID:41899095","NCT06957691","NCT04969926","NCT06781983","NCT05142189","NCT05250284","NCT06834204","NCT03655223","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787188242106","cycle":190,"visit":3,"ts":"2026-08-20T01:10:42.106Z","cancer":{"key":"hereditary diffuse gastric cancer","name":"hereditary diffuse gastric cancer","mondo":{"id":"MONDO:0007648","name":"hereditary diffuse gastric adenocarcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Redirect the HDGC programme toward interception of methylation-driven CDH1 second hits and WNT-niche dependence in pT1a SRCC, run buffering-based (not fitness-based) synthetic-lethal queries for CDH1/CTNNA1, and treat ITGB6/alphavbeta6 as a dual radiotheranostic-plus-immunosuppression target in poor","confidence":0.44,"notebook":"Fresh pack shifts the programme away from a pure dependency hunt and toward interception biology.\n\nL1 is reframed rather than retired. No DepMap/DepMine answer arrived, but two papers change the design. PMID:40033056 shows that tumour-suppressor loss is commonly buffered by *hyperexpression* of synthetic-lethal partners across >9,000 tumours, and that buffered partners are the more robust hits — so the correct first query is not \"what is essential in CDH1-mutant lines\" but \"which genes are transcriptomically hyperexpressed in CDH1/CTNNA1-null DGC and LBC and appear as SL partners in screens\" [INFERRED]. PMID:41218116 supplies the countervailing warning: in engineered colorectal organoids CTNNA1 is a *metastasis-specific* suppressor whose loss promotes invasion/migration with no primary-tumour fitness advantage. If adherens-junction loss is phenotypically an invasion, not a proliferation, event, fitness-based CRISPR screens are structurally blind to it — which plausibly explains two visits of null results. Confidence held at 0.35 with a hard kill criterion and a shift of readout to invasion/orthotopic screens.\n\nTwo new leads. PMID:40485214 states the dominant CDH1 second hit is promoter methylation, with LOH and somatic mutation secondary, and explicitly nominates epigenetic drugs to restore CDH1 function. Combined with PMID:39379994 — lifetime advanced-DGC risk revised down to 13–19%, a third of carriers decline prophylactic gastrectomy, yet nearly every specimen harbours pT1a SRC foci — this defines a real interception niche: reversible, methylation-driven silencing in indolent intramucosal lesions in patients who will not be operated. New L6. The therapeutic-window problem is severe (systemic hypomethylating agents in otherwise healthy carriers) and the gating datum is the fraction of second hits that are methylation (reversible) versus LOH/truncation (irreversible).\n\nPMID:41398956 gives a CDH1/TP53 gastric organoid system and shows fibroblast WNT2B sustains normal epithelium while KRAS-MAPK opens SMAD2/3 enhancers at WNT7B to buy niche independence. The abstract does not report whether CDH1/TP53 organoids without KRAS remain WNT-dependent; if they do, Porcupine inhibition or WNT2B/FZD blockade becomes a niche-directed interception option for pT1a SRCC (new L7, explicitly conditional on that ambiguity; PORCN-inhibitor bone toxicity is [KNOWN]).\n\nL5 strengthens. PMID:42484012 makes ITGB6 functional in gastric cancer — STC1 binds ITGB6, driving PI3K/AKT and JAK2/STAT3/IL-10-dependent M2 polarisation — so αvβ6 is both a surface handle and an immunosuppression node, cross-linking to L3. PMID:42194054 gives the first quantitative αvβ6 radiotheranostic prevalence in any carcinoma (43.8% moderate/strong, 25% strong, marked heterogeneity) — feasibility plus a patient-selection caveat. Still no gastric/SRCC prevalence. L3 unchanged this visit; STC1/M2 is GC-generic, not SRCC-specific, and does not touch TLS maturation.","leadChanges":[{"id":"L1","title":"Spindle-orientation dependency as synthetic lethal partner of adherens-junction loss in CDH1/CTNNA1-null gastric epithelium","level":"LEAD","status":"STRENGTHENED","confidence":0.35},{"id":"L5","title":"Integrin alphavbeta6 as a histopathology-selectable radiotheranostic target in poorly cohesive/signet-ring and HDGC-derived gastric cancer","level":"LEAD","status":"STRENGTHENED","confidence":0.45},{"id":"L6","title":"Epigenetic reactivation of the methylation-silenced wild-type CDH1 allele as interception in pT1a SRCC in carriers declining gastrectomy","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L7","title":"WNT-niche dependence of CDH1-null early gastric lesions as a Porcupine/WNT2B-directed interception target","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Applying the PMID:40033056 buffering framework, which druggable genes are hyperexpressed in CDH1-null/E-cadherin-low DGC and lobular breast and also score as synthetic-lethal partners, and do CDH1- and CTNNA1-null genotypes converge on any ","What fraction of HDGC second hits (and specifically of pT1a SRCC foci) are reversible promoter methylation with an intact retained allele, versus LOH or truncating somatic mutation?","Do CDH1-KO or CDH1/TP53 gastric organoids without KRAS activation remain WNT-niche dependent and Porcupine-inhibitor sensitive, or is diffuse gastric cancer WNT-independent?","What is the membranous alphavbeta6/ITGB6 prevalence and heterogeneity in HDGC prophylactic-gastrectomy pT1a SRCC and advanced poorly cohesive gastric cancer, and is ITGB6 induced by CDH1 or CTNNA1 loss in isogenic epithelium?","Does the STC1-ITGB6-PI3K/AKT-JAK2/STAT3/IL-10 axis operate in diffuse/signet-ring histology, and would ITGB6 blockade reduce M2 polarisation enough to matter for the L3 immunotherapy combination?","Does CTNNA1 loss, like CDH1 loss, act mainly as an invasion/metastasis event with no fitness cost, meaning viability-based dependency screens should be abandoned in favour of invasion and orthotopic readouts?"],"nextQueries":["(CDH1) AND (\"promoter methylation\" OR hypermethylation OR decitabine OR azacitidine OR DNMT) AND (gastric OR \"signet ring\" OR \"lobular breast\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(PORCN OR \"porcupine inhibitor\" OR WNT2B OR WNT7B OR RNF43) AND (gastric AND (organoid OR \"diffuse\" OR \"signet ring\")) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"E-cadherin\" OR CDH1) AND (\"synthetic lethal\" OR \"transcriptomic buffering\" OR \"collateral vulnerability\") AND (\"lobular breast\" OR \"diffuse gastric\" OR ROS1 OR \"synthetic lethality screen\") AND SRC:MED AND PUB_YEAR:[20"],"papersShown":[{"pmid":"40033056","doi":"10.1038/s41588-025-02108-2","year":2025,"isNew":true,"title":"The transcriptomic architecture of common cancers reflects synthetic lethal interactions"},{"pmid":"40485214","doi":"10.1093/hmg/ddaf092","year":2025,"isNew":true,"title":"Second-hit CDH1 gene mechanisms in hereditary diffuse gastric and lobular breast cancer syndrome: frequency and impact on tumorigenesis"},{"pmid":"39379994","doi":"10.1186/s13053-024-00293-5","year":2024,"isNew":true,"title":"Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review"},{"pmid":"41218116","doi":"10.1073/pnas.2510910122","year":2025,"isNew":true,"title":"Forward genetic screening in engineered colorectal cancer organoids identifies regulators of metastasis"},{"pmid":"41398956","doi":"10.1186/s12943-025-02543-z","year":2025,"isNew":true,"title":"Epithelial WNT secretion drives niche escape of developing gastric cancer"},{"pmid":"42214175","doi":"10.1016/j.tranon.2026.102835","year":2026,"isNew":true,"title":"Current opinions on CEA in the diagnosis and prognosis of colorectal cancer"},{"pmid":"42484012","doi":"10.1097/cm9.0000000000004221","year":2026,"isNew":true,"title":"Stanniocalcin 1 promotes gastric cancer progression by activating the PI3K/AKT pathway and inducing M2 macrophage polarization via the JAK2/STAT3/lL-10 axis"},{"pmid":"41952664","doi":"10.1042/bsr20260010","year":2026,"isNew":true,"title":"Tubulogenesis of bovine uterine glands by epidermal growth factor and collagen I in 3D culture systems"},{"pmid":"42194054","doi":"10.3390/biom16050706","year":2026,"isNew":true,"title":"Immunohistochemical Evaluation of Integrin β6 Expression in Triple-Negative Breast Cancer as a Predictive Biomarker for Therapeutic and Diagnostic Radionuclides"},{"pmid":"42188050","doi":"10.3390/metabo16050341","year":2026,"isNew":true,"title":"The Impact of Maternal Obesity and Diabetes on the Development of Congenital Heart Defects (CHDs) in Offspring: A Narrative Review"}],"trialsShown":[{"nct":"NCT05126290","phase":"n/a","status":"RECRUITING","isNew":false,"title":"CTNNA1 Familial Expansion Study"},{"nct":"NCT06726642","phase":"n/a","status":"RECRUITING","isNew":false,"title":"CfDNA in Hereditary And High-risk Malignancies 2"}],"usage":{"input":11158,"output":9077},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"integrin alphavbeta6\" OR ITGB6) AND (gastric OR \"signet ring\" OR \"poorly cohesive\" OR \"diffuse gastric\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(CDH1 OR CTNNA1) AND (DepMap OR \"gene dependency\" OR \"CRISPR screen\" OR \"synthetic lethal\") AND (gastric OR \"lobular breast\" OR organoid) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"evidenceIds":["PMID:40033056","PMID:40485214","PMID:39379994","PMID:41218116","PMID:41398956","PMID:42214175","PMID:42484012","PMID:41952664","PMID:42194054","PMID:42188050","NCT05126290","NCT06726642"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787188005591","cycle":189,"visit":3,"ts":"2026-08-20T01:06:45.591Z","cancer":{"key":"hereditary breast and ovarian cancer syndrome","name":"hereditary breast and ovarian cancer syndrome","mondo":{"id":"MONDO:0003582","name":"hereditary breast ovarian cancer syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Visit 3 returned no evidence-bearing literature, so nothing was promoted; L2 (circulating BRCAness classifiers) and L5 (ctDNA resistance triage) are weakened against their own unmet pre-registered conditions and both face retirement next visit unless independent validation or primary reversion-surve","confidence":0.44,"notebook":"Null-evidence visit. Both fielded queries returned zero papers; the trial slate is entirely registries, cascade-testing and decision-support infrastructure (T1 NCT02302742, T2 NCT03246841, T4 NCT04494945, T5 NCT06914726, T6 NCT02012699, T7 NCT03050268, T8 NCT04009148) plus the already-cited prevention-surgery study NCT02760849. No mechanism, no pharmacodynamics, no zygosity-stratified response data. Under the standard this desk already applied when retiring the founder-allele lead, infrastructural listings do not move mechanistic confidence, so nothing is promoted and NCT03246841 (tumour spectrum by germline genotype) is noted only as the plausible future instrument for the MINAS per-lesion question in L3 rather than as corroboration of it.\n\nTwo consequences follow from the failure, not from new data. L2's pre-registered kill criterion was strict independent-cohort revalidation of the plasma-metabolome and serum-miRNA BRCAness classifiers; that has now gone unaddressed across two consecutive evidence-bearing opportunities while the original AUC 0.98 remains suspect for leakage (PMID:41620477), and the miRNA model remains single-cohort (PMID:41876608). Weakened to 0.25 with an explicit terminal condition: retire next visit absent a held-out external validation cohort or a mechanistic metabolite identification. L5 was created with the stated condition that primary ctDNA reversion-surveillance cohorts appear; only reviews still support it (PMID:40442774, PMID:41772736, PMID:41900841), so it is weakened to 0.32 and likewise placed on notice — a resistance-taxonomy review stack cannot be allowed to accumulate confidence by repetition.\n\nL1 stays CANDIDATE at 0.72 unchanged: the biallelic gate from NCT03601923 (PMID:41686836) plus the PALB2-isolating cohort remain the strongest holdings, and the desk still has no per-gene ATM/CHEK2 breakdown to convert the inferred ATM-failure claim into evidence. L6 is unchanged; its next test is preclinical benchmarking, which literature searching this visit could not have supplied. The concurrent carboplatin+PARPi negative (PMID:41520277) stands as a permanent do-not-repropose.\n\nMethodological correction for next visit: the two queries were over-conjoined (six genes AND zygosity AND four drug names AND outcome terms), which is why they returned nothing rather than because the literature is silent. Next queries decompose the conjunctions and drop outcome-term filters.\n\nWhat I need: zygosity-stratified PARPi outcomes by gene; any first prospective ATR/WEE1 readout in ATM/CHEK2-altered breast/ovarian disease; primary reversion-allele lead-time data; and analytical validation of RAD51-foci IF as a treatment gate.","leadChanges":[{"id":"L2","title":"Circulating BRCAness signatures (metabolome + miRNA) to enrich and time interception in HBOC carriers","level":"LEAD","status":"WEAKENED","confidence":0.25},{"id":"L5","title":"Longitudinal ctDNA resistance-mechanism triage on PARPi: reversion vs trapping loss vs efflux vs fork protection","level":"LEAD","status":"WEAKENED","confidence":0.32}],"unverifiedCitations":0,"openQuestions":["Per-gene, zygosity-stratified PARPi ORR/PFS for PALB2, RAD51C, RAD51D, BARD1, ATM, CHEK2 in breast/ovarian cancer - does the biallelic-only benefit from NCT03601923 (PMID:41686836) replicate outside pancreatic cancer?","Any prospective ATR (ceralasertib/camonsertib) or WEE1 readout specifically in ATM- or CHEK2-altered breast/ovarian disease, and does ATM loss-of-function protein status outperform genotype as the selector?","Is there primary (non-review) data on lead time from ctDNA reversion/PARP1/PARG/ABCB1 detection to radiographic progression, and any mechanism-matched switch cohort?","Has RAD51-foci immunofluorescence in geminin+ cycling cells been analytically validated (CV, cutoff, concordance with resolved biallelic status and HRD scar) for treatment gating in non-BRCA genes?","Do POLQ, USP1 or ATR inhibitor combinations with PARPi have 2024-2026 clinical readouts in HRD or PARPi-resistant disease, and does replicative gap load outperform HRD scar as the predictor?","Does either circulating BRCAness classifier survive external held-out validation - if not, retire L2."],"nextQueries":["(PALB2 OR RAD51C OR RAD51D OR BARD1) AND (biallelic OR \"loss of heterozygosity\") AND (olaparib OR niraparib OR talazoparib OR rucaparib)","(ceralasertib OR camonsertib OR adavosertib OR \"ATR inhibitor\") AND (ATM OR CHEK2) AND (breast OR ovarian)","(\"reversion mutation\" OR \"reversion allele\") AND (ctDNA OR \"circulating tumor DNA\") AND (BRCA1 OR BRCA2 OR PALB2)"],"papersShown":[],"trialsShown":[{"nct":"NCT02302742","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry"},{"nct":"NCT03246841","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes."},{"nct":"NCT02760849","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations"},{"nct":"NCT04494945","phase":"NA","status":"RECRUITING","isNew":false,"title":"Identifying and Caring for Individuals With Inherited Cancer Syndrome"},{"nct":"NCT06914726","phase":"NA","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Patient Centered Clinical Decision Support for Hereditary Cancer Syndromes"},{"nct":"NCT02012699","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Integrated Cancer Repository for Cancer Research"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT04009148","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Cascade Testing in Families With Newly Diagnosed Hereditary Breast and Ovarian Cancer Syndrome"}],"usage":{"input":6980,"output":4323},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(PALB2 OR RAD51C OR RAD51D OR BARD1 OR ATM OR CHEK2) AND (biallelic OR zygosity OR \"loss of heterozygosity\") AND (\"PARP inhibitor\" OR olaparib OR niraparib OR talazoparib OR rucaparib) AND (\"response rate\" OR \"progressio","(\"ATR inhibitor\" OR ceralasertib OR camonsertib OR \"WEE1 inhibitor\" OR adavosertib OR \"POLQ\" OR \"polymerase theta\" OR \"USP1 inhibitor\") AND (ATM OR CHEK2 OR BRCA1 OR BRCA2) AND (\"clinical trial\" OR \"phase I\" OR \"phase II"],"evidenceIds":["NCT02302742","NCT03246841","NCT02760849","NCT04494945","NCT06914726","NCT02012699","NCT03050268","NCT04009148"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787187824597","cycle":188,"visit":3,"ts":"2026-08-20T01:03:44.597Z","cancer":{"key":"familial adenomatous polyposis","name":"familial adenomatous polyposis","mondo":{"id":"MONDO:0021055","name":"classic familial adenomatous polyposis"}},"control":false,"modelLabel":"SCIENCE","summary":"Re-specify the FAP desmoid lead to progression-documented/anatomically at-risk disease (ALTITUDES active-surveillance outcomes were non-inferior), and prosecute the Wnt->JAG1->ADAM17 axis as the shared node linking REC-4881 MEK inhibition to gamma-secretase inhibition in APC-null epithelium.","confidence":0.45,"notebook":"Visit 3 delivered no new interventional data on any FAP prevention agent — eRapa (NCT06950385), REC-4881 (NCT05552755), ONC201 (NCT05630794) and FOG-001 (NCT05919264) all re-appear as recruiting with no readouts. L1/L4 therefore stand unchanged; L2 enters its third consecutive registry-only visit with no human PD or crypt/bone safety signal and is weakened again on priority (target validity untouched).\n\nThe substantive changes are on the desmoid/Notch axis. ALTITUDES (PMID:42173035) reports that one third of intra-abdominal desmoid-type fibromatosis was managed with active surveillance and had event-free survival comparable to other locations — direct pressure against L5's core claim that *earlier* systemic initiation lowers obstruction/transplant events. That cohort was not APC-restricted, so it does not refute the FAP subset, but it does mean the hypothesis must be re-specified to documented progression or anatomically at-risk (mesenteric root, ureteric, pedicle) disease rather than incident desmoid. Two case reports (PMID:41948661, PMID:42253693) reinforce that mechanical catastrophe is a real but sporadic-dominant event. Counterweight: the IPAA-vs-IRA meta-analysis (PMID:42594997, 34 studies/4,700 patients) shows IPAA cuts rectal/pouch-anal cancer (RR 0.22) at the cost of higher desmoid incidence (RR 1.58) plus incontinence and stricture — i.e. the operation that best protects against cancer manufactures the desmoid problem, which is the strongest argument yet that pharmacological desmoid control has programme-level value. L5 net: weakened but sharpened, stays CANDIDATE.\n\nL6 gains feasibility and mechanism. PMID:40506115 documents an actual FAP patient post-proctocolectomy with IPAA receiving gamma-secretase inhibitor therapy for a mesenteric desmoid — precisely the observational cohort L6 proposes; NCT07726771 (ENDOPOL) supplies the pouch-surveillance/chromoendoscopy infrastructure to score it. PMID:41294868 supplies the missing node logic: JAG1 is itself a β-catenin/TCF target and is additionally cleaved by KRAS/ERK/ADAM17 to a nuclear Jag1-ICD driving CSL-independent reverse signalling. Two consequences. (i) Predicted GSI escape in APC-null epithelium is Jag1-ICD reverse signalling, which gamma-secretase blockade should not abolish [INFERRED]. (ii) MEK1/2 inhibition should collapse the ADAM17-dependent arm, giving L3 a mechanistic, non-redundant rationale and a new correlative readout (adenoma ADAM17, JAG1-ICD nuclear stain alongside pERK) plus a rational MEKi+GSI combination hypothesis [SPECULATIVE].\n\nNew from the porcine FAP model (PMID:42516388): TP53 loss did not change polyp burden but reduced polyp-crypt Ki67 and stromal IBA1+ macrophages with lower CCL2/C1q — implying a complement/monocyte programme is engaged in *early* APC-mutant polyps and is proliferation-supporting. Opens a low-confidence myeloid chemoprevention lead.","leadChanges":[{"id":"L5","title":"FAP-associated intra-abdominal desmoid: pharmacological control to displace multivisceral/intestinal transplantation","level":"CANDIDATE","status":"WEAKENED","confidence":0.5},{"id":"L6","title":"Nirogacestat repurposed for duodenal/colorectal adenoma burden in FAP via Notch-blockade-induced secretory differentiation","level":"LEAD","status":"STRENGTHENED","confidence":0.4},{"id":"L3","title":"MEK1/2 inhibition (REC-4881) in FAP polyposis","level":"LEAD","status":"STRENGTHENED","confidence":0.45},{"id":"L2","title":"Direct beta-catenin:TCF interface blockade (FOG-001) as node-matched therapy for APC-null neoplasia","level":"LEAD","status":"WEAKENED","confidence":0.3},{"id":"L8","title":"C1q/CCL2-dependent macrophage remodelling as a proliferation-supporting stromal programme in early APC-mutant polyps","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Within FAP-restricted intra-abdominal desmoid, does an active-surveillance-first strategy (as supported by ALTITUDES, PMID:42173035) yield equivalent obstruction-free survival and transplant-listing rates to immediate nirogacestat, and whic","Does the IPAA-associated 1.58-fold desmoid excess (PMID:42594997) hold within APC-genotype and desmoid-family-history strata, and should anticipated desmoid risk change the IRA-versus-IPAA recommendation given IPAA's 0.22 RR for rectal/pouc","In APC-null adenoma epithelium, is JAG1 cleavage ADAM17/ERK-dependent, and does nuclear Jag1-ICD accumulate as an escape mechanism under gamma-secretase inhibition - i.e. is MEKi+GSI non-redundant in Apc-mutant organoids?","In FAP patients already on nirogacestat for desmoid, what happens to duodenal Spigelman stage and pouch polyp burden, and does crypt IHC show secretory differentiation (MUC2/CHGA up, HES1/OLFM4 down)?","Is the C1q/CCL2-macrophage programme seen in APC1311/+ pigs present in human FAP adenomas, and does its magnitude track adenoma proliferation rather than polyp number?","Does the eRapa duodenal signal replicate in NCT06950385, and does REC-4881 (NCT05552755) show epithelial (adenoma-crypt) pERK suppression with any interim polyp-burden data?"],"nextQueries":["(\"familial adenomatous polyposis\" OR \"germline APC\" OR \"Apc(Min)\") AND (JAG1 OR Jagged1 OR ADAM17 OR \"Notch intracellular domain\" OR nirogacestat) AND SRC:MED AND PUB_YEAR:[2019 TO 2026]","(\"familial adenomatous polyposis\" OR \"Apc(Min)\" OR \"APC-mutant adenoma\") AND (macrophage OR C1q OR CCL2 OR CCR2 OR complement OR \"tumor microenvironment\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"familial adenomatous polyposis\" AND (\"desmoid\" AND (\"active surveillance\" OR \"wait and see\" OR nirogacestat OR sorafenib) )) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42594997","doi":"10.1016/j.gassur.2026.102512","year":2026,"isNew":true,"title":"Comparison of the outcomes of ileal pouch-anal anastomosis and ileorectal anastomosis for patients with familial adenomatous polyposis: A systematic review and meta-analysis"},{"pmid":"42359108","doi":"10.1002/ccr3.73017","year":2026,"isNew":true,"title":"Spindle Cell Fibromatosis of the Breast: A Lesson in Malignancy Mimicry"},{"pmid":"42173035","doi":"10.1016/j.ejso.2026.111903","year":2026,"isNew":true,"title":"Characteristics and outcome of intra-abdominal desmoid-type fibromatosis"},{"pmid":"42253693","doi":"10.1097/rc9.0000000000000533","year":2026,"isNew":true,"title":"Mesenteric desmoid tumor with diagnostic challenge mimicking a malignant small intestinal tumor: a case report"},{"pmid":"42226846","doi":"10.1093/jscr/rjag414","year":2026,"isNew":true,"title":"Diagnostic dilemmas in abdominal wall tumors: surgical implications and use of mesh for primary repair: case series"},{"pmid":"41948661","doi":"10.1016/j.radcr.2026.02.050","year":2026,"isNew":true,"title":"Twist of fate: Acute small-bowel volvulus caused by a giant mesenteric desmoid-type fibromatosis: A case report and literature review"},{"pmid":"42524173","doi":"10.7759/cureus.113498","year":2026,"isNew":true,"title":"Differentiating Sporadic and Familial Adenomatous Polyposis-Associated Congenital Hypertrophy of the Retinal Pigment Epithelium From Congenital Grouped Pigmentation: A Review of Mo"},{"pmid":"42516388","doi":"10.3389/fimmu.2026.1837646","year":2026,"isNew":true,"title":"&lt;i&gt;TP53&lt;/i&gt; loss attenuates C1q-associated macrophage remodeling in early adenomatous polyps in a porcine FAP model"},{"pmid":"40506115","doi":"10.1136/bcr-2025-265189","year":2025,"isNew":true,"title":"Hepatoid carcinoma of the pancreas in a patient with familial adenomatous polyposis"},{"pmid":"41294868","doi":"10.3390/cells14221815","year":2025,"isNew":true,"title":"The Two-Way Role of Jagged1 in Cancer: A Focus on CRC"}],"trialsShown":[{"nct":"NCT05919264","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"FOG-001 in Locally Advanced or Metastatic Solid Tumors"},{"nct":"NCT07726771","phase":"NA","status":"RECRUITING","isNew":false,"title":"Evaluation of the Ileo-anal Pouch in FAP (ENDOPOL)"},{"nct":"NCT02012699","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Integrated Cancer Repository for Cancer Research"},{"nct":"NCT07066046","phase":"NA","status":"RECRUITING","isNew":false,"title":"Artificial Intelligence-assisted Colonoscopy in the Detection and Characterization of Colorectal Lesions"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT05630794","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Testing for Safety and Colorectal Cancer Preventive Effects of ONC201"},{"nct":"NCT05552755","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Evaluate REC-4881 in Participants With Familial Adenomatous Polyposis (FAP)"},{"nct":"NCT06950385","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Phase 3 Trial of eRapa in Patients With Familial Adenomatous Polyposis"}],"usage":{"input":11636,"output":8179},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"desmoid\" AND (\"familial adenomatous polyposis\" OR \"germline APC\")) AND (nirogacestat OR \"gamma-secretase\" OR outcomes OR obstruction OR transplantation) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"Apc(Min)\" OR \"APC-mutant\" OR \"familial adenomatous polyposis\") AND (\"gamma-secretase\" OR Notch OR HES1 OR \"goblet cell\" OR differentiation) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"evidenceIds":["PMID:42594997","PMID:42359108","PMID:42173035","PMID:42253693","PMID:42226846","PMID:41948661","PMID:42524173","PMID:42516388","PMID:40506115","PMID:41294868","NCT05919264","NCT07726771","NCT02012699","NCT07066046","NCT03050268","NCT05630794","NCT05552755","NCT06950385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787187599149","cycle":187,"visit":3,"ts":"2026-08-20T00:59:59.149Z","cancer":{"key":"lynch syndrome","name":"Lynch syndrome","mondo":{"id":"MONDO:0005835","name":"Lynch syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Promote aspirin chemoprevention and MHC-I-independent salvage to CANDIDATE, add a somatic PIK3CA/PTGS2 stratification arm to aspirin, and re-scope immunoprevention around WNT-driven immune exclusion in dMMR adenomas rather than antigen supply alone.","confidence":0.62,"notebook":"CaPP3 gains external corroboration but still no numbers. P5 (PMID:42425128) is a Lancet Gastro Hep commentary whose title asserts low-dose aspirin is effective chemoprevention in Lynch syndrome — independent editorial endorsement of the CaPP3 primary report, but the pack gives title only, so the 100-vs-600 mg non-inferiority margin and per-dose GI-bleed rates remain unverified for a third visit. P6 (PMID:42556070) independently ranks aspirin in Lynch carriers among the strongest evidence base for pharmacological second-primary interception; P8 (PMID:42206489) shows 33 guidelines diverge on chemoprevention despite universal endorsement of colonoscopy, i.e. the translational gap is dosing/eligibility, not principle. P7 (PMID:42357259) adds a stratifier I had not carried: aspirin benefit concentrates in PIK3CA-mutant CRC — PIK3CA is a Monarch [SOMATIC] correlate here, and PGE2→PI3K crosstalk is the plausible link [INFERRED]. L1 accordingly moves to CANDIDATE with a somatic-biomarker arm.\n\nTwo papers hit the escape lead. P4 (PMID:41071311, 84 ICI-treated endometrial cancers — a Lynch-spectrum tissue [KNOWN]) shows MHC-I protein expression, not mutation calling, predicts PFS, and that JAK1 loss is zygosity-dependent: heterozygous loss improved survival, homozygous loss trended worse. So \"JAK1 mutated = ICI-refractory\" is wrong as stated; L5's assay must be MHC-I IHC plus allele-resolved JAK1/B2M/HLA calls. P10 (PMID:42026473) is the first dMMR/Lynch-specific escape datapoint in the programme: in one carrier the recurrent carcinoma achieved CR on PD-1 blockade while a synchronous dMMR ascending-colon adenoma did not, with a CD68-high/CD8-low, B- and NK-poor microenvironment and CTNNB1, NRAS, HLA class II and PTGS2 mutations. Lesion-level, not patient-level, escape — and the resistant compartment is premalignant. L5 → CANDIDATE.\n\nThat same case cuts against my immunoprevention leads. If dMMR adenomas can be immune-excluded via WNT/CTNNB1 rather than B2M-null, antigen supply (L3's logic from PMID:42108525) is not the only bottleneck; L3 weakens and needs an infiltration endpoint, not just ELISPOT. It also caps L2: immuno-ablative PD-1 clears the index tumour without sterilising the metachronous field, so watch-and-wait in carriers cannot substitute for colonoscopy. New LEAD: PGE2–EP2/EP4 blockade (aspirin, or EP4 antagonist) as an infiltration-restoring adjunct to FSP vaccination in dMMR adenomas, mechanistically joining L1 and L3 through beta-catenin-driven DC exclusion [SPECULATIVE]. No change to L4 this visit.","leadChanges":[{"id":"L1","title":"Low-dose aspirin (100-300 mg) for chemoprevention of dMMR cancers in germline MMR carriers","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.7},{"id":"L5","title":"MHC-I-independent salvage for ICI-refractory dMMR/MSI-H disease (B2M/JAK-null escape)","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.42},{"id":"L3","title":"Frameshift-peptide neoantigen vaccination for primary/secondary prevention in MMR carriers","level":"CANDIDATE","status":"WEAKENED","confidence":0.45},{"id":"L2","title":"Genotype-agnostic neoadjuvant / immuno-ablative PD-1 blockade as an organ-sparing strategy in Lynch-associated MSI-H tumours","level":"CANDIDATE","status":"WEAKENED","confidence":0.72},{"id":"L6","title":"PGE2-EP2/EP4 blockade as an infiltration-restoring adjunct to immunoprevention in dMMR adenomas","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["From the CaPP3 primary publication: per-dose incidence of new dMMR cancers, the pre-specified non-inferiority margin, and GI-bleed rates at 100/300/600 mg, with MMR-gene and BMI interaction tests.","Is aspirin chemoprevention benefit in Lynch carriers modified by somatic PIK3CA or PTGS2 status of incident lesions, or is the PIK3CA signal confined to sporadic CRC?","What is the prevalence of protein-level MHC-I loss versus allele-resolved B2M/JAK1/JAK2 truncation and HLA LOH in Lynch-associated versus sporadic MSI-H tumours, before and after ICI exposure, and does JAK1 zygosity behave as in endometrial","How often do synchronous or metachronous dMMR adenomas fail to regress in patients achieving complete tumour response to PD-1 blockade, and are non-regressing lesions characterised by WNT/CTNNB1 activation and myeloid dominance rather than ","Beyond 3 years, what are local regrowth and metachronous-cancer rates under watch-and-wait specifically in germline carriers, and does ctDNA/stool testing (NCT05410977) precede endoscopic detection?","Is there primary literature that tumour TGFBR2 A10 frameshift status predicts benefit from TGF-beta-pathway-edited effector cells in MSI-H disease?"],"nextQueries":["(\"Lynch syndrome\" OR \"mismatch repair\") AND aspirin AND (CAPP3 OR \"dose\") AND (incidence OR \"non-inferiority\" OR bleeding) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","(dMMR OR \"MSI-H\") AND (adenoma OR \"precancerous\" OR crypt) AND (CTNNB1 OR \"beta-catenin\" OR \"EP4\" OR PTGS2) AND (\"immune evasion\" OR \"T cell exclusion\" OR infiltration) AND SRC:MED","(\"Lynch syndrome\" OR \"MSI-H\") AND (\"frameshift peptide\" OR Nous-209 OR \"neoantigen vaccine\") AND (immunogenicity OR ELISPOT OR \"phase 1\" OR prevention) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"41715188","doi":"10.1186/s12935-026-04177-7","year":2026,"isNew":true,"title":"Advances in immunotherapy for colorectal cancer: overcoming resistance in mismatch repair-proficient tumors"},{"pmid":"42192865","doi":"10.3390/cancers18101504","year":2026,"isNew":true,"title":"Multi Omics Integration in Colorectal Cancer: From Molecular Insights to Precision Oncology"},{"pmid":"42200009","doi":"10.3389/fonc.2026.1830436","year":2026,"isNew":true,"title":"Immune microenvironment evolution across the serrated neoplasia pathway and its relevance to immunotherapy"},{"pmid":"41071311","doi":"10.1158/1078-0432.ccr-25-1442","year":2025,"isNew":true,"title":"The Impact of JAK1 Pathogenic Variants and MHC-I Expression on Response to Immune Checkpoint Inhibition in Endometrial Cancer"},{"pmid":"42425128","doi":"10.1016/s2468-1253(26)00124-x","year":2026,"isNew":true,"title":"Low-dose aspirin: effective cancer chemoprevention in Lynch syndrome"},{"pmid":"42556070","doi":"10.1016/j.ctrv.2026.103200","year":2026,"isNew":true,"title":"Pharmacological prevention of second primary cancers: From chemoprevention to precision cancer interception"},{"pmid":"42357259","doi":"10.3390/pharmaceutics18060643","year":2026,"isNew":true,"title":"The Effect of Anti-Inflammatory Drugs on the Incidence of Colorectal Cancer"},{"pmid":"42206489","doi":"10.1016/j.gim.2026.102610","year":2026,"isNew":true,"title":"Cancer surveillance in Lynch syndrome: A scoping review of international and national guidelines"},{"pmid":"42192876","doi":"10.3390/cancers18101515","year":2026,"isNew":true,"title":"Risk Factors in Sporadic Early-Onset Colorectal Cancer, Current Evidence and Emerging Insights: A Systematic Review"},{"pmid":"42026473","doi":"10.1186/s12876-026-04816-3","year":2026,"isNew":true,"title":"Immune checkpoint inhibitor resistance in dMMR high-grade intraepithelial neoplasia with lynch syndrome-associated colon cancer: a case report"}],"trialsShown":[{"nct":"NCT05410977","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Collecting Blood and Stool Samples to Detect Colorectal Cancer or Advanced Neoplasia in Lynch Syndrome Patients"},{"nct":"NCT03805919","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Men at High Genetic Risk for Prostate Cancer"},{"nct":"NCT02978625","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers"},{"nct":"NCT02912559","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair"},{"nct":"NCT07411599","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Dual Administration Of Intraperitoneal And Intravenous TROP2-Directed CAR-NK With TGF-Beta Receptor 2 (TGFBR2) Knock Out (KO) Therapy For Co"},{"nct":"NCT07106359","phase":"NA","status":"RECRUITING","isNew":false,"title":"Initial Testing of a Behavioral Intervention About Genetic Services for Families at Risk of Lynch Syndrome"},{"nct":"NCT02359565","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas,"},{"nct":"NCT04494945","phase":"NA","status":"RECRUITING","isNew":false,"title":"Identifying and Caring for Individuals With Inherited Cancer Syndrome"}],"usage":{"input":11927,"output":7967},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"Lynch syndrome\" OR \"mismatch repair\") AND aspirin AND (CAPP3 OR chemoprevention OR dose) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"MSI-H\" OR dMMR) AND (B2M OR \"beta-2 microglobulin\" OR JAK1 OR \"HLA loss of heterozygosity\") AND (resistance OR escape OR \"checkpoint\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41715188","PMID:42192865","PMID:42200009","PMID:41071311","PMID:42425128","PMID:42556070","PMID:42357259","PMID:42206489","PMID:42192876","PMID:42026473","NCT05410977","NCT03805919","NCT02978625","NCT02912559","NCT07411599","NCT07106359","NCT02359565","NCT04494945"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787187379585","cycle":186,"visit":3,"ts":"2026-08-20T00:56:19.585Z","cancer":{"key":"li-fraumeni syndrome","name":"Li-Fraumeni syndrome","mondo":{"id":"MONDO:0018875","name":"Li-Fraumeni syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"In germline-TP53 breast cancer, HER2 positivity (~50%) and stable-missense p53 IHC (67%) are now confirmed in a second large cohort, making HER2-directed therapy the lead actionable node; FH-deficient uterine smooth muscle tumours are reproducible in LFS, and a subset of 'missense' germline alleles ","confidence":0.55,"notebook":"This visit's pack is mostly clinical-pathological and it moves two leads decisively.\n\nL1 gets its independent corroboration. An 82-patient/100-tumour germline-TP53 breast cohort reports ~50% HER2 positivity, half of those ER co-expressing, and — importantly — no correlation between germline variant type and histology, except that p.R337H carriers presented later (46 vs 35 y) and were uniquely HER2-negative (PMID:39629784). That is a second, larger series concordant with the biallelic-loss/HER2-addiction picture from PMID:42168203, so L1 → CANDIDATE. It also partly answers open question 2: high p53 IHC (>50% nuclei) in 67% of tumours tested, mostly missense carriers, with null pattern in the remainder — i.e. a stable-missense majority that is nominally reactivator/degrader-eligible, though IHC pattern is a surrogate and still needs allele-level pairing (77% missense germline; hotspots 175/181/245/248/273/334/337) [INFERRED]. Those hotspot frequencies define the isogenic panel for L3, which I bump modestly.\n\nL5 gains a second, independent LFS case: a germline-TP53 patient with EGFR-mutant NSCLC and a large FH-deficient uterine fibroid (PMID:42328258), following the three FH-null lesions of PMID:42312930. Two independent reports of FH loss in LFS uterine smooth muscle tumours make this more than a one-series artefact → CANDIDATE. Germline-vs-somatic origin remains unresolved in both abstracts. Supporting infrastructure: FH IHC is already routine in smooth-muscle-tumour workup to exclude HLRCC (PMID:42466435); the pseudohypoxia arm now has a current inventory of HIF-suppressing strategies converging on mTOR/eIF2α translation control (PMID:42202639); ferroptosis induction via system-xc−/GPX4 is being actively mapped in uterine/endometrial disease (PMID:42318797); and oncometabolite-driven gliomagenesis from FH and SDH deficiency (PMID:41637165) argues for extending FH/SDH/2SC IHC to LFS CNS tumours.\n\nL6 is upgraded, not on drug data but on variant-class prevalence: TP53 c.671A>C, predicted p.E224A, is wild-type-like in yeast/human functional assays yet skips exon 6 in minigene, giving frameshift/PTC (PMID:42463867). Two independent splice-class germline alleles now exist (with PMID:42283896), and a fraction of \"missense\" LFS alleles are really splicing lesions — which reactivators and degraders cannot address, and which mis-assigns IHC-based reactivator eligibility.\n\nNew L7: chemotherapy-sparing, genotype-directed backbone. A five-patient LFS series reports limited chemotherapy benefit with concern for treatment-induced second tumours, and unexpected ICI efficacy in PD-L1-high disease (PMID:41498535); osimertinib gave durable control with preserved ovarian reserve over 36 months (PMID:42328258). Both are anecdotal-grade; the value is a testable claim that immune/targeted killing bypasses the uncoupled p53 apoptotic programme.","leadChanges":[{"id":"L1","title":"ERBB2 amplification as the only recurrent actionable co-driver in germline TP53 breast cancer","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.68},{"id":"L5","title":"FH-deficient, fumarate-driven metabolic vulnerability in germline-TP53 mesenchymal tumours","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.52},{"id":"L6","title":"Splice-switching restoration of hypomorphic germline TP53 splice-region alleles","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.33},{"id":"L7","title":"Chemotherapy-sparing backbone in LFS: oncogene-directed TKIs plus PD-L1-selected checkpoint blockade","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L3","title":"Allele-specific vulnerability of germline TP53 variants: P47S-PIN1 axis and colchicine-site tubulin agents","level":"LEAD","status":"STRENGTHENED","confidence":0.45}],"unverifiedCitations":0,"openQuestions":["Are FH-inactivating events in LFS uterine smooth muscle tumours somatic second hits or co-inherited germline HLRCC alleles — resolvable only by paired tumour/germline FH sequencing across the PMID:42312930 and PMID:42328258 cases and regist","Among germline-TP53 tumours with high p53 IHC (67% in PMID:39629784), what fraction have allele-level-confirmed stable missense protein versus cryptic splice/PTC alleles that IHC misclassifies as reactivator-eligible?","Is p.R337H a genuinely distinct therapeutic subclass (HER2-negative, later onset) requiring a different backbone from canonical hotspot-missense LFS breast cancer?","Do germline-TP53 tumours respond to PD-1/PD-L1 blockade at rates comparable to TP53-wild-type matched controls, or does the uncoupled apoptotic programme blunt T-cell-mediated killing as it appears to for CD19 CAR-T?","What fraction of LFS pedigrees carry splice-class alleles (including functional-assay-normal 'missense' calls) once RNA-level testing is applied to registry VUS?","Does short-amplicon/CIN burden predict PLK1/TTK/MPS1 versus ATR/WEE1 sensitivity better than TP53 status alone in germline-TP53 models — still no LFS-specific drug-sensitivity data?"],"nextQueries":["(\"germline TP53\" OR \"Li-Fraumeni\") AND (\"immune checkpoint\" OR pembrolizumab OR \"PD-L1\" OR \"CAR-T\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(TP53 OR \"p53\") AND (\"splice-switching\" OR \"antisense oligonucleotide\" OR minigene OR \"exon skipping\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"TP53-mutant\" OR \"p53-null\") AND (PLK1 OR MPS1 OR TTK OR KIF18A OR PKMYT1) AND (sarcoma OR osteosarcoma OR leiomyosarcoma OR \"breast\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"39629784","doi":"10.1097/pas.0000000000002338","year":2025,"isNew":true,"title":"Clinicopathologic Features of Breast Tumors in Germline TP53 Variant-Associated Li-Fraumeni Syndrome"},{"pmid":"41498535","doi":"10.1002/mgg3.70177","year":2026,"isNew":true,"title":"Clinical Features and Treatment Strategies of Li-Fraumeni Syndrome Patients With Inherited TP53 Mutations"},{"pmid":"42318797","doi":"10.1080/07853890.2026.2688328","year":2026,"isNew":true,"title":"Research progress of ferroptosis in gynecological diseases"},{"pmid":"42466435","doi":"10.1002/rcr2.70687","year":2026,"isNew":true,"title":"Benign Metastasizing Leiomyoma With Myomatous Erythrocytosis Syndrome: First Reported Coexistence as a Unified Hormonal Syndrome"},{"pmid":"42202639","doi":"10.1016/j.redox.2026.104220","year":2026,"isNew":true,"title":"HIF inhibition: Current strategies and clinical challenges"},{"pmid":"41637165","doi":"10.1093/jnen/nlag004","year":2026,"isNew":true,"title":"Gliomas with succinate dehydrogenase deficiency: A case series and brief review of the literature of oncometabolite-driven gliomagenesis"},{"pmid":"42346101","doi":"10.3390/cells15121074","year":2026,"isNew":true,"title":"Determinants of Colorectal Cancer: An Integrative Immunometabolic Framework Linking Biomarkers, Therapy, and the Diet-Microbiota Axis"},{"pmid":"42328258","doi":"10.7759/cureus.111169","year":2026,"isNew":true,"title":"Normal Ovarian Reserve During Long-Term Osimertinib Therapy in a Patient With Li-Fraumeni Syndrome: A Case Report and Literature Review"},{"pmid":"42304520","doi":"10.1186/s40104-026-01454-3","year":2026,"isNew":true,"title":"Quercetin ameliorates aflatoxin B&lt;sub&gt;1&lt;/sub&gt;-induced non-canonical ferroptosis in ovine oocytes through the OPA1/ACSL4 pathway"},{"pmid":"42463867","doi":"10.1038/s41598-026-62400-x","year":2026,"isNew":true,"title":"Missense but mis-spliced: germline TP53 variant c.671A &gt; C (p.E224A) and the path from uncertainty to pathogenicity"}],"trialsShown":[{"nct":"NCT06888388","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Long-term Safety of Nipple Sparing Mastectomy in Women With High Penetrance Breast Cancer Susceptibility Genes in Breast Cancer"},{"nct":"NCT01143454","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Characterization of Patients With Uncommon Presentations and/or Uncommon Diseases Associated With the Cardiovascular System"},{"nct":"NCT01443468","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Clinical and Genetic Studies of Li-Fraumeni Syndrome"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT03176836","phase":"NA","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Li-Fraumeni Syndrome Imaging Study"},{"nct":"NCT05126810","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Willingness to Participate in a Trial Comparing Standard Genetic Counseling Versus Personalized Genetic Counseling"},{"nct":"NCT04541654","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress"},{"nct":"NCT02950987","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Screening With Whole Body MRI For Detection Of Primary Tumors In Children And Adults With Li-Fraumeni Syndrome (LFS) And Other Cancer Predis"}],"usage":{"input":13248,"output":8609},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"fumarate hydratase\" OR \"FH-deficient\" OR \"HLRCC\") AND (\"TP53\" OR \"Li-Fraumeni\" OR leiomyosarcoma) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"germline TP53\" OR \"Li-Fraumeni\") AND (\"p53 immunohistochemistry\" OR \"missense\" OR \"null pattern\" OR \"allele-specific\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:39629784","PMID:41498535","PMID:42318797","PMID:42466435","PMID:42202639","PMID:41637165","PMID:42346101","PMID:42328258","PMID:42304520","PMID:42463867","NCT06888388","NCT01143454","NCT01443468","NCT03050268","NCT03176836","NCT05126810","NCT04541654","NCT02950987"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787187150900","cycle":185,"visit":3,"ts":"2026-08-20T00:52:30.900Z","cancer":{"key":"systemic mastocytosis","name":"systemic mastocytosis","mondo":{"id":"MONDO:0016586","name":"systemic mastocytosis"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise bone endpoints (BMD, osteosclerosis regression) and dose-attenuated avapritinib plus corticosteroid in cytopenic SM-AHN as near-term testable strategies, while retiring BTK inhibition in mastocytosis for lack of any independent mast cell evidence.","confidence":0.72,"notebook":"No HARBOR (NCT04910685) or Summit (NCT05186753) readout in this pack, so the central peripheral-restriction question in L1 stays open and L1 stays a CANDIDATE — I decline to promote on indirect evidence. What the pack does add to L1 is an organ-level disease-modification endpoint I had not been tracking: a bone review reports avapritinib reversing not only SM osteoporosis but osteosclerosis, with bone disease framed as the dominant morbidity in young men with indolent SM (PMID:41677670). That is exactly the population the peripherally restricted agents target, so BMD/fracture and osteosclerosis regression should be pre-specified alongside VAF, tryptase and the anaphylaxis endpoint. Mechanistically it also supports a separable, repurposing-first axis (new L5): neoplastic MCs drive osteoclastogenesis and suppress osteoblasts (PMID:41677670), so an approved antiresorptive (bisphosphonate/denosumab) layered on a KIT D816V inhibitor is testable now, with the caveat that antiresorptives cannot address osteosclerosis and denosumab rebound is a known failure mode [KNOWN].\n\nL2 gains real clinical texture and one contradiction. Answering my own OQ2: in SM-AHN with tumoral CMML, midostaurin+azacitidine was abandoned for haematologic toxicity, whereas reduced-dose avapritinib (100→50 mg) plus dexamethasone gave platelet recovery, organomegaly regression and falling tryptase (PMID:41458267) — a single case, but it reframes the combination question from HMA-additive to dose-attenuated TKI plus steroid. In KIT-negative mast cell leukaemia with FGFR1 rearrangement, venetoclax-azacitidine failed outright before an FGFR1 inhibitor was used (PMID:42180116): record as a negative for reflexive ven/aza in KIT-negative MC neoplasms and spawn L6 (driver-agnostic sequencing when D816V is absent; MCL remains ~1.5 y median OS on current therapy, PMID:40904938). Contradiction to my strict two-compartment model: in non-D816V SM-AML with RUNX1::RUNX1T1 post-allo-HSCT, avapritinib cleared both the MC fraction (14.06%→0.3%) and the fusion to MRD-negativity (PMID:41473436) — so KIT inhibition is not always confined to the MC compartment. Conversely, AML relapsed five years post-transplant without SM relapse, suggesting MCs evade GVL while the AHN does not (PMID:41624689) — compartment separability is real but bidirectional and immune-context dependent.\n\nL4 (BTK) is retired as pre-committed. The one fresh BTK paper is a CLL/SLL-to-immune-disorders review with no mastocytosis or mast cell degranulation data (PMID:41594662); an MCAS pathophysiology review lists PI3K/AKT/mTOR, RAS-MAPK and JAK-STAT amplification without a BTK node (PMID:42592556). No independent SM signal emerged; the CLL confound stands.\n\nStill unlearned: acquired resistance lesions at progression on avapritinib/bezuclastinib.","leadChanges":[{"id":"L1","title":"D816V-selective, CNS-restricted KIT inhibition to extend targeted therapy into indolent SM","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.86},{"id":"L2","title":"Co-mutant myeloid clone (SRSF2/ASXL1/RUNX1/TET2/CBL) as a KIT-independent compartment in advanced SM and SM-AHN","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.75},{"id":"L4","title":"BTK inhibition as an FcEpsilonRI-axis-directed strategy in mast cell neoplasms, starting with SM plus lymphoid AHN","level":"LEAD","status":"RETIRED","confidence":0.1},{"id":"L5","title":"Mast-cell-driven bone remodelling as a treatable axis: KIT inhibitor plus approved antiresorptive in indolent SM osteopathy","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L6","title":"Driver-agnostic molecular triage of KIT-negative mast cell neoplasms: FGFR1 rearrangement and other kinase fusions","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["In HARBOR (NCT04910685) and Summit (NCT05186753), do elenestinib and bezuclastinib match avapritinib on KIT D816V VAF and tryptase reduction while eliminating the 34% cognitive-effect and 4% intracranial-bleed signals, and do they reproduce","Is dose-attenuated avapritinib plus corticosteroid reproducible as a cytopenia-sparing regimen in thrombocytopenic SM-AHN beyond the single CMML case, and how does its AHN-progression-free survival compare with TKI plus azacitidine?","When KIT inhibition clears an AHN clone (non-D816V SM-AML with RUNX1::RUNX1T1), is that because KIT is the shared founder lesion, and do serial per-mutation VAF/single-cell data show SRSF2/ASXL1/RUNX1/TET2/CBL clones unchanged in D816V dise","What are the documented acquired resistance lesions at progression on avapritinib or bezuclastinib in SM — secondary KIT substitutions, RAS-MAPK reactivation, or BCL2/MCL1 dependence — and is any pharmacologically addressable?","Why do neoplastic mast cells resist graft-versus-leukaemia while the associated AML does not, and does that immune-evasion mechanism (antigen loss, checkpoint ligand expression) suggest a tractable target?","How frequent are non-KIT kinase fusions (FGFR1, PDGFRA/B, JAK2) in KIT D816V-negative SM/mast cell leukaemia, and does fusion-directed therapy outperform ven/aza in that subset?"],"nextQueries":["(\"systemic mastocytosis\") AND (avapritinib OR elenestinib OR bezuclastinib) AND (\"bone mineral density\" OR osteoporosis OR osteosclerosis OR fracture) AND SRC:MED","(\"systemic mastocytosis\" OR \"mast cell leukemia\") AND (\"KIT D816V\" ) AND (\"resistance\" OR \"progression\" OR \"variant allele frequency\" OR \"single-cell\") AND (avapritinib OR bezuclastinib OR midostaurin) AND SRC:MED","(\"mast cell leukemia\" OR \"systemic mastocytosis\") AND (\"FGFR1\" OR \"8p11\" OR \"PDGFRA\" OR \"JAK2\" OR \"fusion\") AND SRC:MED"],"papersShown":[{"pmid":"41594662","doi":"10.3390/biom16010123","year":2026,"isNew":true,"title":"BTK Inhibition in Hematology: From CLL/SLL to Emerging Applications Across B-Cell and Immune Disorders"},{"pmid":"41514619","doi":"10.3390/cancers18010107","year":2025,"isNew":true,"title":"Is There a Future for CAR-T Therapy in Acute Myeloid Leukemia?"},{"pmid":"41677670","doi":"10.3390/cells15030307","year":2026,"isNew":true,"title":"Skeletal Involvement in Systemic Mastocytosis: Pathophysiology, Clinical Management, Standards of Care, and Novel Therapeutic Strategies"},{"pmid":"42180116","doi":"10.3389/fonc.2026.1830652","year":2026,"isNew":true,"title":"Case Report: Experience of a rare case of primary acute mast cell leukemia with FGFR1 gene rearrangement"},{"pmid":"41624689","doi":"10.1155/crh/8965147","year":2026,"isNew":true,"title":"Relapse of Acute Myeloid Leukemia With Concomitant Systemic Mastocytosis Five Years Post Allogenic Hematopoietic Stem Cell Transplantation"},{"pmid":"41458267","doi":"10.1093/omcr/omaf240","year":2025,"isNew":true,"title":"Avapritinib and corticosteroids in advanced systemic mastocytosis with tumoral CMML and associated thrombocytopenia"},{"pmid":"41473436","doi":"10.3389/fonc.2025.1728830","year":2025,"isNew":true,"title":"Avapritinib in the treatment of systemic mastocytosis with associated acute myeloid leukemia after poor graft function following allogeneic hematopoietic stem cell transplantation:"},{"pmid":"40904938","doi":"10.14740/jh2104","year":2025,"isNew":true,"title":"Mast Cell Leukemia: Comprehensive Review of Literature With Current Insights and Updates on Management"},{"pmid":"40722727","doi":"10.3390/biomedicines13071655","year":2025,"isNew":true,"title":"Clinical and Biological Characteristics of Four Patients with Aggressive Systemic Mastocytosis Treated with Midostaurin"},{"pmid":"42592556","doi":"10.26502/fjhs.427","year":2026,"isNew":true,"title":"Pathophysiological Drivers of Mast Cell Activation Syndrome and Implications for Treatment"}],"trialsShown":[{"nct":"NCT00935090","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"3'-Deoxy-3'-[18F] Fluorothymidine PET Imaging in Patients With Cancer"},{"nct":"NCT07264959","phase":"n/a","status":"RECRUITING","isNew":false,"title":"An Observational Study in Participants With Indolent Systemic Mastocytosis (ISM)"},{"nct":"NCT04910685","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis"},{"nct":"NCT04996875","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"(Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis"},{"nct":"NCT03779854","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Naive T Cell Depletion for Preventing Chronic Graft-versus-Host Disease in Children and Young Adults With Blood Cancers Undergoing Donor Ste"},{"nct":"NCT05362773","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of MGD024 in Patients With Relapsed or Refractory Hematologic Malignancies"},{"nct":"NCT01137825","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Registry of Older Patients With Cancer"},{"nct":"NCT05186753","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"(Summit) A Study to Evaluate the Efficacy and Safety of CGT9486 Versus Placebo in Patients With Indolent or Smoldering Systemic Mastocytosis"}],"usage":{"input":11036,"output":8705},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"systemic mastocytosis\" OR \"mast cell leukemia\") AND (avapritinib OR bezuclastinib OR elenestinib OR midostaurin) AND (azacitidine OR decitabine OR venetoclax OR \"hypomethylating\") AND SRC:MED","(\"systemic mastocytosis\" OR \"mast cell\") AND (\"acquired resistance\" OR \"secondary mutation\" OR \"RAS\" OR \"MCL1\" OR \"BCL2\") AND (KIT AND D816V) AND SRC:MED"],"evidenceIds":["PMID:41594662","PMID:41514619","PMID:41677670","PMID:42180116","PMID:41624689","PMID:41458267","PMID:41473436","PMID:40904938","PMID:40722727","PMID:42592556","NCT00935090","NCT07264959","NCT04910685","NCT04996875","NCT03779854","NCT05362773","NCT01137825","NCT05186753"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787186921602","cycle":184,"visit":3,"ts":"2026-08-20T00:48:41.602Z","cancer":{"key":"primary myelofibrosis","name":"primary myelofibrosis","mondo":{"id":"MONDO:0009692","name":"primary myelofibrosis"}},"control":false,"modelLabel":"SCIENCE","summary":"Mutant-CALR-directed T-cell engagers now show durable depletion of disease-initiating mutCALR+ stem cells in vivo (promote to DOSSIER), while pharmacological NLRP3 blockade reverses established marrow fibrosis in JAK2V617F mice and the JAK2V617F-PIM1-HIF-1 axis supplies a tractable metabolic node — ","confidence":0.64,"notebook":"Fresh pack moves three leads and opens two.\n\nL1 → DOSSIER. P4 (PMID:41532194) supplies the primary in vivo result the lead has been missing: a murine surrogate bispecific T-cell engager (DX1-2C11) against the mutCALR C-terminus activates CD4/CD8 T cells within 24 h in CALRdel52 transgenic mice, drops platelets, and — explicitly the gap the authors say prior TCE candidates failed to close — depletes mutant stem/progenitor cells in marrow and spleen with mutant-burden reduction *durable in secondary recipients*, i.e. the disease-initiating cell was hit, not just mature progeny. Two independent 2026 reviews (P1 PMID:40857671, P5 PMID:41798678) and P6 (PMID:42038747) converge on the same target logic: one frameshift, one shared neoantigen, functional and absent from normal proteome, displayed via MPL. The lead has now survived three visits of attempted refutation (fibrotic-marrow potency, low antigen density in blast phase, HSC sparing). Caveats logged: P4 is a non-fibrotic ET-like transgenic, no reticulin/collagen endpoint, and mouse T-cell compartment ≠ inflamed human MF marrow. P7 (PMID:41972741) is filed as a resistance route specifically for the peptide-HLA arms (vaccine/TCR): APM defects at peptide generation/loading and MHC-I integrity would spare the antibody/CAR arms, which target surface protein — an argument to prioritise TCE/CAR over vaccine in advanced disease. P8 (PMID:41898674) is a single case (IL-2 + ATRA, type 1 CALR to undetectable VAF); anecdotal, not evidentiary, but flags NK-directed adjuncts.\n\nL4 jumps from model-organism to mammalian causality. P2 (PMID:41298546) shows haematopoietic Nlrp3 deletion abolishes IL-1β/IL-18 elevation in JAK2V617F MPN and, critically, pharmacological NLRP3 blockade in *established* disease regresses thrombocytosis, splenomegaly and bone marrow fibrosis. This relocates the mechanism: NLRP3 acts cell-intrinsically in mutant HSPCs (not in radioresistant WT niche), which sharpens the window argument. Counterweight from the same pack: P10 (PMID:42000137) finds NLRP3 expression *inversely* associated with thrombosis in MPN (OR 0.58) — expression, not activity, and hypothesis-generating, but a possible vascular hazard of blockade that must be pre-specified.\n\nL6 gains a druggable upstream node. P9 (PMID:41629621) shows JAK2V617F reprograms HIF-1 into a non-canonical, oxygen-desensitised regulon via PIM1 kinase, associated with severity, progression and a blast-phase signature (HIF1-MPN-BP); P10 shows SLC2A1 elevated in PMF with thrombosis. GLUT1 remains pharmacologically hostile; PIM1 is not — new lead L7.\n\nNew L8: ropeginterferon phase 3 in early/low-risk PMF (NCT06468033) is the only randomised test of pre-fibrotic clonal interception in the pack.","leadChanges":[{"id":"L1","title":"Mutant CALR neoepitope-directed immunotherapy in CALR-mutant PMF","level":"DOSSIER","status":"STRENGTHENED","confidence":0.82},{"id":"L4","title":"HO-1/BACH1-NLRP3-IL-1beta axis as anti-fibrotic stromal target","level":"LEAD","status":"STRENGTHENED","confidence":0.58},{"id":"L6","title":"GLUT1/GLUT3 glucose-transport dependency downstream of HIF-1 in JAK2V617F MPN","level":"LEAD","status":"STRENGTHENED","confidence":0.55},{"id":"L7","title":"PIM1 kinase inhibition to collapse the JAK2V617F-HIF-1 regulon","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L8","title":"Ropeginterferon alfa-2b for clonal interception in early / low-risk primary myelofibrosis","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["Does mutCALR TCE/CAR efficacy and stem-cell depletion hold in a fibrosis-competent mammalian MF model with marrow reticulin/collagen grade as the endpoint, and do the two human TCE phase 1 programmes show CALR VAF decline without prolonged ","Is the NLRP3 dependency shown for JAK2V617F fibrosis shared by CALR- and MPL-mutant and triple-negative MF, and which agent (canakinumab/anakinra vs small-molecule NLRP3 inhibitor) is the right first test on top of ruxolitinib?","Does the inverse NLRP3-expression/thrombosis association (P10) predict a real vascular hazard of NLRP3 blockade, and how would a trial monitor it alongside the known infection risk?","Can PIM1 inhibition collapse the JAK2V617F-HIF-1 regulon in vivo and reduce fibrosis grade and VAF, and does the HIF1-MPN-BP signature prospectively identify pre-blast-phase patients for enrichment?","Does SENTRY (NCT04562389) selinexor+ruxolitinib survive its randomised control arm, and does response segregate by TP53 wild-type status?","Does the pelabresib phase 3 (NCT07357727) report fibrosis-grade or VAF change, and at what haemoglobin cost?"],"nextQueries":["(PIM1 OR PIM447 OR TP-3654 OR \"PIM kinase\") AND (myelofibrosis OR \"myeloproliferative\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(NLRP3 OR \"IL-1beta\" OR canakinumab OR anakinra OR dapansutrile) AND (myelofibrosis OR \"myeloproliferative neoplasm\") AND (fibrosis OR trial OR CALR) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"bispecific\" OR \"T cell engager\" OR \"CAR T\" OR \"antibody-drug conjugate\") AND (mutCALR OR \"mutant calreticulin\") AND (\"phase 1\" OR \"first-in-human\" OR \"clinical trial\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"40857671","doi":"10.1182/blood.2025028642","year":2026,"isNew":true,"title":"Novel strategies targeting mutant calreticulin in essential thrombocythemia and myelofibrosis"},{"pmid":"41298546","doi":"10.1038/s41467-025-65673-4","year":2025,"isNew":true,"title":"NLRP3-induced systemic inflammation controls the development of JAK2V617F mutant myeloproliferative neoplasms"},{"pmid":"41791669","doi":"10.1016/j.jtha.2026.02.018","year":2026,"isNew":true,"title":"Engineering bone marrow in a dish-a bloody business: preclinical opportunities, translational use cases, and a call for consensus"},{"pmid":"41532194","doi":"10.1002/ajh.70206","year":2026,"isNew":true,"title":"A Murine Bispecific Antibody Efficiently Redirects T Cells Against Calr Mutated Stem Cells In Vivo"},{"pmid":"41798678","doi":"10.1016/j.bneo.2026.100193","year":2026,"isNew":true,"title":"Mutant calreticulin-directed immunotherapies in myeloproliferative neoplasms"},{"pmid":"42038747","doi":"10.1002/hem3.70368","year":2026,"isNew":true,"title":"Mutant calreticulin-Cancer driver and Achilles' heel for ET?"},{"pmid":"41972741","doi":"10.3390/cells15070653","year":2026,"isNew":true,"title":"Messing with Signal 1: How Perturbed MHC Class I Antigen Presentation Contributes to Cancer"},{"pmid":"41898674","doi":"10.3390/ijms27062814","year":2026,"isNew":true,"title":"Interleukin-2 and Tretinoin for Myeloproliferative Neoplasms and to Target Type 1 Calreticulin-Driven Neoplasms: Advancements in Immune Regenerative Medicine"},{"pmid":"41629621","doi":"10.1038/s41375-025-02843-9","year":2026,"isNew":true,"title":"JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms"},{"pmid":"42000137","doi":"10.1016/j.jtha.2026.04.013","year":2026,"isNew":true,"title":"Dysregulation of HIF-1α-regulated and thromboinflammatory genes may contribute to thrombotic risk in patients with BCR::ABL1-negative myeloproliferative neoplasms"}],"trialsShown":[{"nct":"NCT06661915","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)"},{"nct":"NCT07228624","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Ruxolitinib Before, During and After Hematopoietic Cell Transplant in Older Patients With Myelofibrosis and Myelodysplastic Syndrome/Myelopr"},{"nct":"NCT07357727","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF)"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"},{"nct":"NCT07302776","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"TACrolimus Targeted Immunosuppression Cessation in ALlogeneic HCT"},{"nct":"NCT07443306","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Clinical Trial of Flonoltinib Maleate Tablets in the Treatment of JAK Inhibitor Refractory/Relapsed/Intolerant Patients With Intermediate "},{"nct":"NCT07317700","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Clinical Trial of Flonoltinib Maleate for Intermediate or High-Risk Myelofibrosis"},{"nct":"NCT06468033","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"P1101 in Treating Patients With Early PMF or Overt PMF at Low or Intermediate-1 Risk"}],"usage":{"input":11843,"output":8779},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"mutant calreticulin\" OR mutCALR) AND (\"CAR T\" OR \"chimeric antigen receptor\" OR \"bispecific\" OR vaccine) AND (myelofibrosis OR \"myeloproliferative\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","myelofibrosis AND (GLUT1 OR SLC2A1 OR GLUT3 OR SLC2A3 OR \"HIF-1\" OR glycolysis) AND (JAK2V617F OR \"myeloproliferative\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:40857671","PMID:41298546","PMID:41791669","PMID:41532194","PMID:41798678","PMID:42038747","PMID:41972741","PMID:41898674","PMID:41629621","PMID:42000137","NCT06661915","NCT07228624","NCT07357727","NCT06001385","NCT07302776","NCT07443306","NCT07317700","NCT06468033"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787186690049","cycle":183,"visit":3,"ts":"2026-08-20T00:44:50.049Z","cancer":{"key":"essential thrombocythemia","name":"essential thrombocythemia","mondo":{"id":"MONDO:0005029","name":"essential thrombocythemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Bomedemstat's phase 2 in HU-failure ET shows 77% platelet response plus VAF reduction in 85% of evaluable patients but 21% haemorrhagic events and 47% grade 3/4 AEs, making LSD1 inhibition the leading driver-agnostic clonal-control candidate in ET contingent on a therapeutic-window analysis, while a","confidence":0.68,"notebook":"Bomedemstat is the story of this visit. PMID:41758981 [NEW] is the first ET-specific efficacy dataset for LSD1/KDM1A inhibition: in HU-resistant/intolerant ET, 77% (49/64) met the platelet ≤400×10⁹/L-without-thrombosis endpoint, 72% had durable platelet control, 85% durable WBC control, haemoglobin stable, and — the disease-modification signal the desk asked for — a fall in CALR, JAK2 or MPL VAF in 39/46 (85%) evaluable at 24 weeks. That is driver-agnostic clonal pressure, consistent with the GFI1B/RCOR–LSD1 megakaryocyte-maturation dependency [KNOWN], and it moves L2 to CANDIDATE. The window argument is now the weak point, not the mechanism: grade 3/4 AEs in 47% and ≥1 haemorrhagic event in 21% by week 24 in a disease with near-normal life expectancy. The abstract does not resolve whether bleeding tracks platelet nadir, dysfunctional LSD1-arrested megakaryocytes, or acquired von Willebrand physiology [INFERRED] — this must be answered before any chronic-phase positioning, and confidence stays capped at 0.60 pending MK-3543-006 (NCT06079879), still active-not-recruiting. Note also that magnitude of VAF fall, per-genotype breakdown and HSC-fraction clonality are unreported.\n\nL1 gets an independent third-visit corroboration and moves to DOSSIER. PMID:41532194 [NEW] reports a murine mutCALR×CD3 bispecific (DX1-2C11) that activates CD4/CD8 T cells within 24 h in CALRdel52 transgenics, lowers platelets, depletes mutant stem/progenitor compartments in marrow and spleen, and — critically — the reduction of mutant burden persists in secondary recipients, i.e. stem-cell-level clonal depletion, not just mature-cell debulking. The same paper is an honest partial rebuke: it states that the two clinical TCE candidates advanced to phase 1 did not show mutCALR⁺ HSC depletion or normalised haematopoiesis preclinically. So the modality is stronger while the specific clinical assets (including INCA033989, NCT05936359) remain unproven; PMID:40857671 [NEW] adds the framing that the frameshift neoantigen is functional, MPL-presented and absent from normal physiology, plus ADC as a fourth format. DOSSIER is earned on mechanism and format breadth, not on human efficacy, which is still zero.\n\nL4 (MDM2) gains only narrative-review mention in PV (PMID:41144126) — a nudge, not corroboration. L3 gains nothing ET-specific; the CALR/MPL molecular-response gap stands, and bomedemstat has now overtaken ropeg on ET-specific allele-burden evidence. L5 unchanged. Nothing in the pack rescues ruxolitinib in ET; Ruxo-BEAT (NCT02577926) remains unreported.","leadChanges":[{"id":"L1","title":"Mutant-CALR neoepitope-directed immunotherapy in CALR-mutant ET","level":"DOSSIER","status":"STRENGTHENED","confidence":0.76},{"id":"L2","title":"LSD1/KDM1A inhibition to dismantle the megakaryocytic dependency in ET","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.6},{"id":"L4","title":"MDM2 inhibition to reactivate wild-type p53 in chronic-phase MPN","level":"LEAD","status":"WEAKENED","confidence":0.32}],"unverifiedCitations":0,"openQuestions":["Does the 21% haemorrhage rate on bomedemstat in ET track platelet nadir/overshoot, or does LSD1 inhibition produce functionally defective megakaryocytes or acquired von Willebrand physiology - and can platelet-guided or intermittent dosing ","What is the magnitude, per-driver-genotype distribution (CALR vs JAK2 V617F vs MPL) and HSC-fraction localisation of the bomedemstat VAF reductions, and does MK-3543-006 (NCT06079879) reproduce them against BAT?","Do the clinical mutCALR TCEs (INCA033989, NCT05936359) achieve the stem-cell-level, serially transplantable mutant depletion demonstrated by DX1-2C11, or only mature-cell debulking - and at what CRS/cytopenia cost in chronic-phase ET?","Which escape routes emerge under mutCALR-directed pressure: epitope-negative CALR clones, MPL/TpoR downregulation, or outgrowth of TET2/ASXL1-mutant CALR-wild-type clones?","Is there any ET-specific evidence that any agent delays post-ET myelofibrosis or leukaemic transformation, and does the Ruxo-BEAT (NCT02577926) high-risk ET arm add anything to the negative ruxolitinib-in-ET record?","Does ropeginterferon molecular response in ET differ by driver genotype, and can a dose-intensified schedule match bomedemstat's allele-burden signal without added toxicity?"],"nextQueries":["(bomedemstat OR \"MK-3543\" OR \"IMG-7289\") AND (bleeding OR hemorrhage OR \"von Willebrand\" OR \"platelet function\" OR \"allele frequency\") AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","(INCA033989 OR \"JNJ-88549968\" OR \"mutant calreticulin\") AND (\"phase 1\" OR \"first-in-human\" OR \"clinical trial\" OR \"variant allele frequency\") AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","(ropeginterferon OR \"interferon alfa\") AND \"essential thrombocythemia\" AND (CALR OR MPL OR \"molecular response\" OR \"allele burden\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"40181550","doi":"10.1002/ijc.35389","year":2026,"isNew":true,"title":"Therapeutic targeting of chromatin alterations in leukemia and solid tumors"},{"pmid":"39682299","doi":"10.3390/cancers16234113","year":2024,"isNew":true,"title":"Shaping the Future of Myeloproliferative Neoplasm Therapy: Immune-Based Strategies and Targeted Innovations"},{"pmid":"40857671","doi":"10.1182/blood.2025028642","year":2026,"isNew":true,"title":"Novel strategies targeting mutant calreticulin in essential thrombocythemia and myelofibrosis"},{"pmid":"40107287","doi":"10.1055/a-2561-8818","year":2026,"isNew":true,"title":"Platelet Disorders and Medication Strategies"},{"pmid":"40089451","doi":"10.1016/j.tcb.2025.02.010","year":2025,"isNew":true,"title":"Epigenetic drivers of metalloproteinases and metastasis"},{"pmid":"41532194","doi":"10.1002/ajh.70206","year":2026,"isNew":true,"title":"A Murine Bispecific Antibody Efficiently Redirects T Cells Against Calr Mutated Stem Cells In Vivo"},{"pmid":"41758981","doi":"10.1182/bloodadvances.2025017575","year":2026,"isNew":true,"title":"Phase 2 study of the lysine-specific demethylase 1 inhibitor bomedemstat for essential thrombocythemia"},{"pmid":"42053742","doi":"10.1186/s43556-026-00458-9","year":2026,"isNew":true,"title":"Epigenetic modifications in cancer drug resistance: molecular mechanisms and therapeutic interventions"},{"pmid":"41999414","doi":"10.1007/s00277-026-06970-w","year":2026,"isNew":true,"title":"Modern and multidisciplinary care in polycythemia vera"},{"pmid":"41144126","doi":"10.1007/s12672-025-03703-9","year":2025,"isNew":true,"title":"Advances in polycythemia vera treatment with targeted therapies and clinical trials"}],"trialsShown":[{"nct":"NCT06661915","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)"},{"nct":"NCT07357727","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF)"},{"nct":"NCT02577926","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"The Ruxo-BEAT Trial in Patients With High-risk Polycythemia Vera or High-risk Essential Thrombocythemia"},{"nct":"NCT06079879","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of Bomedemstat (IMG-7289/MK-3543) Compared to Best Available Therapy (BAT) in Participants With Essential Thrombocythemia and an Ina"},{"nct":"NCT05320198","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Study of DISC-0974 (RALLY-MF) in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia"},{"nct":"NCT05936359","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neop"},{"nct":"NCT06361641","phase":"NA","status":"RECRUITING","isNew":false,"title":"Functional and Phenotypic Characterization of Monocytes in Myeloproliferative Syndromes"},{"nct":"NCT00935090","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"3'-Deoxy-3'-[18F] Fluorothymidine PET Imaging in Patients With Cancer"}],"usage":{"input":11078,"output":5630},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(bomedemstat OR \"MK-3543\" OR \"IMG-7289\") AND (\"essential thrombocythemia\" OR thrombocythaemia) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"mutant calreticulin\" OR \"mutCALR\" OR \"CALR exon 9\") AND (\"T cell engager\" OR antibody OR \"CAR T\" OR \"immune escape\" OR \"epitope loss\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:40181550","PMID:39682299","PMID:40857671","PMID:40107287","PMID:40089451","PMID:41532194","PMID:41758981","PMID:42053742","PMID:41999414","PMID:41144126","NCT06661915","NCT07357727","NCT02577926","NCT06079879","NCT05320198","NCT05936359","NCT06361641","NCT00935090"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787186494264","cycle":182,"visit":3,"ts":"2026-08-20T00:41:34.264Z","cancer":{"key":"polycythemia vera","name":"polycythemia vera","mondo":{"id":"MONDO:0009891","name":"acquired polycythemia vera"}},"control":false,"modelLabel":"SCIENCE","summary":"Transplant the POIESIS design (randomised, placebo-controlled, TP53-wild-type-restricted, add-on MDM2 inhibition) from myelofibrosis into hydroxyurea-resistant PV with serial deep TP53 NGS as a pre-specified stopping rule, while treating hematocrit as an unvalidated surrogate under hepcidin-mimetic ","confidence":0.45,"notebook":"This visit's pack is MDM2-heavy and hepcidin-adjacent, and it moves three leads.\n\nMDM2 (L5) gains independent, non-meta-analytic corroboration. A dedicated Leukemia review of MDM2 inhibitors in myeloid neoplasms (PMID:42086932) states the core premise explicitly — p53 retained but functionally suppressed by MDM2 overexpression driven by JAK-STAT activation — and supplies the discipline the lead needs: negative phase III AML experience, hematologic toxicity as the dose-limiting class effect, and TP53-mutant clonal selection as the named resistance mechanism. POIESIS (PMID:41793151, NCT06479135) operationalises this as a randomised, placebo-controlled, TP53-WT-restricted, ruxolitinib-run-in add-on design — a template directly transplantable to hydroxyurea-resistant PV, substituting hematocrit control/phlebotomy independence and event capture for SVR35. Countervailing: PMID:41939253 shows TP53 mutation in MPN is driven toward multihit status by inflammation *and therapy*, which raises rather than lowers the prior that p53-pathway pharmacology could accelerate transformation. So L5 → CANDIDATE, but with mandatory deep-coverage serial TP53 NGS as a stopping rule, not a correlative. PV-specific support is still only review-level (PMID:41144126).\n\nHepcidin (L4): the targeted rusfertide/divesiran/sapablursen-plus-thrombosis query returned no event data — an informative absence. What arrived is healthy-volunteer multiple-dose PK/PD (PMID:39888264): once-weekly 60 mg SC gives mechanism-based falls in serum iron, TSAT, Hb and Hct, injection-site-independent PD, low accumulation, injection-site reactions/fatigue/headache only. That confirms deliverability, not clinical benefit, and leaves open question 1 fully open; hematocrit remains a possibly corrupted surrogate under iron restriction. Held at CANDIDATE, confidence nudged only. Tangentially, high-altitude polycythemia biology (PMID:42028782) shows hepcidin suppression plus sustained HIF drives erythrocytosis EPO-independently — [INFERRED] support that the hepcidin axis is a general erythron throttle, not a PV curiosity.\n\nLSD1 (L2) acquires PV specificity for the first time: two independent reviews name bomedemstat (LSD1) and givinostat (HDAC) as disease-modifying agents positioned to displace phlebotomy in PV (PMID:40872603, PMID:41144126). L2 → CANDIDATE. Givinostat is a distinct chemistry and gets its own lead (L7) rather than being folded in — HDAC1/2/3 inhibition suppresses JAK2 V617F-driven erythroid colony formation [KNOWN], with thrombocytopenia/GI as class ceiling.\n\nBEBT-507's class remains undisclosed across a third pack; L1 unchanged, not re-litigated without evidence.","leadChanges":[{"id":"L5","title":"MDM2 inhibition (p53 reactivation) in TP53-wildtype JAK2 V617F PV","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.45},{"id":"L4","title":"Hepcidin/hemojuvelin axis as a pharmacologic lever on PV erythrocytosis","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.52},{"id":"L2","title":"LSD1/KDM1A inhibition on a hypomethylating backbone to break the MPN stem-cell differentiation block","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.5},{"id":"L7","title":"HDAC inhibition (givinostat) as non-cytotoxic cytoreduction in JAK2 V617F PV","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":1,"openQuestions":["Do rusfertide/divesiran/sapablursen reduce thrombotic EVENTS in PV, or only phlebotomy frequency — and does iron-restricted microcytosis leave residual thrombotic risk at hematocrit <45% (PMID:42381746)?","Is there any registered or planned MDM2-inhibitor trial in PV (as opposed to MF/AML), and what TP53 NGS depth, VAF threshold and monitoring interval should serve as a pre-specified stopping rule given therapy-promoted multihit TP53 evolutio","What do primary bomedemstat and givinostat PV trial reports show for JAK2 VAF, marrow histology and thrombotic events — versus mere count control equivalent to hydroxyurea?","What is BEBT-507's molecular target and class (NCT07012109), still undisclosed across three consecutive packs?","Is JAK2 V617F VAF change a validated surrogate for thrombosis- or fibrosis-free survival, and what standardised dPCR/NGS thresholds should PV trials pre-specify?","Given 87% of thrombotic events occur at or before PV diagnosis and 90% are arterial, is any clone-directed agent testable in the pre-diagnostic window, or is antithrombotic optimisation the only accessible lever?"],"nextQueries":["(\"polycythemia vera\") AND (bomedemstat OR givinostat) AND (\"allele burden\" OR JAK2 OR thrombosis OR phlebotomy) AND SRC:MED","(rusfertide OR divesiran OR sapablursen) AND (\"phase 3\" OR VERIFY OR randomized) AND (thrombosis OR \"adverse events\" OR \"iron deficiency\") AND SRC:MED","(\"myeloproliferative\" OR \"polycythemia vera\") AND (\"TP53\" AND (\"clonal selection\" OR \"multihit\" OR \"clonal evolution\")) AND (navtemadlin OR \"MDM2\") AND SRC:MED"],"papersShown":[{"pmid":"40507313","doi":"10.3390/cancers17111834","year":2025,"isNew":true,"title":"Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms"},{"pmid":"39888264","doi":"10.1002/cpdd.1514","year":2025,"isNew":true,"title":"Multiple-Dose Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Subcutaneous Rusfertide, a Hepcidin Mimetic, in Healthy Subjects"},{"pmid":"40872603","doi":"10.3390/ph18081212","year":2025,"isNew":true,"title":"Old Therapy, New Questions: Rethinking Phlebotomy in a Pharmacologic Landscape"},{"pmid":"41793151","doi":"10.1080/14796694.2026.2638989","year":2026,"isNew":true,"title":"POIESIS: a phase III study of add-on navtemadlin in JAK inhibitor-naïve myelofibrosis patients with a suboptimal response to ruxolitinib"},{"pmid":"42028782","doi":"10.3892/ijmm.2026.5835","year":2026,"isNew":true,"title":"High‑altitude polycythemia: Unveiling the molecular landscape beyond erythropoietin (Review)"},{"pmid":"41999414","doi":"10.1007/s00277-026-06970-w","year":2026,"isNew":true,"title":"Modern and multidisciplinary care in polycythemia vera"},{"pmid":"41144126","doi":"10.1007/s12672-025-03703-9","year":2025,"isNew":true,"title":"Advances in polycythemia vera treatment with targeted therapies and clinical trials"},{"pmid":"41097669","doi":"10.3390/cancers17193142","year":2025,"isNew":true,"title":"Advances in the Diagnosis and Treatment of Myeloproliferative Neoplasms (MPNs)"},{"pmid":"42086932","doi":"10.1038/s41375-026-02975-6","year":2026,"isNew":true,"title":"MDM2 inhibitors in myeloid cancers: from basic biology to clinical use in myeloproliferative neoplasms"},{"pmid":"41939253","doi":"10.1002/hem3.70332","year":2026,"isNew":true,"title":"Unraveling the role of &lt;i&gt;TP53&lt;/i&gt; mutations in myeloproliferative neoplasms: Molecular mechanisms of leukemic transformation"}],"trialsShown":[{"nct":"NCT06661915","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)"},{"nct":"NCT07357727","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF)"},{"nct":"NCT07012109","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Study of BEBT-507 Injection in Subjects With Polycythemia Vera (PV)"},{"nct":"NCT07232290","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Phase IIa Study of Flonoltinib Maleate Tablets in the Treatment of Patients With Polycythemia Vera"},{"nct":"NCT02577926","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"The Ruxo-BEAT Trial in Patients With High-risk Polycythemia Vera or High-risk Essential Thrombocythemia"},{"nct":"NCT05320198","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Study of DISC-0974 (RALLY-MF) in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia"},{"nct":"NCT06361641","phase":"NA","status":"RECRUITING","isNew":false,"title":"Functional and Phenotypic Characterization of Monocytes in Myeloproliferative Syndromes"},{"nct":"NCT00935090","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"3'-Deoxy-3'-[18F] Fluorothymidine PET Imaging in Patients With Cancer"}],"usage":{"input":12254,"output":7041},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"polycythemia vera\") AND (rusfertide OR divesiran OR sapablursen) AND (thrombosis OR thromboembolic OR \"red cell mass\" OR viscosity) AND SRC:MED","(\"myeloproliferative\" OR \"polycythemia vera\") AND (idasanutlin OR siremadlin OR \"MDM2 inhibitor\" OR navtemadlin) AND SRC:MED"],"evidenceIds":["PMID:40507313","PMID:39888264","PMID:40872603","PMID:41793151","PMID:42028782","PMID:41999414","PMID:41144126","PMID:41097669","PMID:42086932","PMID:41939253","NCT06661915","NCT07357727","NCT07012109","NCT07232290","NCT02577926","NCT05320198","NCT06361641","NCT00935090"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787186281845","cycle":181,"visit":3,"ts":"2026-08-20T00:38:01.845Z","cancer":{"key":"hodgkin lymphoma","name":"Hodgkin lymphoma","mondo":{"id":"MONDO:0004952","name":"Hodgkins lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Two independent new datasets (primary pediatric HRS transcriptomes with venetoclax sensitivity, PMID:41538304; BV-resistant CD30+ CTCL scRNA showing efflux/endosomal defects and BCL2-driven non-response with BV+BCL2i synergy, PMID:41762706) reframe cHL treatment failure as apoptosis/senescence-progr","confidence":0.6,"notebook":"This visit the pack finally delivered HL-primary biology, and it points somewhere the programme had not been looking: apoptosis resistance rather than antigen presentation. In purified pediatric HRS cells, transcriptomes show disordered multilineage differentiation, upregulated senescence programmes and coordinate downregulation of proapoptotic and mitosis genes — and venetoclax augmented apoptosis in primary HRS cells ex vivo (PMID:41538304). Independently, single-cell analysis of paired biopsies from CD30+ mycosis fungoides shows BV resistance arising from upregulated efflux transporters plus impaired endosomal processing in CD30+ cells, blunted IFNα/γ responses in CD30− cells, and BCL2 upregulation across all tumour cells in non-responsive lesions, with confirmed BV/BCL2-inhibitor synergy (PMID:41762706). Two independent datasets converge on BCL2 as the node that both explains BV failure and is druggable with an approved agent, so I open L6 (CD30 ADC + venetoclax). Mechanistic caveat that must be designed around: PMID:41538304 reports venetoclax-induced apoptosis in HRS cells *and* in HL microenvironment immune cells — in a disease whose cures are T-cell-dependent, that is a therapeutic-window problem, not a bonus [INFERRED]; BCL2 dependence of normal lymphocytes and BCL-xL dependence of platelets bound the dose/schedule [KNOWN]. Senescent-cell antiapoptotic-pathway logic predicts BCL-xL/MCL1 co-dependence in the senescence-high HRS state [SPECULATIVE].\n\nThe same MF dataset materially strengthens L1 and L5. For L1, BV depleting CD30+ tumour-infiltrating Tregs and activating DC/CD8 immunity (PMID:41762706) gives the ADC+PD-1 backbone a second, immune-remodelling rationale beyond payload cytotoxicity, on top of the near-uniform strong CD30 and 9p24.1/PD-L1 phenotype of HRS cells (PMID:42122242); L1 moves to CANDIDATE. For L5, \"impaired endosomal processing\" is now an observed, not merely postulated, resistance route in a CD30+ lymphoma, which is exactly the bottleneck a non-internalizing/extracellularly-cleaved CD30 conjugate bypasses; generic ADC-resistance framing (PMID:41630503, PMID:41090103) supports but does not specify it.\n\nL3 retires. Three consecutive visits without any HL-specific NK, HLA-I-null prevalence or B2M-loss data, against germline evidence pointing to elevated β2M as the risk direction — the missing-self entry criterion is unsupported and I will not re-propose CD30 NK engagers in cHL without prevalence data. L4 weakens: a query explicitly aimed at HL + LAG-3/CIITA/PD-1-refractory returned no HL-specific LAG-3 paper, a informative null; the lead remains pan-tumour extrapolation only.\n\nNext I need HRS-intrinsic BH3 profiling (BCL2/BCL-xL/MCL1 protein, not transcript), serial BV-exposed cHL biopsies scored for ABCB1 versus endocytic machinery, and whether venetoclax spares the CD8/rosette compartment at achievable exposures.","leadChanges":[{"id":"L1","title":"CD30 ADC + PD-1 (± CTLA-4) blockade as chemotherapy-sparing backbone in classical Hodgkin lymphoma","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.72},{"id":"L6","title":"CD30 ADC + BCL2 inhibition to break the senescence/apoptosis-resistant HRS state","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L5","title":"Non-internalizing / extracellularly-cleaved CD30 ADC for CD30-low or endocytosis-impaired relapse after brentuximab vedotin","level":"LEAD","status":"STRENGTHENED","confidence":0.4},{"id":"L4","title":"PD-1/LAG-3 co-blockade for checkpoint-refractory classical Hodgkin lymphoma stratified by MHC class I/II status","level":"LEAD","status":"WEAKENED","confidence":0.34},{"id":"L3","title":"NK-directed targeting of MHC-I-deficient HRS cells (CD30 NK engagers / CAR-NK)","level":"LEAD","status":"RETIRED","confidence":0.12}],"unverifiedCitations":0,"openQuestions":["What are BCL2, BCL-xL and MCL1 protein levels and BH3-profiling dependencies in adult primary HRS cells, and do they differ between BV-naive, BV-refractory and PD-1-refractory cHL?","At venetoclax exposures that kill HRS cells, is the rosetting CD4/CD8 and macrophage compartment spared, or does BCL2 inhibition antagonise the T-cell-dependent efficacy of PD-1 blockade in cHL?","In serial BV-exposed cHL biopsies, is acquired resistance dominated by ABCB1/efflux upregulation, impaired endocytic/endosomal processing, or CD30 loss — and at what CD30 H-score does BV fail?","Is the senescence-like HRS transcriptional programme (PMID:41538304) present in adult cHL and does it predict poor response to antimitotic MMAE payloads, arguing for non-antimitotic payloads or senolytic combinations?","Does LAG-3+ T-cell density or MHC class II loss discriminate non-CR in existing BV+nivolumab±ipilimumab cohorts, or should the checkpoint-resistance axis be abandoned for the apoptosis axis?","Are EBV+ and EBV- cHL distinct with respect to BCL2 family dependence and BV/checkpoint resistance mechanisms?"],"nextQueries":["(\"Hodgkin\" AND (venetoclax OR BCL2 OR \"BH3 profiling\" OR navitoclax OR MCL1)) AND SRC:MED AND PUB_YEAR:[2019 TO 2026]","(\"Hodgkin\" AND (senescence OR \"cell of origin\" OR \"Reed-Sternberg\" ) AND (transcriptome OR \"single-cell\")) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","((\"brentuximab\" AND (ABCB1 OR \"P-glycoprotein\" OR efflux OR endosomal OR \"CD30 loss\")) AND (Hodgkin OR lymphoma)) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"papersShown":[{"pmid":"41542910","doi":"10.1080/19420862.2026.2613548","year":2026,"isNew":true,"title":"The making of multispecific immunoglobulins - a clinical perspective"},{"pmid":"41645963","doi":"10.1080/19420862.2026.2622746","year":2026,"isNew":true,"title":"Expanding the horizons of cancer therapy with next-generation 4-1BB agonists: a review of molecular and clinical strategies to maximize efficacy and ensure safety"},{"pmid":"41538304","doi":"10.1182/bloodadvances.2025016953","year":2026,"isNew":true,"title":"Disordered differentiation and cellular senescence in pediatric Hodgkin Reed-Sternberg cells"},{"pmid":"41758201","doi":"10.1080/07853890.2026.2635774","year":2026,"isNew":true,"title":"Opportunities and challenges for cancer immunotherapy based on antigen cross-presentation"},{"pmid":"41700001","doi":"10.1080/2162402x.2026.2632421","year":2026,"isNew":true,"title":"Trial Watch - bispecific T cell engagers and higher-order multispecific immunotherapeutics"},{"pmid":"41630503","doi":"10.1093/oncolo/oyag020","year":2026,"isNew":true,"title":"Overcoming resistance to antibody-drug conjugates: mechanisms and emerging strategies"},{"pmid":"42087359","doi":"10.1111/jcmm.71143","year":2026,"isNew":true,"title":"Integrating Flow Cytometry in the Diagnostic Work of HIV-Associated Hodgkin's Lymphomas"},{"pmid":"41762706","doi":"10.1002/advs.202517353","year":2026,"isNew":true,"title":"Beyond CD30: Dual-Targeting of Malignant and Regulatory T Cells by Brentuximab Vedotin Remodels the Lymphoma Microenvironment and Overcomes Resistance via BCL2 Inhibition in Mycosi"},{"pmid":"41090103","doi":"10.18632/oncoscience.633","year":2025,"isNew":true,"title":"Targeted therapies and resistance mechanisms in lymphoma: Current landscape and emerging solutions"},{"pmid":"42122242","doi":"10.3390/cancers18091446","year":2026,"isNew":true,"title":"Hodgkin Reed-Sternberg Cells of Classic Hodgkin Lymphoma: Morphology, Phenotype, Genotype, and Cell of Origin"}],"trialsShown":[{"nct":"NCT01896999","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma"},{"nct":"NCT06724237","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Testing Whether High Dose Chemotherapy and Infusion of the Patients' Own Stem Cells Improves Survival in Patients With Peripheral T-cell Lym"},{"nct":"NCT00740805","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Veliparib, Cyclophosphamide, and Doxorubicin Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Non-Hodgkin "},{"nct":"NCT07630545","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Phase I Study in Healthy Volunteers and Parkinson's Disease (PD) Patients."},{"nct":"NCT03876769","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients"},{"nct":"NCT06549595","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study of Surovatamig (AZD0486) Plus Rituximab in Previously Untreated Follicular Lymphoma Patients"},{"nct":"NCT05675410","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study to Compare Standard Therapy to Treat Hodgkin Lymphoma to the Use of Two Drugs, Brentuximab Vedotin and Nivolumab"},{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"}],"usage":{"input":12297,"output":6796},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"Hodgkin lymphoma\" AND (LAG-3 OR LAG3 OR CIITA OR \"MHC class II\") AND (\"PD-1\" OR nivolumab OR pembrolizumab OR refractory)) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"Hodgkin\" AND (CD30 AND (\"antigen loss\" OR downregulation OR \"MDR1\" OR \"ABCB1\" OR \"brentuximab resistance\"))) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"evidenceIds":["PMID:41542910","PMID:41645963","PMID:41538304","PMID:41758201","PMID:41700001","PMID:41630503","PMID:42087359","PMID:41762706","PMID:41090103","PMID:42122242","NCT01896999","NCT06724237","NCT00740805","NCT07630545","NCT03876769","NCT06549595","NCT05675410","NCT05006716"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787186073537","cycle":180,"visit":18,"ts":"2026-08-20T00:34:33.537Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Asciminib's activity appears transcript-architecture dependent — TFR achieved in e19a2/T315I but primary resistance in e13a3 — so test asciminib against isogenic a2 versus a3 BCR::ABL1 constructs before treating NGS-negative asciminib failure as LSC-state resistance.","confidence":0.62,"notebook":"This visit's two queries returned nothing on ABL1 neoepitopes — the immunopeptidomics/HLA-A2 query surfaced a tyrosinase in-silico study (PMID:41098098 aside, PMID:39541331), an AML CAR review (PMID:41280924), post-transplant maintenance (PMID:39644024) and a base-edited LCK T316I dasatinib-resistant universal CAR-T (PMID:39935177, an interesting pharmacologic-gating trick but no CML antigen). L17 therefore takes its first empty dedicated pass: no evidence that E255V is presented on primary CML cells, and NCT06904066 eligibility for CML remains unknown. Weakened; one further empty pass retires it.\n\nThe productive yield is transcript architecture. Two case reports move in opposite directions and together sharpen L18 into a mechanistic claim. An e19a2 (µ-BCR) patient with T315I reached treatment-free remission on third-line asciminib (PMID:38965368) — the myristoyl pocket tolerates a far-3' BCR breakpoint and T315I simultaneously. Conversely, primary asciminib resistance occurred with e13a3 (PMID:41098098), a junction that the earlier review had classed as favourable (PMID:40999990). [INFERRED] The discriminating variable may be the ABL1 side, not BCR: a3 junctions delete ABL1 exon 2, removing SH3-region sequence, and asciminib requires the assembled autoinhibited SH3–SH2–kinase clamp and αI-helix bending to work [KNOWN]. If so, a3 transcripts (e13a3/e14a3/e1a3) are a predicted asciminib-exclusion class independent of kinase-domain genotype — directly testable by comparing asciminib IC50 against isogenic e14a2 versus e14a3 (and e19a2) constructs, with αI-helix crosslinking or SH3-deletion controls. This also imports into L8: the mutation-to-agent matrix must carry a transcript-architecture column, and NGS-negative asciminib failure should be re-read for a3 junctions before being attributed to LSC state. L8 strengthens narrowly (T315I/atypical TFR) while acquiring that caveat.\n\nELN 2025 (PMID:40646132) is the highest-quality item in the pack and lands squarely on L7: guidance now explicitly prefers dose reduction over switching for non-prohibitive toxicity, individualises response-milestone failure, and matures discontinuation data — guideline endorsement of the therapeutic-window logic, though still no randomised dose-reduction trial, which stays the tier-limiting gap. It also reaffirms the control answer: BCR::ABL1 kinase inhibition remains the backbone, and every live lead here is a window, sequencing, monitoring or persistence problem downstream of it, not a rival mechanism.\n\nBlast-phase reviews (PMID:35866251, PMID:39518058) frame advanced disease as TKI plus intensive chemotherapy plus allograft, with no endorsement of concurrent dual-site blockade; L1 stays weak and is not helped.","leadChanges":[{"id":"L18","title":"Transcript-architecture triage: atypical and insertion-bearing BCR::ABL1 fusions as a distinct resistance class and a blind spot in molecular monitoring","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.42},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"DOSSIER","status":"STRENGTHENED","confidence":0.77},{"id":"L8","title":"Sequential ATP-site to allosteric switch: asciminib as non-cross-resistant salvage after ponatinib and in T315I disease","level":"DOSSIER","status":"STRENGTHENED","confidence":0.79},{"id":"L17","title":"Drug-selected ABL1 mutation neoepitopes (E255V) as TCR-T targets in multi-TKI-resistant CML — replacing failed fusion-junction vaccination","level":"LEAD","status":"WEAKENED","confidence":0.22},{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"WEAKENED","confidence":0.2}],"unverifiedCitations":0,"openQuestions":["Is asciminib potency systematically reduced against a3-junction BCR::ABL1 (e13a3/e14a3/e1a3) versus a2 junctions in isogenic constructs, and does the SH3-region deletion explain it mechanistically?","Does ELN 2025 specify quantitative dose-reduction schedules or monitoring intervals that could serve as the comparator arm for a randomised de-escalation trial?","Are there additional case-level or registry reports of atypical-transcript patients treated with asciminib, ponatinib or olverembatinib sufficient to build a variant-to-agent table?","Is the ABL1 E255V neoepitope presented on primary patient CML cells, and does NCT06904066 accept CML with kinase-domain point mutations as participant-specific neoantigens?","Do clinical-grade HDAC6 inhibitors (ricolinostat/citarinostat) have any primary CML-LSC data, or does L11 retire?","Has any independent laboratory replicated FBXO3-mediated DUSP9 degradation in primary CML CD34+ cells (final pass before L16 retirement)?"],"nextQueries":["(asciminib) AND (\"a3\" OR e13a3 OR e14a3 OR e1a3 OR \"SH3 domain\" OR \"myristoyl pocket\" OR \"allosteric\") AND (\"BCR::ABL1\" OR \"BCR-ABL\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"chronic myeloid leukemia\") AND (\"dose reduction\" OR \"de-escalation\" OR \"low dose\") AND (randomi* OR \"phase 3\" OR \"phase III\" OR \"patient-reported\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(HDAC6) AND (ricolinostat OR citarinostat OR \"HDAC6 inhibitor\") AND (leukemia OR \"CD34+\" OR \"stem cell\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"40646132","doi":"10.1038/s41375-025-02664-w","year":2025,"isNew":true,"title":"2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia"},{"pmid":"35866251","doi":"10.1111/bjh.18370","year":2022,"isNew":true,"title":"Treatment of blast phase chronic myeloid leukaemia: A rare and challenging entity"},{"pmid":"41247642","doi":"10.1186/s43556-025-00352-w","year":2025,"isNew":true,"title":"Drug resistance in cancer: molecular mechanisms and emerging treatment strategies"},{"pmid":"38965368","doi":"10.1038/s41375-024-02327-2","year":2024,"isNew":true,"title":"Treatment-free remission after third-line therapy with asciminib in chronic myeloid leukemia with an atypical e19a2 BCR::ABL1 transcript and T315I mutation"},{"pmid":"39935177","doi":"10.1016/j.ymthe.2025.02.012","year":2025,"isNew":true,"title":"Dasatinib-resistant universal CAR-T cells proliferate in the presence of host immune cells and exhibit antitumor activity"},{"pmid":"39644024","doi":"10.1182/hematology.2024000589","year":2024,"isNew":true,"title":"Maintenance strategies for relapse prevention and treatment"},{"pmid":"39518058","doi":"10.3390/cancers16213615","year":2024,"isNew":true,"title":"An Overview of Myeloid Blast-Phase Chronic Myeloid Leukemia"},{"pmid":"39541331","doi":"10.1371/journal.pone.0308927","year":2024,"isNew":true,"title":"Computational analysis of the deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in TYR gene impacting human tyrosinase protein and the protein stability"},{"pmid":"41098098","doi":"10.3324/haematol.2025.288776","year":2026,"isNew":true,"title":"Primary asciminib resistance in a chronic myeloid leukemia patient with the atypical &lt;i&gt;BCR::ABL1&lt;/i&gt; e13a3 transcript: a case study"},{"pmid":"41280924","doi":"10.3389/fimmu.2025.1653350","year":2025,"isNew":true,"title":"Precision medicine with car cells in acute myeloid leukemia: where are we?"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":16952,"output":7448},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"ABL1\" OR \"BCR-ABL\") AND (neoepitope OR \"HLA-A2\" OR \"TCR-transduced\" OR immunopeptidom*) AND (E255V OR T315I OR \"kinase domain mutation\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"atypical BCR::ABL1\" OR e8a2 OR e1a3 OR e6a2 OR e19a2) AND (asciminib OR ponatinib OR olverembatinib OR \"molecular monitoring\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:40646132","PMID:35866251","PMID:41247642","PMID:38965368","PMID:39935177","PMID:39644024","PMID:39518058","PMID:39541331","PMID:41098098","PMID:41280924","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787185855225","cycle":179,"visit":3,"ts":"2026-08-20T00:30:55.225Z","cancer":{"key":"mantle cell lymphoma","name":"mantle cell lymphoma","mondo":{"id":"MONDO:0018876","name":"mantle cell lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"UHRF1 is now independently validated as a SOX11-driven oncogenic dependency in mantle cell lymphoma with a tool drug (CM272) and xenograft regression, making the UHRF1 node the programme's strongest mechanistic thread and retiring the data-free ATR/CHK1/WEE1 hypothesis.","confidence":0.5,"notebook":"Visit 3 delivered one genuinely load-bearing paper. PMID:41876725 (Leukemia) makes UHRF1 an MCL oncogenic driver in its own right: overexpressed in patient specimens, correlated with SOX11 and Ki-67, associated with worse OS; knockdown gives apoptosis plus G2/M arrest and blocks motility/invasion; xenograft regression on silencing and on pharmacological targeting with CM272 (dual G9a/DNMT1 inhibitor [KNOWN]) at tolerable toxicity. Mechanism: SOX11 binds the UHRF1 promoter and transactivates it. This is independent corroboration of the node I inferred at visit 2 from PMID:42068675 (eprenetapopt+palbociclib acting through UHRF1 downregulation), from a different lab, different modality, different readout — so L6 moves to CANDIDATE, and the UHRF1-methylation bridge in L1 becomes experimentally tractable: CM272 is now the cleanest tool to ask whether de-repressing the miR-146a promoter restores ibrutinib sensitivity (the new paper says nothing about miR-146a, so this remains [INFERRED]). I open a new lead (L9) for the SOX11→UHRF1 axis itself, with SOX11 IHC as the built-in patient selector — the nodal/aggressive SOX11-positive subset should be dependent, leukemic non-nodal SOX11-negative MCL predicted resistant [INFERRED]. Window argument: UHRF1 is largely restricted to proliferating cells and maintains DNMT1 targeting, so on-target cost is myelosuppression and global hypomethylation; CM272 tolerability in mice is encouraging but murine-only.\n\nPMID:42265322 adds a second chromatin node, LSD1: IRAIN lncRNA overexpression suppresses MCL proliferation, induces apoptosis and cycle arrest, and lowers LSD1, cyclin D1 and CDK2 with p21 induction; in vitro only, and lncRNA overexpression is not a drug, so I carry LSD1 inhibition as a subordinate arm of L9 rather than its own lead.\n\nL7 dies as pre-committed. A third pack, this time queried explicitly for WEE1/PKMYT1/CHK1/CDK2/cyclin E in MCL, again returned zero MCL experiments; PMID:42025253 restates pan-cancer ATM→ATR/PARP synthetic lethality without MCL data. RETIRED — the ATM anchor stands as a prognostic/chemosensitivity biomarker in MCL, not a target, and the desk should not re-propose ATR/CHK1/WEE1 here without primary MCL data. PMID:42115772 supplies a cautionary counter-signal for L6: germline BRCA2 mutation fosters CDK4/6-inhibitor resistance in breast cancer, so HR-deficient (including ATM-altered) MCL may be palbociclib-refractory rather than sensitised — this must be scored, not assumed.\n\nNo new data on EXS73565 or ABBV-291 targets (second visit unanswered), and nothing on BGB-16673 efficacy, sonrotoclax, or post-CAR-T CD19 retention; L2–L5, L8 unchanged.","leadChanges":[{"id":"L6","title":"Eprenetapopt + palbociclib in TP53-altered, CCND1-driven MCL: redox/replication-stress synthetic lethality","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.6},{"id":"L1","title":"Restore miR-146a-5p / block MAPK-ERK+PI3K-AKT to reverse non-genetic ibrutinib resistance","level":"LEAD","status":"STRENGTHENED","confidence":0.5},{"id":"L9","title":"SOX11-UHRF1 chromatin axis as a direct dependency in SOX11-positive MCL (CM272; LSD1 as second node)","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L7","title":"ATR/CHK1/WEE1 inhibition in ATM-altered, replication-stressed MCL — hypothesis without MCL data","level":"LEAD","status":"RETIRED","confidence":0.15}],"unverifiedCitations":0,"openQuestions":["Does CM272 or UHRF1 knockdown demethylate the miR-146a promoter, restore miR-146a-5p and re-sensitise ibrutinib-tolerant MCL, i.e. are L1 and L9 one node?","Is UHRF1 dependence restricted to SOX11-positive MCL, and does SOX11 knockdown phenocopy UHRF1 loss (epistasis)?","Is HR/ATM/BRCA2 deficiency a resistance modifier for the palbociclib arm of L6, as germline BRCA2 data in breast cancer suggest?","Is eprenetapopt+palbociclib synergy TP53-genotype-restricted (mut vs null vs wildtype), and is RB1 loss or cyclin E-CDK2 the dominant escape route?","What are the disclosed targets of EXS73565 (NCT06980116) and ABBV-291 (NCT06667687) — still unanswered after two visits?","In post-CD19 CAR-T relapse, what fraction retain CD19 by biopsy, and does adding a non-covalent BTKi (NCT07673367) rescue T-cell-failure relapses specifically?"],"nextQueries":["(\"mantle cell lymphoma\" OR \"B-cell lymphoma\") AND (CM272 OR UHRF1 OR SOX11) AND SRC:MED","\"mantle cell lymphoma\" AND (LSD1 OR KDM1A OR iadademstat OR \"G9a\" OR EHMT2 OR DNMT1) AND SRC:MED","\"mantle cell lymphoma\" AND (\"BGB-16673\" OR \"BTK degrader\" OR sonrotoclax OR \"CD19 loss\" OR \"CAR T relapse\") AND SRC:MED"],"papersShown":[{"pmid":"41692895","doi":"10.1186/s43556-026-00411-w","year":2026,"isNew":true,"title":"Tumor cell cycle regulation: integrated perspective of stage characteristics, regulatory networks, and signaling pathway intervention strategies"},{"pmid":"41876725","doi":"10.1038/s41375-026-02915-4","year":2026,"isNew":true,"title":"Targeting UHRF1 induces regression of aggressive mantle cell lymphoma"},{"pmid":"41793262","doi":"10.1002/cpt.70253","year":2026,"isNew":true,"title":"Pharmacokinetic Drug-Drug Interaction Potential of Oral Anticancer Drugs"},{"pmid":"42192915","doi":"10.3390/cancers18101556","year":2026,"isNew":true,"title":"Bradyarrhythmias Associated with Oncologic Treatment-An Updated Review"},{"pmid":"42115772","doi":"10.1038/s41698-026-01481-3","year":2026,"isNew":true,"title":"Germline BRCA2 mutations foster resistance to CDK4/6 inhibitors in breast cancer"},{"pmid":"42112659","doi":"10.1002/jcp.70182","year":2026,"isNew":true,"title":"Decoding the Hexosamine Biosynthesis Pathway: Implications for Novel Therapeutic Strategies in Sarcoma"},{"pmid":"42025253","doi":"10.1016/j.neo.2026.101309","year":2026,"isNew":true,"title":"Ataxia telangiectasia mutated (ATM) kinase as a predictive biomarker in clinical oncology: implications for a precision treatment approach"},{"pmid":"42265322","doi":"10.1038/s41598-026-57074-4","year":2026,"isNew":true,"title":"LncRNA IRAIN inhibits mantle cell lymphoma progression by inducing cell cycle arrest and apoptosis: an in vitro study"},{"pmid":"38279263","doi":"10.3390/ijms25021263","year":2024,"isNew":false,"title":"Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets"},{"pmid":"39492835","doi":"10.1002/mco2.788","year":2024,"isNew":false,"title":"Targeting the DNA damage response in cancer"}],"trialsShown":[{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06742996","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study to Investigate the Efficacy and Safety of Sonrotoclax Plus Zanubrutinib Compared With Placebo Plus Zanubrutinib in Adults With Relap"},{"nct":"NCT07673367","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Nemtabrutinib With CAR T Therapy in Relapsed/Refractory Mantle Cell Lymphoma"},{"nct":"NCT06667687","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study to Evaluate Adverse Events, Change in Disease Activity, and How Intravenously Infused ABBV-291 Moves Through the Body in Adult Partici"},{"nct":"NCT05458297","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of Zilovertamab Vedotin (MK-2140) as Monotherapy and in Combination in Participants With Aggressive and Indolent B-cell Malignancies"},{"nct":"NCT06980116","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Dose Determining Study of EXS73565 in Participants With Relapsed or Refractory B-Cell Malignancies"},{"nct":"NCT05495464","phase":"EARLY_phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Pilot \"Window-3\" Study of Acalabrutinib Plus Rituximab Followed by Brexucabtagene Autoleucel Therapy in Patients With Previously Untreated"},{"nct":"NCT06564038","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study of AZD0486 Monotherapy or in Combination With Other Anti-Cancer Agents for Mature B-Cell Malignancies"}],"usage":{"input":12993,"output":6476},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"mantle cell lymphoma\" AND (UHRF1 OR \"APR-246\" OR eprenetapopt OR palbociclib OR \"CDK4/6\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","\"mantle cell lymphoma\" AND (WEE1 OR PKMYT1 OR \"CHK1\" OR ceralasertib OR elimusertib OR \"CDK2\" OR \"cyclin E\") AND SRC:MED"],"evidenceIds":["PMID:41692895","PMID:41876725","PMID:41793262","PMID:42192915","PMID:42115772","PMID:42112659","PMID:42025253","PMID:42265322","PMID:38279263","PMID:39492835","NCT05006716","NCT06742996","NCT07673367","NCT06667687","NCT05458297","NCT06980116","NCT05495464","NCT06564038"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787185653266","cycle":178,"visit":3,"ts":"2026-08-20T00:27:33.266Z","cancer":{"key":"follicular lymphoma","name":"follicular lymphoma","mondo":{"id":"MONDO:0018906","name":"follicular lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Frontline single-agent mosunetuzumab achieved 100% ORR/71% CR with 89% 2-year PFS in untreated indolent B-NHL and its only failures were CD20 loss and histologic transformation (PMID:42600120), so the desk should now treat CD3-engager-first therapy as the reference FL backbone and prioritise antigen","confidence":0.63,"notebook":"Two pack items matter; the rest is noise (P1/P2 hyper-IgE reviews are retrieval contamination — STAT6 keyword bleed, no FL content).\n\nP3 (PMID:42600120) is the first prospective, chemo-free, frontline test of the L1 hypothesis: eight cycles of mosunetuzumab alone in untreated indolent B-NHL (88% FL) gave 100% ORR / 71% CR, 86% CR after response-adapted pola-obinutuzumab, 2-year PFS 89%, OS 100%, all-grade-1 CRS. In t(14;18)/BCL2-driven disease [SOMATIC], CD3-crosslinked granzyme delivery achieves CR fractions chemoimmunotherapy needs alkylators for [INFERRED], and it does so first-line, not just in the R/R external-control setting of PMID:42415230. Supportive but weaker: 4/4 FL responses with epcoritamab plus Vβ-skewed memory-dominant CTL expansion at elective discontinuation (PMID:42278654), and real-world activity of bispecifics after CAR-T failure (PMID:42315502). L1 → DOSSIER, with the caveat that both randomised readouts (NCT06337318, NCT06549595) are pending and n=42 single-arm cannot exclude late attrition.\n\nCrucially, P3 also answers open question 1 in part and hands me a new lead: all four progressions were escape by antigen or lineage — 2 CD20 loss, 2 histologic transformation. So engager failure in FL is not predominantly exhaustion but target/phenotype escape, which is actionable by antigen switching (CD19: surovatamig NCT06549595, CAR-T) rather than by checkpoint or IMiD rescue [INFERRED]. P4 (PMID:42529676) adds the confound that post-engager \"relapse\" can be an unmasked synchronous clone (ISFN-derived FL after mosunetuzumab for MZL), so paired biopsy with clonality, not imaging, must define escape. New lead L5.\n\nP10 (PMID:42256548) is unexpectedly load-bearing for both immune leads. In follicle-centre lymphoma of skin, one genomic subgroup is defined by immune-evasion mutations including CIITA and B2M [SOMATIC] — direct genetic ablation of MHC-II/I presentation in a follicle-centre neoplasm, the mechanism L3 predicts should erode lenalidomide/CD4-CTL-dependent activity while sparing engagers. A second subgroup carries activating STAT6 plus CREBBP mutations and is uniformly CD23+ — CD23/FCER2 is the canonical IL-4→STAT6 target, i.e. the IL-4 signature readout I prespecified last visit, now observed. P9 (PMID:41838170) frames STAT6/Th2 microenvironment as a chemoresistance axis in haematologic malignancy. L3 and L4 → CANDIDATE, both discounted because PCFCL is a distinct entity from systemic FL and neither paper measures HLA-DR protein or drug response.\n\nL2 weakened again: no FL BTK/degrader data, and the efficacy bar is now a grade-1-CRS chemo-free frontline regimen.","leadChanges":[{"id":"L1","title":"CD3 bispecific engagers displace chemoimmunotherapy in t(14;18)/BCL2-driven FL","level":"DOSSIER","status":"STRENGTHENED","confidence":0.78},{"id":"L5","title":"Antigen/lineage escape, not exhaustion, is the dominant engager failure mode in FL — sequence CD20 to CD19 and biopsy-confirm every 'relapse'","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L3","title":"MHC class II (HLA-DRB1 anchor) status as the stratifier splitting immunomodulatory from MHC-independent immunotherapy in FL","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.52},{"id":"L4","title":"POD24/multi-extranodal FL as a distinct dependency class: STAT6-IL-4/JAK and CARD11-NF-kB on an MHC-independent effector backbone","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.46},{"id":"L2","title":"BTK degradation vs occupancy: is chronic active BCR signalling a maintenance dependency in FL?","level":"LEAD","status":"WEAKENED","confidence":0.24}],"unverifiedCitations":0,"openQuestions":["What is the molecular basis of CD20 loss after frontline mosunetuzumab (MS4A1 truncating/splice mutation vs promoter methylation vs transcriptional downregulation vs trogocytosis), and is it clonally selected from a pre-existing subclone?","Does CD19-directed therapy (surovatamig, CD19 CAR-T) retain efficacy specifically in biopsy-proven CD20-loss FL, and conversely does prior CD20 engager exposure impair CD19 CAR-T fitness?","Why does histologic transformation account for half the failures of frontline engager therapy — is engager pressure selecting TP53/MYC-altered or germinal-centre-exit clones, or is it unmasking pre-existing composite/high-grade disease?","Can fixed-duration engager therapy be stopped safely using an immune biomarker (memory:effector CTL ratio, Vbeta skewing) rather than PET alone, and does this reduce late antigen escape?","In STAT6-mutant, CD23-high FL, does IL4R (dupilumab) or JAK1 blockade kill or merely cytostatically blunt tumour cells, and does concurrent JAK inhibition antagonise engager-mediated T-cell degranulation?","Does HLA-DR/beta-2M protein loss or CIITA/B2M mutation predict lenalidomide-based failure while sparing engager response, in systemic FL rather than cutaneous follicle-centre lymphoma?"],"nextQueries":["(\"follicular lymphoma\" AND (\"CD20 loss\" OR MS4A1 OR \"antigen escape\" OR trogocytosis) AND (mosunetuzumab OR epcoritamab OR odronextamab OR \"CAR T\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"follicular lymphoma\" AND (\"histologic transformation\" OR \"transformed\") AND (bispecific OR \"T-cell engager\" OR TP53 OR MYC) AND (genomic OR clonal OR biopsy)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","((\"follicular lymphoma\" OR \"germinal center B-cell\") AND (CIITA OR B2M OR \"HLA-DR\" OR \"MHC class II\") AND (lenalidomide OR \"immune evasion\" OR \"antigen presentation\")) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"papersShown":[{"pmid":"40040707","doi":"10.3389/fimmu.2025.1516068","year":2025,"isNew":true,"title":"The genetics of hyper IgE syndromes"},{"pmid":"41216363","doi":"10.2147/itt.s532287","year":2025,"isNew":true,"title":"Understanding and Managing Hyper IgE Syndromes"},{"pmid":"42600120","doi":"10.1200/jco-25-02906","year":2026,"isNew":true,"title":"Mosunetuzumab With Response-Adapted Polatuzumab Vedotin and Obinutuzumab in Untreated Indolent B-Cell Non-Hodgkin Lymphoma"},{"pmid":"42529676","doi":"10.1002/jha2.70370","year":2026,"isNew":true,"title":"Unmasking a Composite Lymphoma: Follicular Lymphoma Emerging After Bispecific Antibody Treatment of Marginal Zone Lymphoma"},{"pmid":"42527721","doi":"10.1007/s11912-026-01803-5","year":2026,"isNew":true,"title":"Follicular Lymphoma: Novel Therapies and Strategies for Optimal Therapeutic Sequencing"},{"pmid":"42315502","doi":"10.1038/s41408-026-01546-3","year":2026,"isNew":true,"title":"Real-world outcomes of bispecific antibody therapy after chimeric antigen receptor T-cell therapy in follicular lymphoma"},{"pmid":"42311429","doi":"10.1002/hem3.70398","year":2026,"isNew":true,"title":"Real-world resource utilization, toxicity management, and efficacy outcomes of CD20 × CD3 bispecific antibodies in B-cell lymphoma: A study from the GELTAMO network"},{"pmid":"42278654","doi":"10.3390/ijms27115132","year":2026,"isNew":true,"title":"Clinical Outcomes and Exploratory Longitudinal CTL/Vβ Repertoire Remodeling in Patients with Relapsed or Refractory Large B-Cell Lymphoma and Follicular Lymphoma Treated with Epcor"},{"pmid":"41838170","doi":"10.1007/s00277-026-06932-2","year":2026,"isNew":true,"title":"STAT6: Multidimensional analysis from hematopoietic immune regulation to pathogenesis mechanisms and therapeutic targets in hematologic malignancies"},{"pmid":"42256548","doi":"10.1002/hem3.70382","year":2026,"isNew":true,"title":"Genomic heterogeneity in primary cutaneous follicular center lymphomas reveals different clinicopathological subgroups"}],"trialsShown":[{"nct":"NCT06724237","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Testing Whether High Dose Chemotherapy and Infusion of the Patients' Own Stem Cells Improves Survival in Patients With Peripheral T-cell Lym"},{"nct":"NCT07630545","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Phase I Study in Healthy Volunteers and Parkinson's Disease (PD) Patients."},{"nct":"NCT06549595","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study of Surovatamig (AZD0486) Plus Rituximab in Previously Untreated Follicular Lymphoma Patients"},{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06860594","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Testing the Addition of an Anti-Cancer Drug, Triapine, to the Usual Radiation Therapy for Recurrent Glioblastoma or Astrocytoma"},{"nct":"NCT02390869","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Rituximab and Lenalidomide vs Rituximab Alone as Maintenance After R-chemoterapy for Relapsed/Refractory FL Patients"},{"nct":"NCT05100862","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of Zanubrutinib Plus Anti-CD20 Versus Lenalidomide Plus Rituximab in Participants With Relapsed/Refractory Follicular or Marginal Zo"},{"nct":"NCT06337318","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Comparing Rituximab and Mosunetuzumab Drug Treatments for People With Low Tumor Burden Follicular Lymphoma"}],"usage":{"input":11265,"output":8844},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"follicular lymphoma\" AND (mosunetuzumab OR epcoritamab OR glofitamab OR odronextamab) AND (relapse OR \"CD20 loss\" OR trogocytosis OR \"T-cell exhaustion\" OR \"paired biopsies\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"follicular lymphoma\" AND (STAT6 OR CARD11 OR \"IL-4\" OR JAK1) AND (mutation OR signaling OR microenvironment OR \"follicular helper\")) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"evidenceIds":["PMID:40040707","PMID:41216363","PMID:42600120","PMID:42529676","PMID:42527721","PMID:42315502","PMID:42311429","PMID:42278654","PMID:41838170","PMID:42256548","NCT06724237","NCT07630545","NCT06549595","NCT05006716","NCT06860594","NCT02390869","NCT05100862","NCT06337318"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787185417632","cycle":177,"visit":3,"ts":"2026-08-20T00:23:37.632Z","cancer":{"key":"diffuse large b-cell lymphoma","name":"diffuse large B-cell lymphoma","mondo":{"id":"MONDO:0018905","name":"diffuse large B-cell lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"MALT1 protease inhibition advances to CANDIDATE for ABC-DLBCL but must be biomarker-selected by demonstrable constitutive MALT1-NF-kB dependency (BCL10 cleavage/NF-kB output), not by CARD11 genotype alone; BTK-degrader DLBCL evidence failed to materialise under targeted search.","confidence":0.45,"notebook":"This visit's pack answered the MALT1 question and failed the BTK-degrader question.\n\nMALT1 (L6) moves to CANDIDATE. PMID:41783325 is the first DLBCL-specific MALT1 source in the programme: it names DLBCL as the malignancy where aberrant MALT1 activation is most implicated, distinguishes scaffold from protease function, and reports that safimaltib (JNJ-67856633) has manageable safety plus preliminary antitumour activity in early-phase R/R B-cell malignancy trials — converting my previously [KNOWN] premise into cited claims, and confirming the Treg/autoimmunity axis as the predicted toxicity rather than myelosuppression. PMID:42542590 is the harder and more useful datum: a selective protease inhibitor (CRD-1441551) across three ATL lines and five PDX gave marked sensitivity in only 2/8, modest in 3, none in 3, with response tracking constitutive MALT1–NF-κB activation. [INFERRED] MALT1 protease inhibition is not a general CBM-pathway kill switch; it requires a pharmacodynamically demonstrable dependency. This mandates a predictive assay before any CARD11-mutant/degrader-resistant DLBCL claim — basal BCL10 cleavage and MALT1-dependent NF-κB target output as the stratifier, not CARD11 genotype alone. Also note the ATL data come from TCR-driven CARD11/PLCG1/PRKCB biology, so transferability to BCR-driven ABC-DLBCL is analogical, not demonstrated. Confidence 0.5.\n\nL3 weakened to 0.50. A dedicated 2024–2026 query for BGB-16673/NX-5948/NX-2127/\"BTK degrader\" in DLBCL returned only generic targeted-protein-degradation reviews (PMID:41845415, PMID:41986622, PMID:41174297) — no DLBCL cohort ORR, no genotype breakdown, no emergent-resistance sequencing. Two consecutive visits of class-level, mostly CLL/MCL corroboration without DLBCL-specific efficacy is an informational failure, and PMID:41986622 confirms the degrader/bsAb centre of gravity remains MCL/CLL. The hypothesis is intact; the evidence base for it in DLBCL is not growing.\n\nL5 strengthened to 0.45 on PMID:42099680 (DESCAR-T, n=297 relapsing after 2L CAR-T): salvage ORR 39.1%, CR 27.6%, median OS 6.5 months, median PFS 3.4 months despite bispecific-based salvage in 65%, and 35% of relapses within 2 months. [INFERRED] T-cell redirection is not chemosensitivity-independent rescue once T-cell fitness has been consumed by prior CAR-T — which is precisely the argument for deploying engagers as early biomarker-selected intensification (NCT04980222) rather than as late salvage. Early relapse (<6 months) as an independent prognostic factor supports interim-PET/ctDNA-style early selectors.\n\nNew tracking lead L7: dual EZH1/EZH2 inhibition (tulmimetostat, NCT04104776) in lymphoma cohorts, opened to service the EZB/GCB question that BEBT-908 (L4) only indirectly probes. Trial anchor only.","leadChanges":[{"id":"L6","title":"MALT1 protease inhibition to bypass proximal BCR-resistance mutations in ABC/MCD-DLBCL","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.5},{"id":"L3","title":"BTK degradation plus BCL2/NF-κB co-targeting in ABC/MCD-like DLBCL","level":"CANDIDATE","status":"WEAKENED","confidence":0.5},{"id":"L5","title":"Biomarker-adaptive early T-cell redirection in high-risk frontline DLBCL","level":"LEAD","status":"STRENGTHENED","confidence":0.45},{"id":"L7","title":"Dual EZH1/EZH2 inhibition (tulmimetostat) in EZB/GCB-DLBCL and germinal-centre lymphoma","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["In ABC-DLBCL lines and PDX, does a basal MALT1-activity readout (BCL10 cleavage fragment, MALT1-dependent NF-kB target output) predict safimaltib/CRD-1441551-class response as it did in ATL, and does CARD11 gain-of-function predict sensitiv","What is the DLBCL-specific ORR/CR and Treg/autoimmune toxicity profile of safimaltib (JNJ-67856633) in reported early-phase R/R B-cell malignancy cohorts?","Do BTK-degrader-resistant DLBCL models retain MALT1 dependency, and which resistance alleles (CRBN/E3 loss versus distal CARD11/PLCG2) segregate with MALT1-inhibitor sensitivity?","Is there any DLBCL cohort-level efficacy or emergent-mutation data for BGB-16673 or NX-5948, broken down by LymphGen genotype and prior BTKi class?","Which pre-CAR-T or post-CAR-T T-cell fitness parameters predict bispecific failure, given the 6.5-month median OS after 2L CAR-T relapse - and does frontline ctDNA-selected glofitamab avoid that exhaustion penalty?","Does dual EZH1/EZH2 inhibition (tulmimetostat) show EZH2-mutation-restricted benefit in GCB/EZB lymphoma, and does it overlap the BEBT-908 EZB hypothesis?"],"nextQueries":["(safimaltib OR \"JNJ-67856633\" OR \"MALT1 inhibitor\") AND (\"diffuse large B-cell lymphoma\" OR DLBCL OR \"activated B-cell\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"BGB-16673\" OR \"NX-5948\" OR \"BTK degrader\") AND (\"large B-cell\" OR DLBCL) AND (\"overall response\" OR resistance OR mutation) AND SRC:MED","(tulmimetostat OR \"CPI-0209\" OR \"EZH1/EZH2\") AND lymphoma AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41174297","doi":"10.1038/s41573-025-01316-z","year":2026,"isNew":true,"title":"Induced proximity-based therapeutic modalities"},{"pmid":"41986622","doi":"10.1038/s41375-026-02942-1","year":2026,"isNew":true,"title":"Evolving therapeutic strategies in mantle cell lymphoma: advancements and future directions"},{"pmid":"41988372","doi":"10.1021/acsptsci.5c00730","year":2026,"isNew":true,"title":"Mechanisms and Design Principles of Proteolysis-Targeting Chimeras and Their Emerging Applications"},{"pmid":"41885448","doi":"10.1080/14756366.2026.2636394","year":2026,"isNew":true,"title":"PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators"},{"pmid":"42099680","doi":"10.1002/hem3.70356","year":2026,"isNew":true,"title":"Outcomes and salvage strategies for large B-cell lymphoma progressing after second-line CAR T-cell therapy: A DESCAR-T study from the LYSA group"},{"pmid":"42180980","doi":"10.21037/tcr-2025-1-2830","year":2026,"isNew":true,"title":"Targeting \"undruggable\" cancer proteins: pharmacological challenges and emerging strategies"},{"pmid":"42123307","doi":"10.3390/ijms27093722","year":2026,"isNew":true,"title":"Advancing Immunotherapy in Chronic Lymphocytic Leukemia"},{"pmid":"41845415","doi":"10.1186/s40164-026-00759-3","year":2026,"isNew":true,"title":"Prospects and advances of PROTAC in the treatment of hematologic malignancies"},{"pmid":"41783325","doi":"10.1002/ccs3.70066","year":2026,"isNew":true,"title":"Therapeutic targeting of MALT1 in oncology: Mechanism, inhibitor development, and clinical prospects"},{"pmid":"42542590","doi":"10.1016/j.isci.2026.116850","year":2026,"isNew":true,"title":"The requirement of MALT1 activity for the growth of adult T cell leukemia/lymphoma"}],"trialsShown":[{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06792253","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Study Comparing BEBT-908 Combined With R to SOC for the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma"},{"nct":"NCT04104776","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas"},{"nct":"NCT06781359","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Study on Plasmablastic Lymphoma Patients"},{"nct":"NCT03226704","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Leukapheresis for CAR or Adoptive Cell Therapy Manufacturing"},{"nct":"NCT03223610","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (ViPOR) in Relapsed/Refractory B-cell Lymphoma"},{"nct":"NCT04980222","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate the Safety and Efficacy of Glofitamab in Combination With Rituximab (R) Plus Cyclophosphamide, Doxorubicin, Vincristine,"},{"nct":"NCT02203526","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (TEDDI-R) in Pri"}],"usage":{"input":11484,"output":6344},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"diffuse large B-cell lymphoma\" OR \"DLBCL\") AND (BGB-16673 OR NX-5948 OR NX-2127 OR \"BTK degrader\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(MALT1 AND (inhibitor OR protease)) AND (lymphoma OR \"activated B-cell\" OR CARD11) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41174297","PMID:41986622","PMID:41988372","PMID:41885448","PMID:42099680","PMID:42180980","PMID:42123307","PMID:41845415","PMID:41783325","PMID:42542590","NCT05006716","NCT06792253","NCT04104776","NCT06781359","NCT03226704","NCT03223610","NCT04980222","NCT02203526"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787185210457","cycle":176,"visit":3,"ts":"2026-08-20T00:20:10.457Z","cancer":{"key":"waldenstrom macroglobulinemia","name":"Waldenstrom macroglobulinemia","mondo":{"id":"MONDO:0100280","name":"Waldenstrom macroglobulinemia"}},"control":false,"modelLabel":"SCIENCE","summary":"A WM-specific state-of-the-art review now asserts activity for BTK degraders, non-covalent BTKi and BCL-2 inhibitors in covalent-BTKi-refractory WM, promoting the BTK-degradation lead to DOSSIER and the BCL2-axis lead to CANDIDATE, while a failed venetoclax-plus-chemo trial in LBCL argues WM BCL2i c","confidence":0.6,"notebook":"Visit 3 delivered the first WM-specific — if only review-level — anchor for two leads that were previously pure CLL extrapolation. The SOHO state-of-the-art update (PMID:42509106) states directly that BCL-2 inhibitors, non-covalent BTKi and BTK degraders show promising efficacy in WM patients previously exposed or refractory to covalent BTKi, and that MYD88/CXCR4/TP53 status may inform treatment choice. That is exactly the missing link flagged as open question 5. It does not give me ORRs, durations, or genotype-stratified subsets — abstract-level assertion only — so I promote conservatively.\n\nL2 moves to DOSSIER. Three evidence-bearing visits, and the previously recorded fatal caveat (\"all degrader/allele data are CLL-derived\") is now partially answered by a WM-specific statement of degrader activity post-cBTKi (PMID:42509106), while PMID:41594662 and PMID:41721839 re-confirm the resistance topology (C481 substitutions plus PLCG2, with non-C481 kinase-domain variants \"increasingly recognized\") and add tumour-microenvironment/stromal and bypass-signalling resistance as a second, non-mutational axis. Mechanistically this matters: if TME-driven resistance is co-dominant, protein removal (degrader) plus disruption of niche adhesion (VCAM-1/ILK scaffolding, PMID:39062757) should outperform occupancy alone [INFERRED]. The unresolved gap I keep on the record: WM-specific L528W/T474I incidence is still unmeasured anywhere in this pack.\n\nL5 promotes to CANDIDATE (0.45), not higher. WM-specific BCL2-inhibitor activity is now asserted (PMID:42509106) but no BH3 profiling, no MCL1 dependency map, no numbers. Countervailing datapoint recorded so the desk does not repeat it: PMID:42255257 (LY.18) added venetoclax to R-GDP in R/R LBCL and found no EFS/OS difference versus contemporaneous R-GDP despite ORR 70.8% — adding a BCL2 inhibitor to genotoxic backbones in aggressive B-cell disease has already failed once; design WM cohorts as BTK-degrader + BCL2i fixed duration, not chemo-plus-venetoclax.\n\nNew L6: MYD88-independent T-cell redirection. Glofitamab monotherapy has now been reported in Richter transformation (PMID:42024463), and PMID:42509106/PMID:42278551 flag encouraging preliminary CAR-T and bispecific data in WM. CD20xCD3 engagement and CD19/CD22 CAR (NCT06340737) kill downstream of every NF-κB node lesion — C481S, L528W, PLCG2, CXCR4 S338*, BCL2 mutations — so this is the natural terminal salvage. Specific WM hazards to design around: IgM flare/hyperviscosity during cytokine release, pre-existing immune paresis compounding CD20-directed B-cell aplasia, and plasmacytic CD20-low compartments.\n\nL3 weakened: EXS73565's target remains undisclosed in NCT06980116 for a second consecutive visit; if visit 4 brings nothing, retire and re-open only as a MALT1-vs-IRAK4 preclinical question. L1 unchanged — no new pentixafor imaging, CXCR4 prevalence still unresolved.","leadChanges":[{"id":"L2","title":"BTK degradation and non-covalent BTK occupancy for BTKi-resistant MYD88-mutant WM","level":"DOSSIER","status":"STRENGTHENED","confidence":0.68},{"id":"L5","title":"BCL2-axis dependence and MRD-guided fixed duration in post-BTKi WM","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.45},{"id":"L6","title":"MYD88-node-independent T-cell redirection (CD20xCD3 bispecifics, CD19/CD22 CAR-T) for multi-refractory and transformed WM","level":"LEAD","status":"NEW","confidence":0.38},{"id":"L3","title":"Bypassing BTK entirely: MALT1/IRAK4 blockade downstream of the L265P myddosome","level":"LEAD","status":"WEAKENED","confidence":0.26}],"unverifiedCitations":0,"openQuestions":["What are the actual WM-specific response rates, durations and genotype subsets behind PMID:42509106's claim of BTK-degrader, non-covalent BTKi and BCL-2 inhibitor efficacy in cBTKi-refractory WM - i.e. what are the BGB-16673 and sonrotoclax","What is the frequency of BTK C481S/T474I/L528W and PLCG2 alleles at progression in WM specifically, and does BGB-16673 clear L528W-bearing WM clones?","Is there any WM primary-cell BH3 profiling or MCL1/BCL2L1 dependency map to convert the BCL2 lead from review-level assertion to mechanism, and does MYD88 L265P NF-kB output actually drive BCL2/MCL1 transcription in WM?","Can CD20xCD3 bispecifics be given safely in high-IgM WM without hyperviscosity/flare during step-up dosing, and does the CD20-low plasmacytic compartment predict escape?","What is the true CXCR4-mutation prevalence in systematically tested WM cohorts, and does 68Ga-pentixafor uptake in BTKi-treated WM track CXCR4 S338* and MYD88 MRD rather than bulk?","Does TME/stromal-mediated BTKi resistance (PMID:41721839) operate in WM marrow, and is it degradation-sensitive via the VCAM-1/ILK scaffold?"],"nextQueries":["(\"Waldenstrom\" OR \"lymphoplasmacytic lymphoma\") AND (\"BGB-16673\" OR \"BTK degrader\" OR sonrotoclax OR pirtobrutinib) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"Waldenstrom\" OR \"lymphoplasmacytic lymphoma\") AND (glofitamab OR mosunetuzumab OR epcoritamab OR \"CAR-T\" OR \"bispecific antibody\") AND SRC:MED","(\"Waldenstrom\" OR \"MYD88 L265P\") AND (\"BH3 profiling\" OR MCL1 OR \"BCL2 dependency\" OR \"CXCR4 mutation\" OR pentixafor) AND SRC:MED"],"papersShown":[{"pmid":"41594662","doi":"10.3390/biom16010123","year":2026,"isNew":true,"title":"BTK Inhibition in Hematology: From CLL/SLL to Emerging Applications Across B-Cell and Immune Disorders"},{"pmid":"40944468","doi":"10.1111/ejh.70036","year":2025,"isNew":true,"title":"Bruton Tyrosine Kinase Inhibitors in Mantle Cell Lymphoma: What Are the Current Options?"},{"pmid":"41721839","doi":"10.1007/s00277-026-06775-x","year":2026,"isNew":true,"title":"Mechanisms of resistance to bruton's tyrosine kinase inhibitors: synergistic effects of tumor microenvironment regulation and signaling pathways"},{"pmid":"41447345","doi":"10.1111/jcmm.70987","year":2025,"isNew":true,"title":"The Direction of Modern Therapies in Waldenström Macroglobulinaemia"},{"pmid":"42255257","doi":"10.1016/j.bneo.2026.100233","year":2026,"isNew":true,"title":"A phase 1 study of R-GDP-venetoclax before autologous transplant in relapsed/refractory large B-cell lymphoma (CCTG LY.18)"},{"pmid":"42509106","doi":"10.1016/j.clml.2026.06.016","year":2026,"isNew":true,"title":"SOHO State-of-the-Art Updates and Next Questions: Current Approach to Waldenström Macroglobulinemia"},{"pmid":"42278551","doi":"10.3390/ijms27115026","year":2026,"isNew":true,"title":"Molecular Insights and Novel Therapies for Lymphoproliferative Disorders"},{"pmid":"42024463","doi":"10.1182/bloodadvances.2025018159","year":2026,"isNew":true,"title":"Glofitamab monotherapy in patients with Richter transformation: safety and efficacy from a phase 1 study"},{"pmid":"41963772","doi":"10.1002/dc.70118","year":2026,"isNew":true,"title":"The Atypical and Suspicious for Malignancy Categories of the WHO Reporting System for Lymph Node, Spleen, and Thymus Cytopathology: Review of their Diagnostic Utility, Limitations,"},{"pmid":"41850888","doi":"10.1111/bjh.70445","year":2026,"isNew":true,"title":"Daratumumab plus bortezomib and dexamethasone (Dara-VD) in newly diagnosed Mayo 2004 stage IIIA and IIIB light-chain amyloidosis: Long-term follow-up results from a prospective pha"}],"trialsShown":[{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT00923507","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphopla"},{"nct":"NCT04728893","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)"},{"nct":"NCT06980116","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Dose Determining Study of EXS73565 in Participants With Relapsed or Refractory B-Cell Malignancies"},{"nct":"NCT00039676","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Clinical, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Hematologic Cancer"},{"nct":"NCT06340737","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"AutologousCD22 Chimeric Antigen Receptor (CAR)T Cells in w/Recurrent/Refractory B Cell Lymphomas"},{"nct":"NCT07426484","phase":"phase 4","status":"RECRUITING","isNew":false,"title":"Cosibelimab for CSCC in Patients With Kidney Transplant or Hematologic Malignancy"},{"nct":"NCT07169331","phase":"phase 4","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate the Efficacy and Safety of Zanubrutinib in Chinese Adults With Treatment-Naive Waldenström Macroglobulinemia"}],"usage":{"input":11349,"output":7610},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"Waldenstrom\" OR \"lymphoplasmacytic lymphoma\") AND (venetoclax OR sonrotoclax OR \"BH3 profiling\" OR BCL2 OR MCL1) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"Waldenstrom\" OR \"MYD88 L265P\") AND (\"BTK mutation\" OR PLCG2 OR \"acquired resistance\") AND (zanubrutinib OR ibrutinib OR pirtobrutinib) AND SRC:MED"],"evidenceIds":["PMID:41594662","PMID:40944468","PMID:41721839","PMID:41447345","PMID:42255257","PMID:42509106","PMID:42278551","PMID:42024463","PMID:41963772","PMID:41850888","NCT05006716","NCT00923507","NCT04728893","NCT06980116","NCT00039676","NCT06340737","NCT07426484","NCT07169331"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787184992931","cycle":175,"visit":3,"ts":"2026-08-20T00:16:32.931Z","cancer":{"key":"multiple myeloma","name":"multiple myeloma","mondo":{"id":"MONDO:0009693","name":"plasma cell myeloma"}},"control":false,"modelLabel":"SCIENCE","summary":"p300/CBP-IRF4 is now a cited, myeloma-specific dependency worth prioritising, but catalytic KAT inhibition or dual degradation looks superior to the bromodomain inhibitor (inobrodib) currently in phase 3 — while ex vivo functional T-cell profiling, not antigen density, is the first validated predict","confidence":0.6,"notebook":"The pack's centre of gravity is transcriptional. PMID:41248492 converts L3 from a [KNOWN]-only rationale into a cited, myeloma-specific dependency argument: unbiased network mapping plus quantitative interactome data place p300 as IRF4's dominant coactivator, IRF4 as the most abundant MM-specific dependency, and optimised p300 KAT inhibitors selectively collapse the IRF4 network ex vivo/in vivo with preferential killing of MM over normal cells, synergising with orthogonally transcription-directed agents. Two caveats matter and they cut against the specific molecule I had been tracking: the same paper reports that KAT-site inhibition suppresses IRF4 activity *more completely and at lower exposure* than existing bromodomain inhibitors, and PMID:41044247 shows dual p300/CBP degradation beats bromodomain-only or single-paralog targeting at enhancers (with no evident toxicity in mice, and H2BNTac as an enhancer-addiction marker). So the mechanism strengthens while the modality choice weakens: inobrodib (bromodomain, NCT07772024) may be a pharmacologically suboptimal probe of a correct target, and a negative phase 3 would not falsify p300/CBP dependency. PMID:42139346 supports combination logic — inobrodib + venetoclax + gilteritinib eliminates DNMT3A/FLT3 LSCs — which is the closest cited support for my proposed inobrodib+venetoclax test in t(11;14)/CCND1 [SOMATIC] disease. PMID:41268574 supplies super-enhancer framing (BET/CDK7/9 as orthogonal partners). L3 → CANDIDATE, 0.62, with IRF4 target-gene signature and H2BNTac/H3K27ac as PD readouts and a mandate to compare KAT inhibitor/degrader versus bromodomain classes.\n\nOn the immunotherapy axis, PMID:42463945 is a partial challenge to L1's core premise. An image-based ex vivo BM-MNC assay classifies patients as non-responder/cytotoxic/cytotoxic-expansive by synapse productivity and T-cell morphologic trajectory, and this stratified clinical response and time on therapy for teclistamab/talquetamab monotherapy — i.e. intrinsic T-cell competence, not antigen level, explains a substantial share of primary refractoriness (~40%). PMID:41396414 likewise argues for assessing both BCMA expression and T-cell exhaustion before sequencing. L1 therefore stays CANDIDATE (0.70, not promoted): the density-triggered-switch element remains entirely unmeasured in any cited dataset and now has a competing explanatory variable. I split off L7 — functional immune profiling as an assignment assay routing immune-incompetent patients to non-immunological therapy (p300 KAT inhibition, melflufen, ADC) rather than to a second engager. PMID:42309027 (AL amyloidosis: grade ≥3 infection 25%) reinforces that engager toxicity is largely T-cell/immunoglobulin-mediated, not antigen-dependent.\n\nPMID:42359424 quantifies the EMD bar for single-antigen bispecifics (teclistamab 58.3%, elranatamab 38.5%; only 4 trials, 144 patients), giving L6 a real comparator and further undermining L4, which I now hold at kill-threshold.","leadChanges":[{"id":"L3","title":"p300/CBP bromodomain inhibition (inobrodib) as a transcription-addiction attack orthogonal to proteasome, IMiD and BCMA pressure","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.62},{"id":"L1","title":"Antigen-escape-adapted BCMA immunotherapy: pre-specify BCMA density/shedding and switch antigen rather than re-treat","level":"CANDIDATE","status":"WEAKENED","confidence":0.7},{"id":"L7","title":"Functional ex vivo immune profiling as a treatment-assignment assay: route immune-incompetent myeloma away from T-cell engagers","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L6","title":"Simultaneous dual-antigen T-cell engagement (BCMA+GPRC5D) for extramedullary and antigen-heterogeneous myeloma, with infection prophylaxis as the co-primary des","level":"LEAD","status":"STRENGTHENED","confidence":0.45},{"id":"L4","title":"XPO1 inhibition (selinexor) added to VRd for high-risk NDMM with extramedullary/plasma-cell-leukaemia biology — depth of response is the limiting problem","level":"LEAD","status":"WEAKENED","confidence":0.22}],"unverifiedCitations":0,"openQuestions":["Does catalytic p300 KAT inhibition or dual p300/CBP degradation suppress the IRF4 network more deeply than inobrodib in primary myeloma, and is an IRF4 target-gene signature (or H2BNTac/H3K27ac) a usable clinical PD readout?","Does t(11;14)/CCND1 [SOMATIC] or 1q status predict response to p300/CBP inhibition, and does the inobrodib+venetoclax synergy seen in AML reproduce in BCL2-dependent myeloma?","Does the ex vivo functional immune phenotype (PMID:42463945) predict benefit from antigen switching versus non-immunological salvage, and is it concordant with surface BCMA/GPRC5D density and TNFRSF17 copy number?","What is the mechanism/target of AZD0305 (NCT06106945) — still unstated after three visits?","Is there any +1q-stratified randomised or registry comparison of isatuximab versus daratumumab, and does +1q-associated CD38 downregulation/CDC impairment abolish benefit from either?","Is LIG4 [SOMATIC-likely] alteration in myeloma an exploitable NHEJ-deficiency state (PARP/POLQ/ATR) or only a genomic-instability correlate?"],"nextQueries":["(\"multiple myeloma\") AND (\"inobrodib\" OR \"CCS1477\" OR \"p300 degrader\" OR \"EP300\" OR \"CREBBP\") AND (\"venetoclax\" OR \"t(11;14)\" OR \"IRF4 signature\" OR \"pharmacodynamic\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"multiple myeloma\") AND (\"BCMA\" OR \"TNFRSF17\" OR \"GPRC5D\") AND (\"antigen density\" OR \"receptor quantification\" OR \"soluble BCMA\" OR \"copy number loss\") AND (\"bispecific\" OR \"CAR T\") AND SRC:MED AND PUB_YEAR:[2025 TO 202","(\"multiple myeloma\") AND (\"1q21\" OR \"gain(1q)\" OR \"amp(1q)\") AND (\"isatuximab\" OR \"daratumumab\") AND (\"CD38 expression\" OR \"complement\" OR \"progression-free survival\") AND SRC:MED"],"papersShown":[{"pmid":"39825161","doi":"10.1007/s10565-024-09984-0","year":2025,"isNew":true,"title":"The important role of the histone acetyltransferases p300/CBP in cancer and the promising anticancer effects of p300/CBP inhibitors"},{"pmid":"41044247","doi":"10.1038/s41588-025-02336-6","year":2025,"isNew":true,"title":"Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer"},{"pmid":"41268574","doi":"10.3389/fcell.2025.1674470","year":2025,"isNew":true,"title":"Super enhancers as key drivers of gene regulatory networks in normal and malignant hematopoiesis"},{"pmid":"42309027","doi":"10.1016/j.leukres.2026.108267","year":2026,"isNew":true,"title":"Efficacy and safety of BCMA-directed bispecific antibodies in relapsed and/or refractory systemic AL amyloidosis: A systematic review and meta-analysis"},{"pmid":"42463945","doi":"10.1038/s41375-026-03047-5","year":2026,"isNew":true,"title":"Functional immune profiling translates T cell dynamics into predictive biomarkers for myeloma immunotherapy"},{"pmid":"41396414","doi":"10.1007/s12185-025-04128-4","year":2026,"isNew":true,"title":"Characteristics and utilization of the three BCMA-targeted therapies in multiple myeloma"},{"pmid":"41017162","doi":"10.1002/art.43404","year":2026,"isNew":true,"title":"Sjögren Disease-B Cells at the Brink: From Autoimmunity to Lymphomagenesis and the Rise of Novel B Cell-Targeted Therapies"},{"pmid":"42359424","doi":"10.7759/cureus.111438","year":2026,"isNew":true,"title":"Efficacy of Bispecific Antibodies in Relapsed or Refractory Multiple Myeloma With Extramedullary Disease: A Systematic Review and Meta-Analysis"},{"pmid":"42139346","doi":"10.1126/sciadv.aec9305","year":2026,"isNew":true,"title":"P300/CBP inhibition with inobrodib in combination with gilteritinib and venetoclax targets leukemia stem cells in epigenetic mutant AML"},{"pmid":"41248492","doi":"10.1158/0008-5472.can-25-3440","year":2026,"isNew":true,"title":"Catalytic Inhibition of p300 Preferentially Targets IRF4 Oncogenic Activity and Tumor Growth in Multiple Myeloma"}],"trialsShown":[{"nct":"NCT06106945","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"AZD0305 as Monotherapy or in Combination With Anticancer Agents in Participants With Multiple Myeloma"},{"nct":"NCT05714839","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Investigate the Safety and Efficacy of Belantamab for the Treatment of Multiple Myeloma When Used as Monotherapy and in Combinati"},{"nct":"NCT03937635","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Lenalidomide, and Dexamethasone With or Without Daratumumab in Treating Patients With High-Risk Smoldering Myeloma"},{"nct":"NCT04566328","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Testing the Use of Combination Therapy in Adult Patients With Newly Diagnosed Multiple Myeloma, the EQUATE Trial"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT07772024","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Inobrodib, Pomalidomide and Dexamethasone Versus Standard Available Therapy in Relapsed or Refractory Multiple Myeloma"},{"nct":"NCT04898790","phase":"NA","status":"RECRUITING","isNew":false,"title":"Improving Cognitive Function in Older Adults Undergoing Stem Cell Transplant"},{"nct":"NCT07485647","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Identifying Effective and Cost-Conscious Maintenance Daratumumab Dosing"}],"usage":{"input":12804,"output":7936},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"multiple myeloma\") AND (\"talquetamab\" OR \"teclistamab\" OR \"cevostamab\") AND (\"antigen density\" OR \"TNFRSF17\" OR \"GPRC5D loss\" OR \"single-cell\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"multiple myeloma\") AND (\"inobrodib\" OR \"CCS1477\" OR \"p300\" OR \"CBP\") AND (\"IRF4\" OR \"MYC\") AND SRC:MED"],"evidenceIds":["PMID:39825161","PMID:41044247","PMID:41268574","PMID:42309027","PMID:42463945","PMID:41396414","PMID:41017162","PMID:42359424","PMID:42139346","PMID:41248492","NCT06106945","NCT05714839","NCT03937635","NCT04566328","NCT06904066","NCT07772024","NCT04898790","NCT07485647"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787184770338","cycle":174,"visit":3,"ts":"2026-08-20T00:12:50.338Z","cancer":{"key":"myelodysplastic syndrome","name":"myelodysplastic syndrome","mondo":{"id":"MONDO:0018881","name":"myelodysplastic syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"IRAK4 is now a clinically drugged, MDS-relevant target but only modestly active alone (PMID:40634180, PMID:40670672), so the desk pivots to IRAK4-inhibitor combinations — chiefly CELMoD/GSPT1-degrader co-targeting via c-Myc destabilization — while PRMT5 is downgraded for lack of any myeloid programm","confidence":0.5,"notebook":"This visit's pack was a targeted IRAK4/PRMT5 probe, and it answered two open questions asymmetrically.\n\nOQ2 is largely resolved. An IRAK4-selective inhibitor with clinical data in myeloid disease exists: emavusertib (CA-4948), with TakeAim Leukemia data and preclinical MDS activity reported (PMID:40634180). But the same pack tempers it — IRAK4 inhibitors show \"only modest clinical efficacy\" as single agents in AML (PMID:40670672). So target validation strengthens while the monotherapy premise weakens. L3 (pacritinib) keeps its CANDIDATE level: the axis is real and now has MDS-specific preclinical support, but pacritinib hits IRAK1, not the genetically validated IRAK4 (PMID:40333990), and the ceiling for single-agent innate-kinase blockade looks low. The constructive output is a new lead: IRAK4 inhibition plus CELMoD-mediated GSPT1 degradation, where the screen hit CC-885 synergised with IRAK4 loss/inhibition and converged on c-Myc destabilisation — GSPT1 loss slows translation of short-half-life proteins, and IRAK4 inhibition independently destabilises c-Myc protein, validated in AML patient cells (PMID:40670672). [KNOWN] GSPT1/eRF3a is an essential translation-termination factor and prior GSPT1 degraders were myelosuppressive, so the window in a cytopenic disease is the whole argument and must be measured on normal CD34+ colonies.\n\nOQ3 is answered negatively. A PRMT5-plus-myeloid query returned no myeloid clinical or trial data — only GSK3326595 delivered by bone-targeted nanoparticle in osteosarcoma (PMID:42006004). L5 is weakened: no PRMT5 programme in myeloid neoplasms surfaced, and the haematopoietic window remains unquantified. Logged so the desk does not re-propose PRMT5 as near-term translational.\n\nP7 (PMID:41143913) independently names IDH1/2-mutant MDS as an emerging WHO-adjacent subgroup with multiple trials underway, giving L4 its first citation independent of NCT06566742 — promoted to CANDIDATE, held at 0.48 because no response data exist for pre-blast-phase IDH1 intervention.\n\nTwo concordant reviews (PMID:40563403, PMID:40349084) place inflammasome-driven HSC pyroptosis and stromal reprogramming upstream of the kinase leads — new lead for inflammasome-directed therapy in lower-risk MDS, distinct from IRAK4 blockade.\n\nL1, L2, L6 unchanged: nothing in the pack touched XPO1, BCL-xL platelet sparing (the PROTAC reviews cover GPX4/PARP/epigenetic targets only, PMID:41885448), or VAF trajectories. OQ4–6 carry forward.","leadChanges":[{"id":"L3","title":"Innate-immune kinase blockade (pacritinib: IRAK1/CSF1R/JAK2/FLT3) in MDS and MDS/MPN overlap","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.54},{"id":"L7","title":"IRAK4 inhibition combined with CELMoD-mediated GSPT1 degradation in MDS-EB and MDS-derived secondary AML — convergent c-Myc destabilization","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L4","title":"IDH1 inhibition (olutasidenib) as clonal interception in IDH1-mutant CCUS and lower-risk MDS/CMML","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.48},{"id":"L5","title":"PRMT5 inhibition to reverse U2AF1-like missplicing in MDS and MDS-derived secondary AML","level":"LEAD","status":"WEAKENED","confidence":0.38},{"id":"L8","title":"Inflammasome-driven HSC pyroptosis and stromal reprogramming as the upstream target in lower-risk MDS","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["What are the actual response rates, duration and toxicity of emavusertib in MDS specifically (TakeAim Leukemia MDS cohort), and do spliceosome-mutant or U2AF1-like-signature patients respond preferentially?","Has any GSPT1-directed CELMoD (e.g. CC-90009-class) been dosed in MDS or post-MDS sAML, and what were the haematological toxicity and CRBN-loss resistance patterns that would bound an IRAK4-inhibitor combination?","Is any PRMT5 inhibitor in a myeloid-neoplasm clinical trial at all, and is there any quantitative measure of PRMT5-inhibition effect on normal human CD34+ self-renewal?","Do luspatercept or imetelstat reduce SF3B1/TET2/ASXL1 VAF in LR-MDS, and does baseline inflammasome/IL-1 activity predict failure of either agent?","Is there any published response data for XPO1 inhibitor plus venetoclax stratified by TP53 status in MDS, and does venetoclax add benefit in MDS-derived secondary AML?","Are there platelet-sparing BCL-xL modalities (lineage-directed degraders, intermittent dosing) with myeloid data, and does a BCL2:BCL2L1 ratio prospectively select responders?"],"nextQueries":["(emavusertib OR \"CA-4948\") AND (myelodysplastic OR MDS OR \"TakeAim\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(GSPT1 OR \"CC-90009\" OR eragidomide OR CELMoD) AND (myelodysplastic OR \"acute myeloid leukemia\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","((NLRP3 OR inflammasome OR S100A9 OR \"IL-1beta\" OR anakinra) AND (myelodysplastic OR \"lower-risk MDS\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"40563403","doi":"10.3390/biom15060761","year":2025,"isNew":true,"title":"Myelodysplastic Neoplasms (MDS): Pathogenesis and Therapeutic Prospects"},{"pmid":"40670672","doi":"10.1038/s41375-025-02695-3","year":2025,"isNew":true,"title":"Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization"},{"pmid":"40349084","doi":"10.1186/s12935-025-03793-z","year":2025,"isNew":true,"title":"Bone marrow microenvironment in myelodysplastic neoplasms: insights into pathogenesis, biomarkers, and therapeutic targets"},{"pmid":"40634180","doi":"10.1016/j.clml.2025.05.020","year":2025,"isNew":true,"title":"Meeting Report From the 2024 Symposium on IRAK4 in Cancer: Highlights and Clinical Updates"},{"pmid":"41606955","doi":"10.1080/15384047.2026.2621606","year":2026,"isNew":true,"title":"Glutamine transporter SLC1A5 inhibits autophagy-mediated CD276 degradation to promote esophageal cancer progression"},{"pmid":"42006004","doi":"10.1016/j.bioactmat.2026.03.032","year":2026,"isNew":true,"title":"Manganese-potentiated cGAS-STING activation with ATM/PRMT5 inhibition remodels the immunosuppressive microenvironment in osteosarcoma &lt;i&gt;via&lt;/i&gt; bone-targeted delivery"},{"pmid":"41143913","doi":"10.1007/s11899-025-00762-1","year":2025,"isNew":true,"title":"Myelodysplastic syndromes: Updates on Genomic Landscape, Molecular Subtypes, &amp; Targeted Therapies"},{"pmid":"42092750","doi":"10.1080/10717544.2026.2665871","year":2026,"isNew":true,"title":"Targeted proteoform degradation for precision drug design, delivery, and therapy"},{"pmid":"41885448","doi":"10.1080/14756366.2026.2636394","year":2026,"isNew":true,"title":"PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators"},{"pmid":"42326738","doi":"10.1016/j.bonr.2026.101930","year":2026,"isNew":true,"title":"Genomic landscape and tumor immune microenvironment of osteosarcoma: Bridging mechanistic insights to precision therapeutics"}],"trialsShown":[{"nct":"NCT07228624","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Ruxolitinib Before, During and After Hematopoietic Cell Transplant in Older Patients With Myelofibrosis and Myelodysplastic Syndrome/Myelopr"},{"nct":"NCT06399640","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Eltanexor and Venetoclax in Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT06782373","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Assess the Effectiveness and Safety of Pacritinib in Patients With VEXAS Syndrome (PAXIS)"},{"nct":"NCT06303193","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysp"},{"nct":"NCT04898790","phase":"NA","status":"RECRUITING","isNew":false,"title":"Improving Cognitive Function in Older Adults Undergoing Stem Cell Transplant"},{"nct":"NCT02521493","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syn"}],"usage":{"input":13018,"output":8232},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(PRMT5 AND (inhibitor OR GSK3326595 OR PF-06939999 OR JNJ-64619178) AND (leukemia OR myelodysplastic OR myeloid)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","((IRAK4 OR emavusertib OR CA-4948) AND (myelodysplastic OR \"lower-risk MDS\" OR AML)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:40563403","PMID:40670672","PMID:40349084","PMID:40634180","PMID:41606955","PMID:42006004","PMID:41143913","PMID:42092750","PMID:41885448","PMID:42326738","NCT07228624","NCT06399640","NCT06904066","NCT06566742","NCT06782373","NCT06303193","NCT04898790","NCT02521493"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787184544334","cycle":173,"visit":3,"ts":"2026-08-20T00:09:04.334Z","cancer":{"key":"chronic lymphocytic leukemia","name":"chronic lymphocytic leukemia","mondo":{"id":"MONDO:0004948","name":"B-cell chronic lymphocytic leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Hold BTK degraders at CANDIDATE while adding immunoglobulin/infection endpoints (degraders may spare T cells versus covalent BTKi), set a kill criterion for the DDR-synthetic-lethality lead after two CLL-data-free packs, and open a low-confidence MDM2-reactivation lead for TP53-wild-type CLL.","confidence":0.55,"notebook":"This visit's pack was thin and review-heavy: no primary data on A428D, CRBN, or degrader escape arrived, so open questions 1–4 stand entirely unmoved. Nothing here justifies promotion of L1 to DOSSIER, and I am declining to promote on a narrative review.\n\nThe one CLL-specific new item is PMID:42192981, which addresses the therapeutic-window half of L1 rather than its efficacy half: covalent BTKi-associated hypogammaglobulinaemia and opportunistic infection are attributed partly to off-target T-cell/myeloid kinase inhibition, and the review argues non-covalent inhibitors and BTK degraders — being more selective — may preserve T-cell function. Mechanistically that matters because my stated on-target expectation for degraders was XLA-like humoral failure; if the infection burden of covalent agents is substantially off-target (TEC/BMX/EGFR-family, ITK) [KNOWN], degraders could carry a *lower* infectious penalty than the class average, though total BTK protein removal (not just catalytic block) could equally be worse for B-cell fitness. This is a testable divergence, not a resolved one; it is explicitly flagged as long-term-unstudied in the source. L1 stays CANDIDATE, confidence nudged to 0.70, with IgG trajectory and pathogen-stratified infection rates now a named primary safety endpoint in NCT05006716/NCT07221500 rather than an afterthought.\n\nL6 is weakened again. A second consecutive pack returned only pan-cancer DDR reviews (PMID:42025253 restates that ATM loss sensitizes to ATR and PARP inhibition; PMID:42098732, PMID:41402978 are generic synthetic-lethality/immunotherapy syntheses) and zero CLL ex vivo or clinical data. Two evidence-bearing visits with no substrate is a signal about the literature, not a gap in my queries. I am setting an explicit kill criterion: if a targeted query for primary-CLL ATR/WEE1/CHK1 sensitivity returns nothing next visit, L6 retires. PMID:42025253 also usefully reinforces germline/somatic discipline — pathogenic ATM variants in ~1/100 people [GERMLINE] means heterozygous carriers among 11q-deleted CLL patients may have altered DDRi tolerability, a stratification I keep.\n\nNew lead from PMID:42086932: MDM2 inhibition to reactivate wild-type p53. CLL is predominantly TP53-wild-type at diagnosis [KNOWN], the exact setting where the review reports disease-modifying activity (myelofibrosis) after negative phase III AML trials, and where combination with BCL-2 antagonists is proposed — a natural venetoclax/sonrotoclax partner since p53 reactivation raises PUMA/BAX tone. The review's own warning is the lead's main risk: MDM2 inhibitors select TP53-mutant clones, which in CLL is the single worst prognostic event. Opened at low confidence (0.25); no CLL data exist in this pack. Noted and not pursued: NCT06904066 (neoantigen TCR) — CLL's low mutational burden makes it a poor fit [KNOWN].","leadChanges":[{"id":"L1","title":"BTK protein degradation for BTKi-resistant CLL/SLL with scaffold or kinase-impaired BTK mutants","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.7},{"id":"L6","title":"ATR/CHK1/WEE1 synthetic lethality in ATM-deleted (11q) and TP53-disrupted CLL","level":"LEAD","status":"WEAKENED","confidence":0.18},{"id":"L7","title":"MDM2 inhibition to reactivate wild-type p53 in TP53-wild-type CLL, combined with BCL2 antagonism","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["What is the pretreatment prevalence of BTK A428D subclones in BTKi-exposed CLL, and what ddPCR/ctDNA VAF floor is required to exclude patients from degrader monotherapy?","Do BGB-16673 or NX-5948 cohorts show lower IgG nadirs and fewer opportunistic/fungal infections than covalent BTKi controls, as the selectivity argument predicts, or does total BTK removal worsen humoral deficiency?","Are CRBN/DDB1/neddylation-pathway losses or BTK loss-of-expression observed at all as degrader-specific escape, or is adenine-pocket binding failure the sole clinical route?","Does any primary CLL ex vivo dataset show ATR/CHK1/WEE1-inhibitor sensitivity, and is it restricted to CD40L/CpG-stimulated proliferation-centre mimics versus quiescent circulating cells? (retirement trigger for L6)","Has any MDM2 inhibitor been tested in CLL or SLL cells, and does p53 reactivation synergize with venetoclax specifically in TP53-wild-type cases without selecting TP53-mutant subclones?","Is Richter transformation enriched on BTK degraders, and does it co-occur with A428D or with TP53 disruption?"],"nextQueries":["(\"chronic lymphocytic leukemia\" OR \"CLL cells\") AND (\"ATR inhibitor\" OR ceralasertib OR berzosertib OR adavosertib OR WEE1 OR prexasertib) AND (\"primary cells\" OR \"ex vivo\" OR CD40L OR \"proliferation center\") AND SRC:MED","(\"chronic lymphocytic leukemia\" OR \"B-cell lymphoma\") AND (MDM2 OR navtemadlin OR idasanutlin OR siremadlin OR \"p53 reactivation\") AND (venetoclax OR BCL2 OR apoptosis) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"BTK degrader\" OR bexobrutideg OR \"BGB-16673\" OR \"NX-5948\") AND (immunoglobulin OR hypogammaglobulinemia OR infection OR neutropenia OR \"T cell\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"41402978","doi":"10.1186/s12957-025-04101-9","year":2025,"isNew":true,"title":"Research progress of DNA damage repair (DDR) and DDR inhibitors in tumor immunotherapy"},{"pmid":"42187721","doi":"10.3390/biology15100759","year":2026,"isNew":true,"title":"Disrupting the Undruggable: Emerging Modalities for Targeting Protein-Protein Interactions in Oncology"},{"pmid":"42259777","doi":"10.1038/s41392-026-02714-4","year":2026,"isNew":true,"title":"Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases"},{"pmid":"42086932","doi":"10.1038/s41375-026-02975-6","year":2026,"isNew":true,"title":"MDM2 inhibitors in myeloid cancers: from basic biology to clinical use in myeloproliferative neoplasms"},{"pmid":"42192981","doi":"10.3390/cancers18101621","year":2026,"isNew":true,"title":"The Immunologic Paradox of BTK Inhibitors in Chronic Lymphocytic Leukemia: Selectivity, Hypogammaglobulinemia, and Infection Risk"},{"pmid":"42098732","doi":"10.1186/s12964-026-02932-x","year":2026,"isNew":true,"title":"Synthetic lethality in cancer: mechanism exploration and therapeutic applications"},{"pmid":"42025253","doi":"10.1016/j.neo.2026.101309","year":2026,"isNew":true,"title":"Ataxia telangiectasia mutated (ATM) kinase as a predictive biomarker in clinical oncology: implications for a precision treatment approach"},{"pmid":"40422251","doi":"10.3390/cells14100748","year":2025,"isNew":false,"title":"Cancer Vulnerabilities Through Targeting the ATR/Chk1 and ATM/Chk2 Axes in the Context of DNA Damage"},{"pmid":"41614897","doi":"10.3390/cimb48010067","year":2026,"isNew":false,"title":"Replication Stress in Cancer: Mechanistic Insights and Therapeutic Opportunities for Radiosensitization"},{"pmid":"40759474","doi":"10.14791/btrt.2025.0017","year":2025,"isNew":false,"title":"Therapeutic Targeting of DNA Damage Response Pathways in &lt;i&gt;TP53&lt;/i&gt;- and &lt;i&gt;ATM&lt;/i&gt;-Mutated Tumors"}],"trialsShown":[{"nct":"NCT02966756","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of Venetoclax in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma"},{"nct":"NCT07221500","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Study of NX-5948 in Adults With CLL/SLL Previously Treated With a Bruton's Tyrosine Kinase Inhibitor and a B-cell Lymphoma-2 Inhibitor (DA"},{"nct":"NCT07774390","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Ibrutinib Plus Venetoclax Long-Term Outcomes in CLL"},{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT07277231","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Sonrotoclax (BGB-11417) Plus Zanubrutinib (BGB-3111) Compared With Venetoclax Plus Acalabrutinib in Adults With Previ"},{"nct":"NCT05082519","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Caloric Restriction and Activity to Reduce Chemoresistance in B-ALL"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"}],"usage":{"input":12493,"output":6199},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic lymphocytic leukemia\" AND (\"A428D\" OR CRBN OR cereblon) AND (degrader OR PROTAC OR bexobrutideg OR \"NX-5948\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic lymphocytic leukemia\" AND (ATR inhibitor OR ceralasertib OR WEE1 OR adavosertib OR CHK1) AND (ATM OR \"11q deletion\" OR TP53) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"evidenceIds":["PMID:41402978","PMID:42187721","PMID:42259777","PMID:42086932","PMID:42192981","PMID:42098732","PMID:42025253","PMID:40422251","PMID:41614897","PMID:40759474","NCT02966756","NCT07221500","NCT07774390","NCT05006716","NCT06904066","NCT07277231","NCT05082519","NCT03147612"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787184340531","cycle":172,"visit":3,"ts":"2026-08-20T00:05:40.531Z","cancer":{"key":"acute lymphoblastic leukemia","name":"acute lymphoblastic leukemia","mondo":{"id":"MONDO:0004967","name":"acute lymphoblastic leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"In post-CD19 failure B-ALL, most relapses retain CD19 and CD22-directed salvage (inotuzumab or CD22 CAR-T, equivalent on multivariate analysis) yields ~51% CR but only ~236-day median RFS with sanctuary-site failure — so CD22 salvage should be designed explicitly as an antigen-stratified bridge to H","confidence":0.6,"notebook":"This visit's pack answers open question 3 with real numbers and reshapes the post-CD19 arm of the programme. In 43 r/r B-ALL patients progressing after blinatumomab and/or CD19 CAR-T, only 34.9% relapsed CD19-negative — so the majority of failures are effector/persistence failures with antigen retained — and CD22-directed salvage (CD22 CAR-T 55.8% vs inotuzumab 44.2%) gave CR/CRi 51.1%, MRD-negativity only 30.2%, median RFS 236 days, with 59% of responders relapsing and no difference between modalities on multivariate analysis; extramedullary disease predicted worse remission and prior CD19 resistance predicted shorter RFS (PMID:41963478). A three-patient series post-CAR-T *and* post-allo-HSCT shows inotuzumab can still induce MRD-negative BM remission (including PET-documented extramedullary regression) without sinusoidal obstruction syndrome, but both relapses were sanctuary-site (CNS, breast) at 8 and 9.5 months (PMID:42387626). Read together: CD22 salvage is a bridge, not a destination, its failure mode is sanctuary/extramedullary, and the choice between InO and CD22 CAR should be driven by something other than efficacy priors — antigen density, prior SOS risk, bridging intent. A mechanistic review adds the third escape route I had under-weighted: myeloid lineage switch, enriched after CAR-T and associated with KMT2A rearrangement, driven by epigenetic reprogramming and bipotent progenitors (PMID:42023212) — so relapse work-up must include myeloid immunophenotyping, not just CD19/CD22 flow. L2 accordingly moves to DOSSIER: both arms are now instantiated by independent cohorts, and the lead has survived two falsification attempts (MRD as trigger endpoint, and now the durability claim, which I am explicitly downgrading to bridge-to-HSCT).\n\nThe KMT2A guardrail gains a constructive half. A review of adult KMT2Ar B-ALL positions menin inhibitors as the mechanistically matched agent, with antigen loss and lineage switch as the specific immunotherapy resistance routes in this subtype (PMID:42593564), converging with PMID:42023212. This reorients L6 away from venetoclax-containing doublets (which failed to prevent PDX outgrowth, PMID:42294111) toward a menin-inhibitor backbone with venetoclax/MEK as the add-on, tested on PDX survival; differentiation syndrome and MEN1 escape mutations are the named liabilities [KNOWN].\n\nNothing in the pack touched ZFP36L2 (the T-lineage query returned only an unrelated Andersen-Tawil case report, PMID:42253636), so L1/L3/L5 stand unchanged. L4 (exosomal MALAT1/METTL14→HMGB1) is retired per the pre-registered rule: still single-laboratory, no independent primary-NK replication, and a poor METTL14 window; it may re-enter on replication.\n\nNext I need menin-inhibitor primary/PDX data in ALL, CD22 antigen-density predictors of InO vs CD22-CAR failure, CNS-directed strategy in post-CD19 salvage, and the still-untouched Ph-like/JAK question.","leadChanges":[{"id":"L2","title":"CD19 re-engagement sequencing: T-cell engager AZD0486 after CAR-T failure, triggered by NGS-MRD/B-cell recovery","level":"DOSSIER","status":"STRENGTHENED","confidence":0.72},{"id":"L6","title":"KMT2A-rearranged infant ALL requires triplets, not venetoclax doublets — negative-result guardrail plus a triplet design","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.45},{"id":"L4","title":"Low-confidence: exosomal MALAT1/METTL14 → HMGB1 axis as an NK-directed chemoresistance node","level":"LEAD","status":"RETIRED","confidence":0.1}],"unverifiedCitations":0,"openQuestions":["Does CD22 antigen site density (or cytoplasmic-only CD22) prospectively discriminate inotuzumab failure from CD22 CAR-T failure after CD19-directed therapy, given the two modalities were statistically equivalent on multivariate analysis (PM","Can consolidative allo-HSCT (or a second cellular product) after CD22 salvage convert the observed ~236-day median RFS into durable remission, and does CNS-directed prophylaxis reduce the sanctuary-site relapses seen after inotuzumab?","What is the actual incidence of therapy-driven myeloid lineage switch in KMT2A-rearranged ALL under menin inhibition versus under CD19 CAR-T, and does menin inhibition accelerate or suppress it?","Is there primary-sample or PDX (not review-level) evidence for menin inhibitor plus venetoclax or plus chemotherapy in KMT2A-rearranged ALL, with survival rather than synergy-index endpoints?","Does ZFP36L2-low status predict benefit from dexamethasone + trametinib or dexamethasone + GSI in primary T-ALL/PDX, and does ZFP36L2 loss raise BCL2 enough to confer venetoclax sensitivity (L1/L5 link)?","Is there ALL-specific clinical or PDX evidence for JAK inhibition in Ph-like/CRLF2-rearranged disease — still uncovered by this programme after three visits?"],"nextQueries":["(\"acute lymphoblastic leukemia\" AND (\"menin inhibitor\" OR revumenib OR ziftomenib OR SNDX-5613) AND (KMT2A OR MLL)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"acute lymphoblastic leukemia\" AND (CRLF2 OR \"Ph-like\" OR JAK2) AND (ruxolitinib OR \"JAK inhibitor\" OR dasatinib)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"B-cell acute lymphoblastic leukemia\" AND CD22 AND (\"antigen density\" OR \"site density\" OR \"CD22 CAR\") AND (relapse OR resistance)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"42023212","doi":"10.3389/fimmu.2026.1692287","year":2026,"isNew":true,"title":"CD19-negative relapse after CAR-T cell therapy: mechanisms of antigen escape and lineage switch"},{"pmid":"42290672","doi":"10.3892/ol.2026.15678","year":2026,"isNew":true,"title":"Biological and pathogenic roles of major genes harbored in intrachromosomal amplification of chromosome 21 in childhood acute lymphoblastic leukemia (Review)"},{"pmid":"42258947","doi":"10.1016/j.neo.2026.101322","year":2026,"isNew":true,"title":"A malignant symbiosis: The neuro-metabolic symphony rewires the tumor microenvironment"},{"pmid":"42312176","doi":"10.1021/acsptsci.6c00005","year":2026,"isNew":true,"title":"Cyclin-Dependent Kinases 4 and 6 Inhibitors: An Emerging Therapeutic Framework from Growth Suppression to Tumor Clearance"},{"pmid":"42253636","doi":"10.1002/jha2.70316","year":2026,"isNew":true,"title":"T-Cell Acute Lymphoblastic Leukemia in a Young Patient With Andersen-Tawil Syndrome Successfully and Safely Treated With Intensive Chemotherapy Including Potential Precipitating Dr"},{"pmid":"42247509","doi":"10.1126/sciadv.aee7295","year":2026,"isNew":true,"title":"The impactful role of the HDACs in the regulation of gene expression and as targets for disease therapy"},{"pmid":"41963478","doi":"10.1038/s41698-026-01413-1","year":2026,"isNew":true,"title":"CD22-targeted immunotherapy for B-cell acute lymphoblastic leukemia progressing following CD19-targeted immunotherapy"},{"pmid":"42593564","doi":"10.1007/s00277-026-07191-x","year":2026,"isNew":true,"title":"Therapeutic Advances in Adult B-cell Acute Lymphoblastic Leukemia with KMT2A Rearrangements"},{"pmid":"41858754","doi":"10.1016/j.omton.2026.201171","year":2026,"isNew":true,"title":"The evolving landscape of CAR T cell therapy in children and young adults with B cell acute lymphoblastic leukemia"},{"pmid":"42387626","doi":"10.1002/cnr2.70601","year":2026,"isNew":true,"title":"Salvage Therapy With Inotuzumab Ozogamicin in Relapsed/Refractory B-ALL After CAR-T Therapy and HSCT: A Case Series"}],"trialsShown":[{"nct":"NCT05480904","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Characterizing Sleep Among Long-term Survivors of Childhood Cancer"},{"nct":"NCT07070219","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study of CTD402 in T-ALL/LBL Patients"},{"nct":"NCT03876769","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06137118","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"AZD0486 as Monotherapy in B-cell Acute Lymphoblastic Leukaemia"},{"nct":"NCT06710418","phase":"NA","status":"RECRUITING","isNew":false,"title":"Evaluating the Effects of Hemoglobin Threshold-specific Packed Red Blood Cell Transfusions on Quality of Life and Functional Outcomes in Pat"},{"nct":"NCT03007147","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblasti"},{"nct":"NCT05621291","phase":"NA","status":"RECRUITING","isNew":false,"title":"A Multicenter Study to Evaluate Next-Generation Sequencing (NGS) Testing and Monitoring of B-Cell Recovery to Guide Management Following Chi"}],"usage":{"input":13637,"output":7559},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"acute lymphoblastic leukemia\" AND (ZFP36L2 OR \"gamma-secretase\" OR NOTCH1 OR trametinib OR MEK) AND (glucocorticoid OR dexamethasone OR prednisolone)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"B-cell acute lymphoblastic leukemia\" AND (CD22 OR inotuzumab OR \"CAR-NK\") AND (\"antigen loss\" OR \"CD19-negative\" OR \"after CAR\" OR \"lineage switch\")) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:42023212","PMID:42290672","PMID:42258947","PMID:42312176","PMID:42253636","PMID:42247509","PMID:41963478","PMID:42593564","PMID:41858754","PMID:42387626","NCT05480904","NCT07070219","NCT03876769","NCT06904066","NCT06137118","NCT06710418","NCT03007147","NCT05621291"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787184121632","cycle":171,"visit":17,"ts":"2026-08-20T00:02:01.632Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Fusion-junction peptide vaccination is immunogenic but not disease-modifying in CML (GIMEMA 10-year follow-up), so shift immunotherapy effort to drug-selected mutation neoepitopes (ABL1 E255V TCR-T) and, separately, to transcript-architecture-resolved monitoring/therapy selection for atypical and in","confidence":0.42,"notebook":"FBXO3 query returned only PMID:41850237 itself — no independent replication, inhibitor still unnamed in the abstract. That is the first of the two dedicated empty passes I prespecified for L16; weakened, one pass from retirement.\n\nThe neoantigen query was productive and mostly cautionary. GIMEMA CML0206/SI0207 (109 patients, b3a2/b2a2 p210 breakpoint peptides plus GM-CSF, 10 years post-vaccination follow-up) is the definitive negative for fusion-junction vaccination: 80% developed peptide-specific CD4+ responses with no toxicity, yet only 30% had any short-term transcript reduction and most had stable fluctuating molecular disease (PMID:40333294). Immunogenicity without molecular depth — record it so the desk never re-proposes junction-peptide vaccination as an adjunct to TKI. That answers Q3 negatively for the vaccine route but opens the mutation route: HLA-A2-restricted TCRs were isolated against the imatinib-selected ABL1 E255V neoepitope, which was naturally processed and presented, while the T315I peptide was non-immunogenic in the same system (PMID:39931057). This is a different antigen class — drug-selected somatic point mutation, not the constitutive fusion — and it is a testable therapeutic arm for the surveillance thesis, so I open L17 rather than force it into L5. Structural liability [INFERRED]: the epitope exists only while the E255V clone is under selection, so antigen loss equals clone reversion, and HLA-A2 restriction plus off-target cross-reactivity screening are the gating steps; asciminib/ponatinib already cover E255V [KNOWN], which caps the clinical niche to compound mutants.\n\nSTIM1 at 12.8 years median gives L5 its first new supporting citation in five visits: molecular recurrence-free survival plateaus at 37%/35% (120/156 months), no progression, 20-year OS 88%, and a late recurrence proven by DNA breakpoint analysis to be the original clone, not new disease (PMID:41574312). Persistent original clone plus a hard plateau is exactly burden-independent, host-set relapse timing. Strengthened modestly; the IL-6/MCP-1 decision tree itself is still unreplicated.\n\nFour papers converge on transcript architecture as an unhandled axis (new L18): a multiplex RT-qPCR/HRM assay quantifying p190/p210/p230/p203 to 0.001% across 895 samples with Sanger junction confirmation (PMID:41506866); a review grading e13a3/e14a3 favourable versus e1a3/e6a2 resistance-prone (PMID:40999990); and two insertion-bearing atypical fusions — e8a2+SPECC1L with ABL1 V379I failing dasatinib then olverembatinib and salvaged only by haplo-SCT (PMID:41211450), and e4a2+CSE1L dasatinib-refractory but ponatinib-responsive (PMID:40881880). Case-report anecdote, but it also threatens L7/L5 operationally: standard IS assays may be blind to these junctions, so a dose-reduction molecular safety net or TFR gate could be monitoring nothing. V379I is also a new gap in L8's mutation-to-agent matrix — asciminib activity untested.","leadChanges":[{"id":"L5","title":"Immune-readiness gating of TKI discontinuation: IL-6/MCP-1 cytokine signature plus innate-like CD8dim/NK effector clonality, with peg-IFN-alpha as expansion age","level":"LEAD","status":"STRENGTHENED","confidence":0.42},{"id":"L16","title":"FBXO3-mediated DUSP9 degradation sustains MAPK output in the persistent CML LSC: FBXO3 inhibition plus ATP-site TKI","level":"LEAD","status":"WEAKENED","confidence":0.18},{"id":"L17","title":"Drug-selected ABL1 mutation neoepitopes (E255V) as TCR-T targets in multi-TKI-resistant CML — replacing failed fusion-junction vaccination","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L18","title":"Transcript-architecture triage: atypical and insertion-bearing BCR::ABL1 fusions as a distinct resistance class and a blind spot in molecular monitoring","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does any independent laboratory reproduce FBXO3 dependence or DUSP9 stabilisation with p-ERK loss in primary CML CD34+ cells, and what is the identity of the inhibitor used in PMID:41850237?","Does NCT06904066 accept CML, and would a drug-selected ABL1 point-mutation epitope (E255V) qualify as a participant-specific neoantigen on that platform?","Is the ABL1 E255V neoepitope presented on primary patient CML cells (immunopeptidomics or autologous killing), and what fraction of multi-TKI-failure patients are HLA-A2+ with an E255V-containing clone?","Is asciminib active against ABL1 V379I and against insertion-rescued atypical fusions (e8a2/SPECC1L, e4a2/CSE1L), and does any registry report mutation-resolved asciminib failure genotypes beyond A337V/P465S?","How often do standard IS RT-qPCR assays under-report atypical or p190/p210 co-expressing transcripts, and has any dose-reduction or TFR cohort been re-analysed with junction-resolved assays?","Do clinical-grade HDAC6 inhibitors (ricolinostat/citarinostat) show any primary CML-LSC activity with asciminib, or does L11 retire for silence?"],"nextQueries":["(\"ABL1\" OR \"BCR-ABL\") AND (neoepitope OR \"HLA-A2\" OR \"TCR-transduced\" OR immunopeptidom*) AND (E255V OR T315I OR \"kinase domain mutation\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"atypical BCR::ABL1\" OR e8a2 OR e1a3 OR e6a2 OR e19a2) AND (asciminib OR ponatinib OR olverembatinib OR \"molecular monitoring\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(ricolinostat OR citarinostat OR \"HDAC6 inhibitor\") AND (\"chronic myeloid leukemia\" OR \"leukemic stem cell\" OR CD34) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"40722725","doi":"10.3390/biomedicines13071654","year":2025,"isNew":true,"title":"Precision Medicine in Hematologic Malignancies: Evolving Concepts and Clinical Applications"},{"pmid":"40333294","doi":"10.3390/vaccines13040419","year":2025,"isNew":true,"title":"Therapeutic Vaccinations with p210 Peptides in Imatinib-Treated Chronic Myeloid Leukemia Patients: 10 Years Follow-Up of GIMEMA CML0206 and SI0207 Studies"},{"pmid":"41630047","doi":"10.1186/s13020-026-01338-8","year":2026,"isNew":true,"title":"Electroacupuncture alleviates migraine through CXCL13/CXCR5-mediated communication"},{"pmid":"41506866","doi":"10.1136/jcp-2025-210447","year":2026,"isNew":true,"title":"Quantitative reverse transcription PCR coupled with high-resolution melting for simultaneous detection and quantification of four isoforms of BCR::ABL1"},{"pmid":"41211450","doi":"10.3389/fonc.2025.1711888","year":2025,"isNew":true,"title":"Case Report: Dual resistance to dasatinib/olverembatinib in accelerated-phase cml: identification of a novel &lt;i&gt;SPECC1L&lt;/i&gt;-inserted e8a2 &lt;i&gt;BCR::ABL1&lt;/i&gt; t"},{"pmid":"40999990","doi":"10.3892/or.2025.8995","year":2025,"isNew":true,"title":"The silent players: Atypical &lt;i&gt;BCR‑ABL &lt;/i&gt;isoforms as biomarkers and therapeutic hurdles in CML pathogenesis (Review)"},{"pmid":"41574312","doi":"10.1016/j.bneo.2025.100177","year":2026,"isNew":true,"title":"Extended long-term follow-up and the survival of Stop Imatinib study"},{"pmid":"40881880","doi":"10.3389/fonc.2025.1596256","year":2025,"isNew":true,"title":"Novel e4a2 BCR∷ABL1 transcript with insertion of CSE1L exons 9 and 10 in a CML patient: a case report"},{"pmid":"39931057","doi":"10.3389/fimmu.2025.1518691","year":2025,"isNew":true,"title":"T cell receptors specific for an imatinib-induced mutation in BCR-ABL for adoptive T cell therapy"},{"pmid":"41850237","doi":"10.1016/j.xcrm.2026.102686","year":2026,"isNew":false,"title":"FBXO3-mediated DUSP9 ubiquitination promotes leukemia stem cell maintenance and tyrosine kinase inhibitor resistance in chronic myeloid leukemia"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":16691,"output":8070},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(FBXO3 OR \"F-box only protein 3\") AND (DUSP9 OR \"MAP kinase phosphatase\" OR \"leukemic stem cell\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"BCR::ABL1\" OR \"BCR-ABL\") AND (\"fusion junction\" OR neoantigen OR \"TCR-transduced\" OR \"peptide vaccine\") AND (\"chronic myeloid leukemia\" OR CML) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"evidenceIds":["PMID:40722725","PMID:40333294","PMID:41630047","PMID:41506866","PMID:41211450","PMID:40999990","PMID:41574312","PMID:40881880","PMID:39931057","PMID:41850237","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787183895137","cycle":170,"visit":3,"ts":"2026-08-19T23:58:15.137Z","cancer":{"key":"acute myeloid leukemia","name":"acute myeloid leukemia","mondo":{"id":"MONDO:0018874","name":"acute myeloid leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Proteasome inhibition (bortezomib) is now the leading repurposable NOXA/MCL1-neutralising partner for venetoclax-resistant AML and should be tested in primary blasts/PDX with normal-CD34+ controls, while TIM3-directed NK engagement advances to CANDIDATE but must first exclude NK-on-NK self-targeting","confidence":0.55,"notebook":"The pack lands mainly on the apoptotic-priming axis and on TIM3, and it both helps and cuts.\n\nP4 (PMID:42599272) is the first human mechanistic read-out for TIM3 in AML/MDS: in sabatolimab+decitabine (NCT03066648), TIM3 was broadly expressed across NK, myeloid and T compartments; therapy expanded cytotoxic NK subsets and type I IFN signalling, and responders expanded cytotoxic CD4+ clones — one CD4+ T-LGLL patient with a blast-reactive TCR had a 23-month CR. Two consequences for L6/VINCENT. Supportive: the NK arm of the construct is the right effector axis, and NK re-arming rather than checkpoint release is where TIM3 biology actually lives. Corrosive: fewer than 1% of marrow CD8+ T cells showed canonical exhaustion, so VINCENT's claimed \"depletion of dysfunctional T cells\" is unlikely to be the operative mechanism; and TIM3 expression on NK cells themselves makes a CD16×TIM3 construct a plausible NK-fratricide/self-targeting risk that no abstract has excluded. L6 moves to CANDIDATE on independent human corroboration of the effector mechanism, but the confidence stays flat and the falsification list now leads with NK-on-NK cross-linking and the untargeted-LNP benchmark.\n\nP8 (PMID:41883151) opens the most actionable new repurposing bet: bortezomib synergises with venetoclax across AML lines including acquired-resistant derivatives, independent of RAS or TP53 status, via NOXA (plus BIM/PUMA) upregulation neutralising MCL1 — NOXA required for the effect. This is the same node L2 attacks pharmacologically differently (XPO1-mediated MCL1 output vs proteasome-mediated NOXA stabilisation), and NOXA is a short-lived proteasome substrate [KNOWN], so the mechanism is coherent rather than phenotypic. Caveats: cell lines only in the abstract, no primary blasts, PDX or normal CD34+ data; and bortezomib added to intensive AML chemotherapy has been repeatedly unhelpful historically [KNOWN], so this must be positioned as a venetoclax-resensitisation partner, not an induction add-on. New LEAD at 0.4.\n\nP9 (PMID:42326325) nominates WNK1 — CRISPR-essential, highest in FLT3-ITD AML, inhibition (WNK463) raises BIM/PUMA, suppresses DNA-replication genes, synergises with venetoclax, WNK1-high predicts venetoclax resistance. New LEAD but low (0.3): WNK1 governs NCC/NKCC electrolyte handling and vascular tone in normal tissue [KNOWN], so systemic inhibition risks hyperkalaemia/hypotension; WNK463 is a tool compound.\n\nP10 (PMID:41929632) consolidates TP53-mutant venetoclax resistance into BCL-2-independence, post-mitochondrial executioner defects, BCL-2-family mutations, monocytic plasticity and fatty-acid metabolism — mechanistic support for L2's MCL1 premise and for pursuing executioner-phase (BAX) genotyping, still with no prevalence numbers. Q3 remains unanswered; Q1/Q2/Q5/Q6 untouched.","leadChanges":[{"id":"L6","title":"TIM3-directed nanoformulated venetoclax with NK engagement (VINCENT) for venetoclax-resistant AML","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.47},{"id":"L8","title":"Bortezomib as a NOXA-dependent venetoclax resensitiser in intrinsically and acquired-resistant AML","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L9","title":"WNK1 kinase as a FLT3-ITD-enriched dependency that primes AML for venetoclax","level":"LEAD","status":"NEW","confidence":0.28},{"id":"L2","title":"XPO1 inhibition (eltanexor) to resensitise R/R AML/MDS to venetoclax","level":"LEAD","status":"STRENGTHENED","confidence":0.48}],"unverifiedCitations":1,"openQuestions":["Does bortezomib+venetoclax synergy survive in primary venetoclax-refractory and monocytic AML blasts and PDX, is it PMAIP1/NOXA-dependent there, and does it spare normal CD34+ colony formation?","Does an anti-CD16 x anti-TIM3 construct cause NK self-targeting/fratricide or CD16 shedding, given that TIM3 is expressed on NK cells (PMID:42599272), and does VINCENT beat an untargeted venetoclax-LNP?","What is the clinical prevalence of BAX/BAK and other post-mitochondrial executioner lesions at venetoclax relapse, and do they abolish benefit from MCL1-directed strategies (L2, bortezomib) as well?","Is the WNK1 dependency genotype-restricted (FLT3-ITD) and on-target, and can any schedule separate leukaemic apoptosis from WNK1-SPAK electrolyte/blood-pressure toxicity?","Which biomarker segregates ATRA benefit on the DAC+VEN backbone in DECIDER-2, and does ATRA-driven monocytic differentiation antagonise venetoclax in a subset?","What is the composition and mechanism of QTX-2101 (NCT07504458), and can it displace IV arsenic trioxide in APL?"],"nextQueries":["(\"acute myeloid leukemia\") AND (bortezomib OR carfilzomib OR proteasome) AND (venetoclax OR NOXA OR PMAIP1) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"acute myeloid leukemia\") AND (BAX OR BAK1 OR \"executioner\") AND (mutation OR loss) AND (venetoclax OR relapse) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"acute myeloid leukemia\" OR \"myelodysplastic\") AND (CD16 OR \"NK cell engager\") AND (fratricide OR \"antigen sink\" OR HAVCR2) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41657780","doi":"10.3389/fphar.2025.1742651","year":2025,"isNew":true,"title":"Novel therapeutic strategies targeting resistance mechanisms in hematologic malignancies: from BCL2 inhibition to immunomodulatory approaches"},{"pmid":"41402230","doi":"10.1080/19420862.2025.2602993","year":2026,"isNew":true,"title":"P329G-engager: a universal mix &amp; match antibody-based adaptor platform for cancer immunotherapy"},{"pmid":"42233094","doi":"10.1016/j.gendis.2025.101965","year":2026,"isNew":true,"title":"The multifaceted landscape of T cell exhaustion in organ transplantation: From molecular mechanisms (epigenetics, transcription, metabolism) to induction strategies"},{"pmid":"42599272","doi":"10.1158/2326-6066.cir-26-0160","year":2026,"isNew":true,"title":"TIM3 blockade with hypomethylating therapy restores NK-cell and cytotoxic CD4+ T-cell activity in patients with AML or MDS"},{"pmid":"42004227","doi":"10.1016/j.gendis.2025.101974","year":2026,"isNew":true,"title":"Identification of PLXNC1 as a novel biomarker for consensus molecular subtype 4 in colorectal cancer"},{"pmid":"41995989","doi":"10.1007/s10147-026-03038-7","year":2026,"isNew":true,"title":"The new era of AML therapy: current standards and emerging targets"},{"pmid":"41959738","doi":"10.1016/j.gendis.2025.101855","year":2026,"isNew":true,"title":"Context-dependent actions of STING pathway in colitis and associated colon cancer"},{"pmid":"41883151","doi":"10.1158/1535-7163.mct-25-0986","year":2026,"isNew":true,"title":"Bortezomib Restores Venetoclax Sensitivity in Acute Myeloid Leukemia Cell Lines with Intrinsic and Acquired Resistance"},{"pmid":"42326325","doi":"10.3389/fonc.2026.1828240","year":2026,"isNew":true,"title":"Targeting WNK1 suppresses acute myeloid leukemia progression and enhances sensitivity to venetoclax"},{"pmid":"41929632","doi":"10.3389/fcell.2026.1779094","year":2026,"isNew":true,"title":"Mechanistic overview and suggested strategies to overcome BCL-2 inhibitor resistance in &lt;i&gt;TP53-&lt;/i&gt;mutated acute myeloid leukemia"}],"trialsShown":[{"nct":"NCT07504458","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Pivotal Open-label Phase 3 Clinical Study of QTX-2101 in Adult Patients With Acute Promyelocytic Leukemia"},{"nct":"NCT06399640","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Eltanexor and Venetoclax in Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT05554393","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Comparing Cytarabine + Daunorubicin Therapy Versus Cytarabine + Daunorubicin + Venetoclax Versus Venetoclax + Azacitidine in Younger Patient"},{"nct":"NCT06710418","phase":"NA","status":"RECRUITING","isNew":false,"title":"Evaluating the Effects of Hemoglobin Threshold-specific Packed Red Blood Cell Transfusions on Quality of Life and Functional Outcomes in Pat"},{"nct":"NCT06317649","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Venetoclax and HMA Treatment of Older and Unfit Adults With FLT3 Mutated Acute Myeloid Leukemia (AML) (A MyeloMATCH Treatment Trial)"},{"nct":"NCT06917911","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing the Addition of Venetoclax or Gemtuzumab Ozogamicin (GO) to Usual Treatment Regimen (Cytarabine and Daunorubicin, \"7+3\") for Core Bi"},{"nct":"NCT02521493","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syn"}],"usage":{"input":13160,"output":7185},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"acute myeloid leukemia\") AND (TIM3 OR HAVCR2) AND (NK OR engager OR sabatolimab) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"acute myeloid leukemia\") AND (BAX AND mutation) AND (venetoclax OR apoptosis) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41657780","PMID:41402230","PMID:42233094","PMID:42599272","PMID:42004227","PMID:41995989","PMID:41959738","PMID:41883151","PMID:42326325","PMID:41929632","NCT07504458","NCT06399640","NCT06904066","NCT05554393","NCT06710418","NCT06317649","NCT06917911","NCT02521493"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787183682459","cycle":169,"visit":3,"ts":"2026-08-19T23:54:42.459Z","cancer":{"key":"renal cell carcinoma","name":"renal cell carcinoma","mondo":{"id":"MONDO:0005086","name":"renal cell carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"ACLY is the convergent lipogenic node in ccRCC — set transcriptionally by HIF-2α/LPCAT1 and ATF4, post-transcriptionally by CDK13→METTL16 m6A/YTHDC2, and post-translationally by FBXW7 — so the next decisive experiment is pharmacological ACLY blockade (bempedoic acid, ACSVL1/SLC27A2-verified) plus CD","confidence":0.5,"notebook":"Fresh pack is almost entirely lipogenic-axis material, and it converts L7 from a review-level guess into the programme's best-supported metabolic node. P2 (PMID:39781455) is the primary study behind last visit's review citation: HIF-2α binds the LPCAT1 promoter directly, LPCAT1 knockdown collapses triglyceride synthesis, and the mechanism runs through NF-κB→FBXW7-mediated ubiquitination of ACLY — i.e. ACLY protein level is the convergence point, wired to the VHL/HIF-2α axis that defines ccRCC. P8 (PMID:41680470) hits the same node from an orthogonal direction: CDK13 phosphorylates METTL16 at Ser329, installing m6A on *ACLY* mRNA read by YTHDC2, stabilising it; disruption suppresses lipid deposition, growth and metastasis in vitro and in vivo. P5 (PMID:40472739) supplies genetic in vivo convergence in a proximal-tubule HIF1α TRACK model: ATF4 deletion downregulates the fatty-acid metabolism programme (ACLY named) and reduces cystic pre-cancerous lesions. Three independent regulatory layers — transcriptional (HIF-2α/ATF4), post-transcriptional (m6A/YTHDC2), post-translational (FBXW7) — all set ACLY abundance. L7 promotes to CANDIDATE (0.58); the unmet requirement is still pharmacology: no citation here shows ACLY inhibition (bempedoic acid, ACSVL1/SLC27A2-dependent activation [KNOWN]) in ccRCC, and adult-kidney ACLY dependence remains unresolved (nephron-progenitor requirement, P1/prior review).\n\nTwo new leads carved out rather than merged, because their druggable handles differ. L8: the CDK13–METTL16–ACLY epitranscriptomic axis — a kinase entry point upstream of lipogenesis. Caveat flagged: \"1NM-PP1\" in P8 most plausibly reflects an analog-sensitive CDK13 allele, not a clinical-grade inhibitor [INFERRED]; the translatable test is selective CDK12/13 inhibitors, and [KNOWN] CDK12/13 loss induces HR-deficiency-like states, so PARP combination is a testable second axis [SPECULATIVE]. L9: ATF4/ISR dependence, druggable indirectly via GCN2/PERK modulation, with the explicit caveat that P5's model is HIF1α-transgenic, not VHL-null.\n\nTwo retirements. L1 (ITPRIP/DANGER–deferasirox ferroptosis induction) dies: two evidence-bearing visits, no independent support for ITPRIP as an RCC target, and a competing iron-depletion mechanism already carved into L6. Ferroptosis in ccRCC survives only as the lipid-composition question inside L7/L5, where P1 (PMID:41039547) frames lipid reprogramming/ferroptosis crosstalk as synergistic with anti-angiogenics and IO. L4 (Wnt/sFRP-4) retires as pre-announced — no patient-level Wnt resistance cohort appeared.\n\nNotebook negatives: an ALOX5/CPT1A-directed query returned only reviews (P1, P3, P4), so L5 gets no corroboration this visit and stays at 0.5 with its in vivo zileuton question unanswered. P6, P7, P9, P10 are off-target for RCC intervention design. Trials T2/T3/T7 (AZD6750, VMD-102, DCC-2812) are undisclosed-mechanism early-phase GU/solid-tumour studies; no subtype-resolved nccRCC readouts from T1/T4 yet.","leadChanges":[{"id":"L7","title":"ACLY/LPCAT1 lipogenic axis downstream of HIF-2alpha and VHL/PPARgamma as a ccRCC metabolic vulnerability","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.58},{"id":"L8","title":"CDK13–METTL16–YTHDC2 epitranscriptomic control of ACLY: a kinase entry point to ccRCC lipogenesis","level":"LEAD","status":"NEW","confidence":0.32},{"id":"L9","title":"ATF4/integrated-stress-response dependence for lipid-droplet accumulation and early tumourigenesis in HIF-driven ccRCC","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L1","title":"Deferasirox-mediated disruption of the ITPRIP(DANGER)/NRF2/FTH1 axis to force ferroptosis in VHL-null ccRCC","level":"LEAD","status":"RETIRED","confidence":0.12},{"id":"L4","title":"Wnt/β-catenin reactivation as a targetable node in sunitinib-resistant RCC (ZC3H13/m6A–sFRP-4 axis)","level":"LEAD","status":"RETIRED","confidence":0.1}],"unverifiedCitations":0,"openQuestions":["Does bempedoic acid (with confirmed ACSVL1/SLC27A2 expression) or a direct ACLY inhibitor reduce growth of VHL-null ccRCC lines/PDX, and is the effect non-additive with ACLY knockdown and additive with belzutifan?","Is the CDK13→METTL16(S329)→m6A→YTHDC2→ACLY axis reproducible with selective CDK12/13 inhibitors or degraders rather than an analog-sensitive allele, and does CDK13 inhibition create a PARP-inhibitor-sensitising HR-deficient state in ccRCC?","Does ATF4 loss suppress established VHL-null ccRCC tumours (not just pre-cancerous lesions in a HIF1α transgenic), and is GCN2/PERK modulation a usable surrogate?","Does ACLY or LPCAT1 loss sensitise ccRCC to RSL3/IKE (predicting lipid-composition control of ferroptosis threshold) or protect against it, and what is adult renal ACLY dependence?","Does zileuton or FLAP inhibition restore sunitinib/axitinib sensitivity in ALOX5-high resistant RCC in vivo, epistatic with CPT1A/etomoxir — still unanswered after a targeted query returned only reviews?","Do OPTIC RCC (NCT05361720) or NCT03866382 report subtype-resolved responses for MET-altered papillary vs FH-deficient vs TFE3-fusion nccRCC?"],"nextQueries":["(\"renal cell carcinoma\" OR ccRCC) AND (\"ATP citrate lyase\" OR ACLY OR bempedoic OR SLC27A2 OR ACSS2) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"renal cell carcinoma\" OR ccRCC) AND (CDK12 OR CDK13 OR METTL16 OR YTHDC2 OR \"m6A\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"renal cell carcinoma\" OR ccRCC) AND (zileuton OR ALOX5 OR CPT1A OR etomoxir OR \"fatty acid oxidation\") AND (sunitinib OR axitinib OR cabozantinib OR resistance) AND SRC:MED"],"papersShown":[{"pmid":"41039547","doi":"10.1186/s12943-025-02457-w","year":2025,"isNew":true,"title":"Lipid reprogramming and ferroptosis crosstalk in clear cell renal cell carcinoma: metabolic vulnerabilities and therapeutic targeting"},{"pmid":"39781455","doi":"10.7150/ijbs.103032","year":2025,"isNew":true,"title":"HIF-2α/LPCAT1 orchestrates the reprogramming of lipid metabolism in ccRCC by modulating the FBXW7-mediated ubiquitination of ACLY"},{"pmid":"41063965","doi":"10.3389/fcell.2025.1664292","year":2025,"isNew":true,"title":"Emerging roles of metabolic biomarkers in renal cell carcinoma: from molecular mechanisms to clinical implications"},{"pmid":"41451091","doi":"10.3389/fmed.2025.1735808","year":2025,"isNew":true,"title":"HIF-2α inhibitors in clear cell renal cell carcinoma: a clinical pharmacy perspective on lipid metabolism, therapeutic management, and resistance strategies"},{"pmid":"40472739","doi":"10.1016/j.neo.2025.101188","year":2025,"isNew":true,"title":"Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma"},{"pmid":"41869709","doi":"10.1080/07853890.2025.2601401","year":2026,"isNew":true,"title":"Application and mechanistic research of novel therapeutic strategies in cisplatin-resistant small cell lung cancer"},{"pmid":"41837490","doi":"10.1080/14756366.2026.2639168","year":2026,"isNew":true,"title":"LDH isozymes as targets for cancer therapy"},{"pmid":"41680470","doi":"10.1038/s12276-025-01634-7","year":2026,"isNew":true,"title":"CDK13 drives clear cell renal carcinoma through METTL16-mediated m&lt;sup&gt;6&lt;/sup&gt;A modification of ACLY mRNA"},{"pmid":"42207498","doi":"10.1080/19490976.2026.2681842","year":2026,"isNew":true,"title":"The impact of gut microbiota and metabolite-driven immune cell spatiotemporal dynamics on tumors"},{"pmid":"41498391","doi":"10.1080/21623945.2025.2610540","year":2026,"isNew":true,"title":"Disease-associated adipose browning: current evidence and perspectives"}],"trialsShown":[{"nct":"NCT03866382","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare G"},{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT05361720","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Genetic Testing to Select Therapy for the Treatment of Advanced or Metastatic Kidney Cancer, OPTIC RCC Study"},{"nct":"NCT05155033","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Phase II Trial of Combination Anti-PD-1 and Aldesleukin for Metastatic Melanoma and Renal Cell Carcinoma"},{"nct":"NCT04788095","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"App-Based Mindfulness Intervention for the Improvement of Quality of Life in Patients With Metastatic Renal Cell Cancer"},{"nct":"NCT06966024","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Study of DCC-2812 in Participants With Advanced Genitourinary Cancers"},{"nct":"NCT07160335","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Phase I Clinical Study to Evaluate the PK Profile, Efficacy, Safety and Immunogenicity of HLX17 vs. Keytruda® in Multiple Resected Solid T"}],"usage":{"input":13749,"output":7195},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"renal cell carcinoma\" OR ccRCC) AND (ALOX5 OR zileuton OR \"5-lipoxygenase\" OR CPT1A OR \"fatty acid oxidation\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"renal cell carcinoma\" OR ccRCC) AND (ACLY OR \"ATP citrate lyase\" OR LPCAT1 OR bempedoic OR SCD1) AND SRC:MED"],"evidenceIds":["PMID:41039547","PMID:39781455","PMID:41063965","PMID:41451091","PMID:40472739","PMID:41869709","PMID:41837490","PMID:41680470","PMID:42207498","PMID:41498391","NCT03866382","NCT07115043","NCT07636785","NCT05361720","NCT05155033","NCT04788095","NCT06966024","NCT07160335"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787183471200","cycle":168,"visit":16,"ts":"2026-08-19T23:51:11.200Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Both targeted queries returned no on-topic primaries, so FBXO3-DUSP9 (L16), asciminib dual-site combination (L1) and the asciminib mutation-resolved failure spectrum (L8) are all weakened for evidential silence, while the programme's BCR::ABL1-kinase-inhibition spine (L7/L8) stands unaltered.","confidence":0.5,"notebook":"This visit's pack is a calibration miss: both fielded queries — one on FBXO3/BC-1215/DUSP9 in leukaemia, one on asciminib kinase-domain mutation spectra — returned zero on-topic primaries. Seven of ten papers are off-disease (sepsis m6A, microplastics, tissue-engineering nanocomposites, paediatric germline WGS, CD19-CAR in extramedullary B-ALL); two proteostasis/PTM reviews are re-seen. Nothing here touches BCR::ABL1 [SOMATIC] biology directly, and nothing challenges the programme's spine: kinase inhibition of the fusion remains the solved mechanism, with the desk's two DOSSIER leads (L7 exposure-window de-escalation, L8 sequential ATP-site→allosteric switch) sitting squarely on it. That convergence is unchanged; what moves is confidence in the unreplicated satellites.\n\nL16 (FBXO3–DUSP9–MAPK in persistent LSCs) takes the direct hit. A query written specifically to find independent FBXO3/DUSP9 leukaemia data returned nothing, so PMID:41850237 remains one laboratory, one paper, with the tool inhibitor still unnamed in the abstract. Weakened; prespecified retirement stands if two further dedicated passes stay empty.\n\nL8: the mutation-resolved failure spectrum I have asked for across four visits is again absent. P2 (PMID:41373445) is new but is a narrative T315I review — it restates the third-generation-TKI framing without new sequencing, and offers no asciminib-failure genotypes, so it cannot count as corroboration of the mutation-to-agent matrix. Confidence trimmed for that persistent hole, not for any contradiction; the Japanese PMS and phase 1 T315I efficacy data stand. P10 (re-seen) reinforces the upstream problem: in US community practice, kinase-domain profiling is performed largely irrespective of failure/warning signals, so registry-based mutation-resolved outcome data may simply not exist at usable density [INFERRED].\n\nL1: NCT03906292 is again ACTIVE_NOT_RECRUITING without readout, and P2 discusses T315I management as sequential single-agent choice, not concurrent dual-site blockade. Weakened again; the lead survives only as an advanced-phase/compound-mutant retrospective question.\n\nTwo notebook entries to prevent future error. First, NCT02689440 remains readout-free — the retired dasatinib+venetoclax lead stays retired. Second, PMID:41372419 (PEACE duplex sequencing) shows >25% of driver mutations in therapy-exposed normal tissue, including TP53, are treatment-attributable. Tempting as a cumulative-exposure argument for L7, this does not transfer: the cohort is chemotherapy/immunotherapy-exposed metastatic cancer, and imatinib-class TKIs are not classical genotoxins [KNOWN]. I explicitly decline to use it as de-escalation rationale, and record that decision.\n\nNew watch item, not yet a lead: NCT06904066 (participant-specific neoantigen TCR-transduced PBL in haematologic malignancies) is the first vehicle in this programme's reach for testing BCR::ABL1 fusion-junction peptide immunity [KNOWN, e14a2 junction epitopes], which would give L5's surveillance thesis a therapeutic arm. Needs CML enrolment data before promotion.","leadChanges":[{"id":"L16","title":"FBXO3-mediated DUSP9 degradation sustains MAPK output in the persistent CML LSC: FBXO3 inhibition plus ATP-site TKI","level":"LEAD","status":"WEAKENED","confidence":0.24},{"id":"L8","title":"Sequential ATP-site to allosteric switch: asciminib as non-cross-resistant salvage after ponatinib and in T315I disease","level":"DOSSIER","status":"WEAKENED","confidence":0.78},{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"WEAKENED","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Has any independent laboratory reproduced FBXO3 dependence (or DUSP9 stabilisation with p-ERK loss) in primary CML CD34+ cells, and what is the identity of the inhibitor used in PMID:41850237?","Does any biobank or registry publish mutation-resolved asciminib failure genotypes beyond A337V/P465S, and which ATP-site agent rescues each — given that community-practice profiling is uncoupled from failure signals (PMID:41778234)?","Does NCT06904066 enrol CML, and is BCR::ABL1 e14a2/e13a2 fusion-junction peptide among the participant-specific neoantigens targeted — i.e. can L5's surveillance thesis acquire a therapeutic arm?","Is there any prospective randomised dose-reduction trial (or matched-exposure re-analysis of PMID:41668074) with MR4.0/MR4.5, TFR and PRO co-primary endpoints, and does the 50 mg dasatinib MR4.5 gap survive adjustment for unequal follow-up?","Has the IL-6/MCP-1 plus CD8dim/NK clonality discontinuation decision tree been replicated in an independent DMR cohort adjusted for TKI duration and prior interferon?","Do clinical-grade HDAC6 inhibitors (ricolinostat/citarinostat) show any primary CML-LSC activity with asciminib, or does L11 retire for silence?"],"nextQueries":["(FBXO3 OR \"F-box only protein 3\") AND (DUSP9 OR \"MAP kinase phosphatase\" OR \"leukemic stem cell\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"BCR::ABL1\" OR \"BCR-ABL\") AND (\"fusion junction\" OR neoantigen OR \"TCR-transduced\" OR \"peptide vaccine\") AND (\"chronic myeloid leukemia\" OR CML) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"chronic myeloid leukemia\") AND (\"dose reduction\" OR \"de-escalation\" OR \"half dose\") AND (randomized OR randomised) AND (\"MR4\" OR \"deep molecular response\" OR \"treatment-free remission\" OR \"quality of life\") AND SRC:MED"],"papersShown":[{"pmid":"41372419","doi":"10.1038/s41586-025-09792-4","year":2026,"isNew":true,"title":"Somatic evolution following cancer treatment in normal tissue"},{"pmid":"41373445","doi":"10.3390/ijms262311285","year":2025,"isNew":true,"title":"Chronic Myeloid Leukemia and the T315I &lt;i&gt;BCR::ABL1&lt;/i&gt; Mutation"},{"pmid":"42030647","doi":"10.1016/j.redox.2026.104178","year":2026,"isNew":true,"title":"m&lt;sup&gt;6&lt;/sup&gt;A epitranscriptomic remodeling links redox stress to mitochondrial quality control and programmed cell death in sepsis-induced myocardial dysfunction"},{"pmid":"41701972","doi":"10.1182/bloodadvances.2025018604","year":2026,"isNew":true,"title":"CD19 CAR T-cell outcomes in relapsed/refractory extramedullary B-ALL: a multisite, retrospective cohort review"},{"pmid":"42272558","doi":"10.1039/d6ra01646d","year":2026,"isNew":true,"title":"Role of polymeric nanocomposite for tissue engineering applications"},{"pmid":"42234944","doi":"10.1200/po-26-00032","year":2026,"isNew":true,"title":"Germline Whole-Genome Sequencing in Early-Onset Pediatric Solid Tumors Implicates Novel Risk Factors"},{"pmid":"42198480","doi":"10.3390/toxics14050354","year":2026,"isNew":true,"title":"Exposure to Polystyrene Microplastics Disrupts Blood Cell Homeostasis and Metabolic Profiles in Pregnant Mice and Offspring: The Role of Oxidative Stress and Inflammation"},{"pmid":"42259777","doi":"10.1038/s41392-026-02714-4","year":2026,"isNew":false,"title":"Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases"},{"pmid":"42221857","doi":"10.1093/pcmedi/pbag014","year":2026,"isNew":false,"title":"Protein modification systems as cancer biomarkers and therapeutic targets"},{"pmid":"41778234","doi":"10.21873/cdp.10518","year":2026,"isNew":false,"title":"&lt;i&gt;BCR::ABL1&lt;/i&gt; Mutational Profiling in US Patients With Chronic-phase Chronic Myeloid Leukemia on Tyrosine Kinase Inhibitors"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":16627,"output":6135},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(FBXO3 OR \"F-box protein 3\" OR BC-1215) AND (leukemia OR \"leukaemia\" OR \"stem cell\" OR DUSP9) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"chronic myeloid leukemia\" OR CML) AND (asciminib) AND (\"kinase domain\" OR mutation OR resistance) AND (sequencing OR NGS OR spectrum) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:41372419","PMID:41373445","PMID:42030647","PMID:41701972","PMID:42272558","PMID:42234944","PMID:42198480","PMID:42259777","PMID:42221857","PMID:41778234","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787183266011","cycle":167,"visit":3,"ts":"2026-08-19T23:47:46.011Z","cancer":{"key":"papillary renal cell carcinoma","name":"papillary renal cell carcinoma","mondo":{"id":"MONDO:0017884","name":"papillary renal cell carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Fumarate-driven succination of RPA1 crippling ATR-CHK1/HR (PMID:42050641) makes FH-deficient papillary RCC a testable BRCAness setting for PARP/WEE1/platinum, while randomised nccRCC data (PMID:41874435) elevate ipi/nivo and bevacizumab+erlotinib to candidate status and KIM-1's injury-inducible tubu","confidence":0.58,"notebook":"Visit 3 turns on three things. First, P6 (PMID:41874435) reports SUNNIFORECAST as a *randomised* positive trial for ipilimumab/nivolumab in nccRCC with OS benefit over standard therapy, alongside consistent pembrolizumab+lenvatinib activity in KEYNOTE-B61/ARON-1. This is the same parent trial as PMID:42235464, so it is not fully independent, but the framing shifts from \"exploratory subgroup signal\" to \"positive randomised histology-agnostic trial with a non-significant pRCC-specific subgroup.\" L2 moves to CANDIDATE at modest confidence, with the caveat printed: the pRCC exploratory subgroup remains p=0.085, so the actionable question is a centrally-reviewed pRCC-restricted confirmatory design, not adoption. Second, P6 and P3 (PMID:42084236) independently converge on bevacizumab+erlotinib as the principal systemic consideration for FH-deficient RCC and add high response rates for sintilimab+axitinib in the same subset — L6 to CANDIDATE. P3 also flags FH-deficient tumours with concurrent SMARCB1/INI-1 loss via fumarate-driven CIMP silencing; [SPECULATIVE] INI-1 IHC should be added to the NCT04981509 correlative panel because SMARCB1-null biology would predict platinum sensitivity and, [KNOWN], EZH2 inhibitor tractability rather than VEGF/EGFR dependence. Also noted: WHO 2022 abolished the type 1/type 2 split (P6), so L1 and L6 should be re-specified as MET-driven versus FH-deficient molecularly defined classes; L1 itself gains no efficacy data (PAPMET2, SAMETA still pending) and stays at 0.6.\n\nThird and most mechanistically substantive: P8 (PMID:42050641) shows fumarate succinates RPA1 at Cys481/486, cutting ssDNA binding, TOPBP1 recruitment and ATR-CHK1 activation, with reduced homologous recombination in FH-mutant cells. That is a chemically explicit BRCAness in FH-deficient RCC and opens a synthetic-lethality lead distinct from the VEGF/EGFR repurposing axis (new L7). Because the ATR-CHK1 arm is already crippled, the sharper predictions are PARP inhibition, WEE1 inhibition (removing the remaining G2 brake) and platinum/gemcitabine replication stress, with POLQ inhibition as the HR-deficient backstop; ATR inhibitors may be redundant or synergistic and that ambiguity is testable in UOK262/UOK268.\n\nL3 weakens. P10 (PMID:42157797) and P2 (PMID:42238184) show HAVCR1/KIM-1 is induced on injured proximal tubule in cisplatin AKI and shed into urine/plasma — the antigen is injury-inducible on *normal* tubule and has a soluble decoy pool. That is on-target off-tumour risk plus a sink, so KIM-1 immunoconjugates must use membrane-retained epitopes, avoid nephrotoxic partners, and cannot use plasma KIM-1 naively as PD. XmAb819 DLT data still absent.","leadChanges":[{"id":"L2","title":"Ipilimumab/nivolumab as first-line systemic therapy in advanced pRCC","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55},{"id":"L6","title":"Dual VEGF/EGFR blockade plus PD-L1 inhibition in FH-deficient/HLRCC-associated and type 2 papillary RCC","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55},{"id":"L7","title":"Fumarate-induced BRCAness in FH-deficient papillary RCC: RPA1 succination as an exploitable replication-stress defect","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"Proximal-tubule lineage as the therapeutic window: KIM-1/HAVCR1-directed agents and tubule-selective toxins","level":"LEAD","status":"WEAKENED","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["Does fumarate-driven RPA1 succination translate into measurable PARPi/WEE1i/platinum sensitivity in FH-deficient RCC models, and is ATR inhibition redundant or synergistic given the pre-existing ATR-CHK1 defect?","Is there any centrally-reviewed, pRCC-restricted (or molecularly classified per WHO 2022) OS analysis of SUNNIFORECAST, and what biomarker subset would power a confirmatory ipi/nivo trial?","What are the primary readouts of PAPMET2 (NCT05411081) and SAMETA (savolitinib+durvalumab), and does benefit track with MET alteration versus inflamed/PD-L1 signature?","What is the primary evidence base for sintilimab+axitinib in FH-deficient RCC, and how does it compare with bevacizumab+erlotinib response rates?","How frequent is SMARCB1/INI-1 co-loss in FH-deficient RCC, and does it redirect therapy toward platinum or EZH2 inhibition?","Has XmAb819 (NCT05433142) cleared dose escalation without dose-limiting AKI, and what does that imply for membrane-epitope-selected KIM-1 constructs?"],"nextQueries":["(\"FH-deficient\" OR HLRCC OR \"fumarate hydratase\") AND (\"renal cell\") AND (PARP OR olaparib OR WEE1 OR adavosertib OR ATR OR \"replication stress\" OR \"homologous recombination\") AND SRC:MED AND PUB_YEAR:[2019 TO 2026]","(papillary OR \"non-clear cell\") AND (\"renal cell carcinoma\") AND (savolitinib OR SAMETA OR PAPMET2 OR \"sintilimab\" OR \"ipilimumab nivolumab\") AND (\"overall survival\" OR \"progression-free\") AND SRC:MED AND PUB_YEAR:[2024 ","(SMARCB1 OR \"INI-1\") AND (\"renal cell carcinoma\") AND (EZH2 OR tazemetostat OR platinum) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"papersShown":[{"pmid":"42150423","doi":"10.1016/j.redox.2026.104224","year":2026,"isNew":true,"title":"Impact of mitochondrial reductive stress due to respiratory chain limitation on cancer via posttranslational modifications"},{"pmid":"42238184","doi":"10.1016/j.crtox.2026.100300","year":2026,"isNew":true,"title":"Loss of KLF15 expression characterizes proximal tubule injury in cisplatin-induced acute kidney injury: A multi-omics study"},{"pmid":"42084236","doi":"10.1097/pai.0000000000001325","year":2026,"isNew":true,"title":"Renal Cell Carcinoma With Concurrent Loss of SMARCB1/INI-1 and Fumarate Hydratase By Immunohistochemistry: A Case Report With Review of the Literature"},{"pmid":"42328258","doi":"10.7759/cureus.111169","year":2026,"isNew":true,"title":"Normal Ovarian Reserve During Long-Term Osimertinib Therapy in a Patient With Li-Fraumeni Syndrome: A Case Report and Literature Review"},{"pmid":"42178367","doi":"10.1093/oncolo/oyag204","year":2026,"isNew":true,"title":"The seventh kidney cancer research summit: progress in accelerating cures"},{"pmid":"41874435","doi":"10.1097/cco.0000000000001233","year":2026,"isNew":true,"title":"Unclear territory: navigating metastatic nonclear cell renal cell carcinoma"},{"pmid":"42122230","doi":"10.3390/cancers18091435","year":2026,"isNew":true,"title":"Rethinking Advanced Renal Cell Carcinoma: Integrative Genomics, Immunotherapy, and Molecular-Orthomolecular Strategies"},{"pmid":"42050641","doi":"10.1186/s40170-026-00435-4","year":2026,"isNew":true,"title":"Oncometabolite fumarate impairs ATR-CHK1 signaling by succinating RPA1 in fumarate hydratase-deficient renal cell carcinoma cells"},{"pmid":"42043678","doi":"10.1007/s12672-026-05082-1","year":2026,"isNew":true,"title":"The crosstalk between epigenetics and metabolism in the malignant cell"},{"pmid":"42157797","doi":"10.5812/ijpr-164432","year":2026,"isNew":true,"title":"KIM-1 as an Early Diagnostic Biomarker of Cisplatin-Induced Acute Kidney Injury"}],"trialsShown":[{"nct":"NCT03866382","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare G"},{"nct":"NCT06792552","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Phase I Study of SIM0505 in Participants With Advanced Solid Tumors"},{"nct":"NCT05287945","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Study of Orellanine in Metastatic Clear-Cell or Papillary Renal Cell Carcinoma"},{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT05411081","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing Cabozantinib With or Without Atezolizumab in Patients With Advanced Papillary Kidney Cancer, PAPMET2 Trial"},{"nct":"NCT05433142","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Study of XmAb®819 in Subjects With Advanced Clear Cell Renal Cell Carcinoma"},{"nct":"NCT04981509","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing of Bevacizumab, Erlotinib, and Atezolizumab in Combination for Advanced-Stage Kidney Cancer"},{"nct":"NCT04071223","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer "}],"usage":{"input":12237,"output":7559},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"hereditary leiomyomatosis\" OR HLRCC OR \"FH-deficient\") AND (\"renal cell\") AND (bevacizumab OR erlotinib OR atezolizumab OR NRF2) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(ENPP3 OR CDH6 OR HAVCR1 OR \"KIM-1\") AND (\"bispecific\" OR \"antibody-drug conjugate\" OR nephrotoxicity OR \"proximal tubule\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"evidenceIds":["PMID:42150423","PMID:42238184","PMID:42084236","PMID:42328258","PMID:42178367","PMID:41874435","PMID:42122230","PMID:42050641","PMID:42043678","PMID:42157797","NCT03866382","NCT06792552","NCT05287945","NCT00001238","NCT05411081","NCT05433142","NCT04981509","NCT04071223"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787183044847","cycle":166,"visit":3,"ts":"2026-08-19T23:44:04.847Z","cancer":{"key":"medullary thyroid carcinoma","name":"medullary thyroid carcinoma","mondo":{"id":"MONDO:0015277","name":"medullary thyroid gland carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Promote DLL3-directed T-cell engagement in MTC to CANDIDATE on independent standardized-assay and pooled-efficacy evidence (pooled DLL3-inhibitor ORR 21%, CRS 49%), design the MTC phase 2 around a single standardized DLL3 assay with paired biopsies, and treat DLL3-low/heterogeneous MTC as a separate","confidence":0.5,"notebook":"Fresh pack is DLL3-heavy and RET-review-heavy; the MET query returned nothing MTC-specific, which is itself informative.\n\nDLL3 (L5). Three independent new sources move this from single-case anecdote toward a modality with a real efficacy envelope. PMID:39558076 provides a standardized-assay landscape showing DLL3 is enriched in pulmonary NEN but spans a *wide range* in extrapulmonary high-grade NEN — i.e. MTC's 89% positivity/35% high (PMID:41345358) sits in a class where inter- and intratumoural heterogeneity, not absence of target, is the limiting variable [INFERRED]. PMID:40110579 (21 trials, n=2452) gives the sober denominator: pooled ORR 21%, DCR 57%, mPFS 3.54 mo, CRS 49%, thrombocytopenia 23% — pooled across ADC and engager platforms, so it under-represents tarlatamab specifically, but it caps expectations for the MTC phase 2 and argues for combination-immunotherapy arms (PFS 4.2 vs 3.36 mo). PMID:40496850 and PMID:40284515 confirm patient stratification and heterogeneity-driven resistance as the field's stated bottleneck. L5 therefore earns CANDIDATE on independent corroboration while confidence stays modest; the design consequence is paired pre/post biopsy with a single standardized DLL3 assay rather than the local SP347 cut alone, and CRS/thrombocytopenia as expected, quantified toxicities.\n\nNew lead L6: DLL3-low/heterogeneous MTC. If ~54% of MTC is DLL3-low (PMID:41345358) and expression is graded rather than binary in EP-NEN (PMID:39558076), engager monotherapy will fail a majority; the platform menu — next-payload ADCs, trispecific engagers (HPN328), CAR-T/NK, DLL3 radioligands (PMID:40284515, PMID:40496850) — offers modalities with different target-density thresholds. Entered low-confidence as a stratification/modality-matching hypothesis, explicitly noting rovalpituzumab tesirine's historical failure [KNOWN] as the reason ADC re-entry needs a new payload.\n\nL4 (MET) weakened on feasibility, not mechanism: a targeted MTC∩MET/capmatinib/tepotinib/crizotinib search returned zero MTC-specific datapoints, so the 18.2% MET figure remains extrapolated from a mixed RETgistry cohort. The new Chinese RET-TKI AE consensus (PMID:42161875) documents liver-enzyme abnormality, hypertension and neutropenia as class effects independent of tumour type — overlapping toxicity with MET TKIs and with cabozantinib's VEGFR2 burden, reinforcing staggered dosing. PMID:42107510 sharpens the RET window argument (enteric/autonomic/sensory neurons, renal development, spermatogenesis) for all RET-combination leads.\n\nNo new evidence on RET-wildtype MTC, ESR2/NTRK1, or ERK-hyperactivation; those questions carry forward.","leadChanges":[{"id":"L5","title":"DLL3-directed T-cell engagement (tarlatamab) in DLL3-high MTC after RET inhibitor failure","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.56},{"id":"L6","title":"Modality-matching for DLL3-low/heterogeneous MTC: next-payload ADCs, trispecific engagers, CAR-T/NK and DLL3 radioligands","level":"LEAD","status":"NEW","confidence":0.28},{"id":"L4","title":"MET-directed rescue at selective RET inhibitor progression: cabozantinib re-sequencing or selpercatinib + selective MET TKI, gated on MET amplification","level":"LEAD","status":"WEAKENED","confidence":0.45}],"unverifiedCitations":0,"openQuestions":["What is the MTC-specific frequency of acquired MET amplification at selpercatinib/pralsetinib progression, and is any human dosing precedent available for selective RET plus selective MET TKI co-administration?","Does the standardized DLL3 assay (PMID:39558076) concord with SP347 >=50% on MTC blocks, and what density threshold separates tarlatamab responders from non-responders?","Do calcitonin and CEA kinetics under T-cell engagement track radiographic response tightly enough to serve as a co-primary endpoint, given engager-induced tumour lysis and inflammation?","Is DLL3-low MTC enriched for SSTR2 or FAP positivity, permitting single-biopsy triage between engager, radioligand and MET/MEK arms?","What drives RET-wildtype MTC (RAS-mutant and quadruple-negative), and is there any supported somatic role for NTRK1 or ESR2 there?","Can ERK hyperactivation-induced toxicity be exploited in RET-driven MTC as an alternative to MAPK suppression?"],"nextQueries":["(RET AND (selpercatinib OR pralsetinib) AND resistance AND (\"MET amplification\" OR \"acquired alteration\" OR bypass)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"medullary thyroid\" AND (\"RET wild-type\" OR \"RAS mutant\" OR quadruple-negative OR HRAS OR KRAS) AND (sequencing OR genomic OR transcriptomic)) AND SRC:MED","(DLL3 AND immunohistochemistry AND (threshold OR \"H-score\" OR heterogeneity) AND (\"neuroendocrine\" OR \"medullary thyroid\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"39558076","doi":"10.1038/s41698-024-00739-y","year":2024,"isNew":true,"title":"Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms"},{"pmid":"40284515","doi":"10.3390/pharmaceutics17040520","year":2025,"isNew":true,"title":"Targeting DLL3: Innovative Strategies for Tumor Treatment"},{"pmid":"40496850","doi":"10.3389/fimmu.2025.1592291","year":2025,"isNew":true,"title":"Harnessing delta-like ligand 3: bridging biomarker discovery to next-generation immunotherapies in refractory small cell lung cancer"},{"pmid":"41930492","doi":"10.3892/mmr.2026.13874","year":2026,"isNew":true,"title":"Mechanism of and research progress on alterations in the RET gene in thyroid cancer (Review)"},{"pmid":"42107510","doi":"10.1016/j.phrs.2026.108237","year":2026,"isNew":true,"title":"FDA-approved RET protein-tyrosine kinase inhibitors in the management of RET-driven thyroid and lung cancer"},{"pmid":"42316992","doi":"10.1111/cts.70642","year":2026,"isNew":true,"title":"Challenges in Implementing Revocation of Oncology Drugs Under Conditional Early Approval in Japan: Regulatory Insights From Comparisons With FDA/EMA"},{"pmid":"42279395","doi":"10.3390/cancers18111814","year":2026,"isNew":true,"title":"The Role of Cytology, Histology and Molecular Pathology in the Diagnostic Process of Thyroid Nodules"},{"pmid":"42161875","doi":"10.3760/cma.j.cn112152-20260107-00014","year":2026,"isNew":true,"title":"[Expert consensus on adverse events management of highly selective RET-TKIs (2026 edition)]"},{"pmid":"40110579","doi":"10.3892/ol.2025.14974","year":2025,"isNew":true,"title":"Safety and efficacy outcomes of delta‑like ligand 3 inhibitors for the treatment of solid tumors: A systematic review and single‑arm meta‑analysis"},{"pmid":"40747199","doi":"10.7759/cureus.87085","year":2025,"isNew":true,"title":"A Case of Micro-medullary Thyroid Carcinoma Presenting as Cancer of Unknown Primary"}],"trialsShown":[{"nct":"NCT03866382","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare G"},{"nct":"NCT06161532","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Sacituzumab Govitecan With or Without Atezolizumab Immunotherapy in Rare Genitourinary Tumors (SMART) Such as High Grade Neuroendocrine Carc"},{"nct":"NCT04280081","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of Selpercatinib (LY3527723) in Participants With Advanced Solid Tumors Including RET Fusion-positive Solid Tumors, Medullary Thyroi"},{"nct":"NCT06444880","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Phase II Trial of Ubamatamab Alone or in Combination With Cemiplimab in MUC16-Expressing SMARCB1-Deficient Malignancies"},{"nct":"NCT07713901","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Database Linkage Study to Evaluate the Risk of Medullary Thyroid Carcinoma"},{"nct":"NCT07016230","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study Investigating Tarlatamab (AMG 757) in Patients With Metastatic/Locally Advanced Small-Cell Lung Cancer (SCLC) and Other Poorly Differe"},{"nct":"NCT07259304","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Social Health, Activity Behaviors, and Quality of Life Among Young Adult Cancer Survivors"},{"nct":"NCT04071223","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer "}],"usage":{"input":12115,"output":6679},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"medullary thyroid\" AND (\"MET amplification\" OR capmatinib OR tepotinib OR crizotinib OR cabozantinib) AND (resistance OR selpercatinib)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"medullary thyroid\" AND (DLL3 OR tarlatamab OR \"T-cell engager\") AND (calcitonin OR response OR \"cytokine release\")) AND SRC:MED"],"evidenceIds":["PMID:39558076","PMID:40284515","PMID:40496850","PMID:41930492","PMID:42107510","PMID:42316992","PMID:42279395","PMID:42161875","PMID:40110579","PMID:40747199","NCT03866382","NCT06161532","NCT04280081","NCT06444880","NCT07713901","NCT07016230","NCT07259304","NCT04071223"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787182838551","cycle":165,"visit":3,"ts":"2026-08-19T23:40:38.551Z","cancer":{"key":"paraganglioma","name":"paraganglioma","mondo":{"id":"MONDO:0000448","name":"paraganglioma"}},"control":false,"modelLabel":"SCIENCE","summary":"Succinate-driven UBC12/UBE2M inactivation in SDH-deficient cells (PMID:39537588) reframes the SDHB neddylation dependency as an E2-switch onto UBE2F-CRL5 and argues against pan-NAE inhibitors such as pevonedistat, which should be tested for a paradoxical growth-promoting effect before any clinical p","confidence":0.62,"notebook":"Visit 3 pack is thin on paraganglioma primary data (P3, P4, P5, P6, P8, T4–T8 are off-target or normal-tissue biology) but contains one mechanistically decisive paper.\n\nP2 [NEW] (PMID:39537588) is the important one. In SDH-deficient AML, accumulated succinate itself drives multi-drug resistance by phosphorylating UBC12/UBE2M and impairing its E2 activity in cullin neddylation, stabilising oncoproteins pre-transcriptionally; lowering succinate (fludarabine) restores drug sensitivity. Read against L5's CRISPR screen (PMID:42181244), where *Ube2m* loss *increased* Sdhb-null proliferation while *Ube2f* loss suppressed it, the two datasets converge on an E2-switch model: [INFERRED] succinate partially inactivates the UBE2M→CRL1/2 arm, and SDH-deficient cells become disproportionately reliant on the UBE2F→SAG/RBX2-CRL5 arm. This both corroborates neddylation as a succinate-regulated node in SDH-deficient cells and **undercuts pan-NAE inhibition**: pevonedistat would phenocopy the pro-tumour UBE2M-off state as well as hitting UBE2F, and P2 predicts a resistance-promoting outcome. I therefore promote L5 to CANDIDATE on the mechanism while de-prioritising pevonedistat monotherapy in favour of E2/UBE2F- or SAG-CRL5-selective tools (HA-9104) with explicit measurement of UBE2M-arm substrates. Normal-tissue caution now sharper: MLN4924 alters hepatocyte cardiolipin synthesis (P4) and granulosa-cell CPT1A/FAO (P6) — a fatty-acid-oxidation and mitochondrial window problem in an already OXPHOS-crippled chromaffin lineage.\n\nL1 promotes to DOSSIER. Three independent 2026 reviews (P7, P9, P10) now state belzutifan's approval as standard-of-care systemic therapy for metastatic PPGL, with durable responses, hypertension improvement and QoL preservation (P9), and situate it inside cluster-based decision-making (P7). P10 adds a resistance route I had not logged: HIF-independent pVHL functions, meaning VHL-mutant lesions may retain HIF2α-blockade-insensitive drivers. The tier reflects an established axis, not a solved one — P7 states plainly that cluster-guided targeted therapy is still absent from guidelines for lack of mechanism, patient-derived preclinical models and head-to-head trials, and genotype-resolved LITESPARK-015 correlates remain unpublished for a third consecutive visit.\n\nL6 (MGMT/temozolomide) retires per pre-commitment: no PPGL MGMT data in this pack; P9 mentions CVD chemotherapy without any methylation stratification.\n\nNew low-confidence L7: succinate-lowering as a resensitising strategy, taken directly from P2's fludarabine result plus P1's succinate-dependent/independent taxonomy. This is a different therapeutic logic from HIF2α blockade — normalise the oncometabolite rather than one downstream effector — and it is testable in existing SDHB models against cabozantinib/CVD/temozolomide.\n\nNext: kill or confirm the E2 directionality in human SDHB-deficient chromaffin cells, and find any PPGL PDX/organoid resource, which P7 identifies as the field's rate-limiting gap.","leadChanges":[{"id":"L1","title":"HIF2α antagonism in pseudohypoxic (cluster 1) paraganglioma","level":"DOSSIER","status":"STRENGTHENED","confidence":0.8},{"id":"L5","title":"Neddylation / UBE2F-CRL5 as a synthetic-lethal vulnerability of SDHB-deficient paraganglioma","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.5},{"id":"L7","title":"Succinate lowering as a resensitising strategy in SDHx-mutant metastatic paraganglioma","level":"LEAD","status":"NEW","confidence":0.28},{"id":"L6","title":"Alkylator/MGMT axis in metastatic SDHx paraganglioma (low-confidence placeholder)","level":"LEAD","status":"RETIRED","confidence":0.12}],"unverifiedCitations":0,"openQuestions":["Does pan-NAE inhibition (pevonedistat) actually promote rather than suppress growth of SDHB-deficient chromaffin cells, as the succinate→p-UBC12 model predicts, and is UBE2F-selective inhibition separable from it?","Is p-UBC12/UBE2M phosphorylation and reduced CRL1/2 neddylation demonstrable in human SDHx-mutant PPGL tissue, and is CRL5-NOXA the effector of the UBE2F dependency?","Have LITESPARK-015 genomic correlates or any on-treatment post-belzutifan PPGL biopsies been published showing PAS-B mutation, HIF1α switching, or HIF-independent pVHL-driven escape?","Do any patient-derived PPGL models (PDX, organoid, allograft) with defined SDHB/SDHD/EPAS1 genotypes now exist, given P7 names their absence as the field's rate-limiting gap?","Is post-177Lu-DOTATATE progression in SDHB-mutant PGL driven by SSTR2 loss versus uptake heterogeneity, and has NCT06427798 reported any 212Pb-VMT-alpha-NET PPGL response or dosimetry data?","Can plasma or tumour succinate be pharmacologically lowered in SDH-deficient models, and does it restore sensitivity to cabozantinib or alkylators?"],"nextQueries":["(UBE2F OR UBE2M OR UBC12 OR \"SAG\" OR RBX2 OR \"cullin-RING\") AND (SDHB OR \"succinate dehydrogenase\" OR succinate) AND SRC:MED AND PUB_YEAR:[2024 TO 2027]","(pheochromocytoma OR paraganglioma) AND (\"patient-derived xenograft\" OR organoid OR \"cell line\" OR allograft OR hPheo1) AND SRC:MED AND PUB_YEAR:[2023 TO 2027]","(pheochromocytoma OR paraganglioma) AND (\"DOTATATE\" OR \"radioligand\" OR SSTR2) AND (resistance OR progression OR heterogeneity OR \"alpha emitter\" OR 212Pb) AND SRC:MED AND PUB_YEAR:[2024 TO 2027]"],"papersShown":[{"pmid":"40285898","doi":"10.1007/s10565-025-10022-w","year":2025,"isNew":true,"title":"SDH defective cancers: molecular mechanisms and treatment strategies"},{"pmid":"39537588","doi":"10.1038/s41467-024-53398-9","year":2024,"isNew":true,"title":"Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation"},{"pmid":"40003962","doi":"10.3390/ijms26041497","year":2025,"isNew":true,"title":"Non-Invasive Assessment of Neurogenesis Dysfunction in Fetuses with Early-Onset Growth Restriction Using Fetal Neuronal Exosomes Isolating from Maternal Blood: A Pilot Study"},{"pmid":"39019009","doi":"10.1016/j.xcrm.2024.101653","year":2024,"isNew":true,"title":"Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway"},{"pmid":"38794205","doi":"10.3390/ph17050635","year":2024,"isNew":true,"title":"Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing"},{"pmid":"41939244","doi":"10.34133/research.1223","year":2026,"isNew":true,"title":"Inhibiting TRIM21 Neddylation Rejuvenates Oocyte Quality in PCOS by Regulating Ubiquitination of CPT1A"},{"pmid":"42503916","doi":"10.3760/cma.j.cn112137-20260228-00568","year":2026,"isNew":true,"title":"[Pheochromocytoma and paraganglioma in the era of precision medicine: from molecular clusters to clinical decision-making]"},{"pmid":"42026869","doi":"10.1016/j.xhgg.2026.100617","year":2026,"isNew":true,"title":"Characterization of von Hippel Lindau gene variants in an African American cohort"},{"pmid":"42025325","doi":"10.1210/clinem/dgag182","year":2026,"isNew":true,"title":"Approach to the patient with metastatic pheochromocytoma and paraganglioma: advances in systemic therapy"},{"pmid":"42313274","doi":"10.1007/s10689-026-00579-8","year":2026,"isNew":true,"title":"Von Hippel-Lindau disease: pathophysiological and clinical advances"}],"trialsShown":[{"nct":"NCT06427798","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Somatostatin-Receptors (SSTR)-Agonist [212Pb]VMT-alpha-NET in Metastatic or Inoperable SSTR+ Gastrointestinal Neuroendocrine Tumor and Pheoc"},{"nct":"NCT06479811","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"[212Pb]VMT-Alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive Gastrointestinal Neuroendocrine Tumors, Pheochromocytoma/Par"},{"nct":"NCT03206060","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma"},{"nct":"NCT00004847","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Diagnosis of Pheochromocytoma"},{"nct":"NCT06377033","phase":"NA","status":"RECRUITING","isNew":false,"title":"Using the EHR to Advance Genomic Medicine Across a Diverse Health System"},{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT01660984","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Natural History Study of Children and Adults With Medullary Thyroid Cancer"}],"usage":{"input":12740,"output":7362},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(pheochromocytoma OR paraganglioma) AND (belzutifan OR \"LITESPARK\") AND (SDHB OR genotype OR biomarker OR resistance) AND SRC:MED AND PUB_YEAR:[2024 TO 2027]","(neddylation OR pevonedistat OR NAE1 OR UBE2F OR \"cullin-RING\") AND (pheochromocytoma OR paraganglioma OR \"succinate dehydrogenase\" OR SDHB) AND SRC:MED"],"evidenceIds":["PMID:40285898","PMID:39537588","PMID:40003962","PMID:39019009","PMID:38794205","PMID:41939244","PMID:42503916","PMID:42026869","PMID:42025325","PMID:42313274","NCT06427798","NCT06479811","NCT03206060","NCT00004847","NCT06377033","NCT00001238","NCT04924075","NCT01660984"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787182622992","cycle":164,"visit":3,"ts":"2026-08-19T23:37:02.992Z","cancer":{"key":"pheochromocytoma","name":"pheochromocytoma","mondo":{"id":"MONDO:0008233","name":"pheochromocytoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Selective RET inhibitors (selpercatinib/pralsetinib) produced clinical benefit in 9/9 pooled advanced RET-mutant pheochromocytomas including 2 CR and 5 PR (PMID:41801283), making RET-genotype-directed therapy the highest-yield actionable lead alongside belzutifan, while MGMT-guided temozolomide now ","confidence":0.72,"notebook":"This visit was the RET visit. Open question 6 is answered: a pooled analysis of nine advanced RET-mutant pheochromocytomas treated with selective RET inhibitors (8 selpercatinib, 1 pralsetinib) reports 2 CR, 5 PR, 2 SD — clinical benefit in 9/9, PFS 5.5–56.3 months, and normalisation or improvement of urinary catecholamines/metanephrines in 7, with only two G3 dose reductions (PMID:41801283). That moves RET from \"MTC-only\" inference to direct PPGL evidence and creates a new lead at the top of the actionable list, since RET is a Monarch causal anchor here [GERMLINE, MEN2] with somatic/fusion cases too. Mechanistically the target is constitutive RAS-MAPK/PI3K-AKT/JAK-STAT output from an activated RTK — direct inhibition, not synthetic lethality (PMID:41977363, PMID:41930492). Named resistance routes: secondary RET mutations (solvent-front/gatekeeper) and MET/EGFR bypass (PMID:41977363). Window argument: RET is required for enteric neural, renal and thyroid development, and GDNF-RET drives pulmonary neuroendocrine cell biology (PMID:41968620) — hence the hypertension/oedema/transaminitis profile [KNOWN]; catecholamine normalisation itself is the on-target PD readout.\n\nL7 (temozolomide) gains its first PPGL-specific support: a 2025 systemic-therapy review states SDHB-mutated PPGLs show heightened temozolomide sensitivity associated with MGMT promoter hypermethylation and reduced MGMT expression (PMID:41301064), corroborated as a cautiously-interpreted tissue biomarker (PMID:41300999). Critically, the assay design must change: MGMT gene-body methylation correlates positively with transcript and anticorrelates with promoter methylation in IDH-wild-type/non-glioma cohorts, so promoter-only assays misclassify (PMID:40464417). Any archival PPGL study should therefore report total gene methylation plus protein, not promoter PCR alone. Promote L7 to CANDIDATE.\n\nL1 is reinforced but not promoted: two independent reviews confirm the 2025 belzutifan approval as a biomarker-guided option for cluster-1 PPGL (PMID:41300999, PMID:41301064), yet neither supplies cluster-stratified response rates, so the VHL/SDHx-versus-EPAS1 question stands and DOSSIER is not earned.\n\nNew lead L10: VEGFR-axis multikinase inhibition (cabozantinib, sunitinib, anlotinib) as the sequencing partner/comparator for belzutifan — cabozantinib improves PFS after prior therapy in NENs (PMID:41300999) and shows meaningful PPGL activity (PMID:41301064). Notebook negative, so the desk stops re-proposing it: checkpoint-inhibitor monotherapy in PPGL yields only modest responses (PMID:41301064); dual blockade/TKI-ICI remains unproven.\n\nNext: find whether any prospective RET-inhibitor PPGL arm exists, RET resistance genotypes in chromaffin tissue, and archival MGMT total-methylation cohorts.","leadChanges":[{"id":"L9","title":"Selective RET inhibition (selpercatinib/pralsetinib) in RET-mutant/fusion pheochromocytoma","level":"LEAD","status":"NEW","confidence":0.68},{"id":"L7","title":"Succinate-driven hypermethylation as a temozolomide-sensitivity rationale in SDHx PPGL (MGMT-guided)","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.5},{"id":"L1","title":"HIF-2α inhibition (belzutifan) in cluster-1 pseudohypoxic PPGL","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.8},{"id":"L10","title":"VEGFR-axis multikinase inhibition (cabozantinib/sunitinib/anlotinib) as sequencing partner and comparator for cluster-1 PPGL","level":"LEAD","status":"NEW","confidence":0.48}],"unverifiedCitations":0,"openQuestions":["Does a prospective selpercatinib/pralsetinib arm exist or can one be opened for RET-mutant/fusion metastatic PPGL, and are germline MEN2 and somatic/fusion RET cases equally responsive (PMID:41801283)?","What are the acquired-resistance genotypes on selective RET inhibitors in chromaffin tumours specifically - solvent-front/gatekeeper RET mutations versus MET/EGFR bypass - and does cabozantinib salvage them?","Still open: cluster-stratified belzutifan response rates in NCT04924075 (VHL vs SDHx vs EPAS1) and the acquired-resistance genotype (EPAS1 gatekeeper, HIF-1alpha switching, MYC/mTOR bypass); do EPO/CgA kinetics predict escape before RECIST?","In archival SDHx versus cluster-2 PPGL, what is the prevalence of MGMT promoter versus gene-body methylation, and does total gene methylation predict temozolomide response better than promoter status (PMID:40464417, PMID:41301064)?","Does UBE2F-dependent neddylation vulnerability replicate in human SDHB-deficient PPGL models with a marrow-sparing window for pevonedistat?","What is the optimal sequencing of belzutifan, VEGFR-axis TKI and SSTR2 radioligand therapy in cluster-1 disease, and does SSTR2 expression survive belzutifan-induced dedifferentiation?"],"nextQueries":["(\"pheochromocytoma\" OR \"paraganglioma\") AND (cabozantinib OR sunitinib OR anlotinib OR lenvatinib) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\") AND (belzutifan OR \"HIF-2\") AND (resistance OR progression OR \"cluster 1\" OR SDHB) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\" OR \"chromaffin\") AND (neddylation OR UBE2F OR pevonedistat OR MLN4924 OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"40464417","doi":"10.1158/1535-7163.mct-24-0977","year":2025,"isNew":true,"title":"Beyond the Promoter: Total MGMT Gene Methylation Modulates Response to DNA-Alkylating Agents in Glioma"},{"pmid":"41300999","doi":"10.3390/cancers17223632","year":2025,"isNew":true,"title":"Emerging Diagnostics and Therapies in Neuroendocrine Neoplasms: A Critical Review"},{"pmid":"41301064","doi":"10.3390/cancers17223702","year":2025,"isNew":true,"title":"Update on Systemic Therapies for Metastatic/Unresectable Pheochromocytomas and Paragangliomas and Future Directions"},{"pmid":"41930492","doi":"10.3892/mmr.2026.13874","year":2026,"isNew":true,"title":"Mechanism of and research progress on alterations in the RET gene in thyroid cancer (Review)"},{"pmid":"41976235","doi":"10.3390/molecules31071195","year":2026,"isNew":true,"title":"Molecularly Targeted Therapies in Oncology: Mechanisms, Resistance, and Combination Strategies"},{"pmid":"41977363","doi":"10.3390/ijms27073180","year":2026,"isNew":true,"title":"RET Signaling Pathway in Human Cancer: Oncogenic Mechanisms, Selective Inhibitors, and Emerging Resistance Strategies"},{"pmid":"42116529","doi":"10.3322/caac.70086","year":2026,"isNew":true,"title":"Medullary thyroid carcinoma and RET molecular testing: A virtual tumor board on clinical decision-making"},{"pmid":"41968620","doi":"10.1002/1873-3468.70341","year":2026,"isNew":true,"title":"GDNF-RET signaling drives pulmonary neuroendocrine cell hyperplasia and allergic airway inflammation"},{"pmid":"41994561","doi":"10.1016/j.omton.2026.201146","year":2026,"isNew":true,"title":"Targeted therapies in pediatric oncology: A start"},{"pmid":"41801283","doi":"10.1007/s12020-025-04525-z","year":2026,"isNew":true,"title":"Efficacy of RET inhibitors in the management of advanced, RET mutated, pheochromocytoma. Pooled analysis of published cases with the addition of 2 new cases"}],"trialsShown":[{"nct":"NCT06427798","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Somatostatin-Receptors (SSTR)-Agonist [212Pb]VMT-alpha-NET in Metastatic or Inoperable SSTR+ Gastrointestinal Neuroendocrine Tumor and Pheoc"},{"nct":"NCT06479811","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"[212Pb]VMT-Alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive Gastrointestinal Neuroendocrine Tumors, Pheochromocytoma/Par"},{"nct":"NCT03206060","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma"},{"nct":"NCT00004847","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Diagnosis of Pheochromocytoma"},{"nct":"NCT06377033","phase":"NA","status":"RECRUITING","isNew":false,"title":"Using the EHR to Advance Genomic Medicine Across a Diverse Health System"},{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT01660984","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Natural History Study of Children and Adults With Medullary Thyroid Cancer"}],"usage":{"input":13471,"output":7409},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"pheochromocytoma\" OR \"paraganglioma\") AND (RET AND (selpercatinib OR pralsetinib OR \"RET inhibitor\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\") AND (MGMT OR \"promoter methylation\" OR \"epigenetic\" OR hypermethylation) AND (temozolomide OR alkylating) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"evidenceIds":["PMID:40464417","PMID:41300999","PMID:41301064","PMID:41930492","PMID:41976235","PMID:41977363","PMID:42116529","PMID:41968620","PMID:41994561","PMID:41801283","NCT06427798","NCT06479811","NCT03206060","NCT00004847","NCT06377033","NCT00001238","NCT04924075","NCT01660984"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787182413181","cycle":163,"visit":3,"ts":"2026-08-19T23:33:33.181Z","cancer":{"key":"gastrointestinal stromal tumor","name":"gastrointestinal stromal tumor","mondo":{"id":"MONDO:0011719","name":"gastrointestinal stromal tumor"}},"control":false,"modelLabel":"SCIENCE","summary":"Promote frontline broad-spectrum KIT coverage (velzatinib, NCT07585266) to CANDIDATE on converging 2025-2026 review/editorial consensus that line-by-line TKI sequencing covers only partial slices of the polyclonal secondary-KIT spectrum; retire the GIST PARP/HRD lead for lack of any genetic lesion; ","confidence":0.6,"notebook":"Thin pack, mostly off-target (tirzepatide, pediatric ALL, myokines, network-ML). Four items are usable, and none of them are the correlatives I asked for.\n\nNothing in this pack addresses OQ2: the rogaratinib SDH-deficient serial-biopsy WES has still not published, and the FGFR-resistance query returned no GIST-specific paper. L2 therefore persists unchanged at CANDIDATE — no promotion, since promotion requires new evidence and there is none for the pseudohypoxia/FGF3-FGF4 axis this visit. The one FGFR item, P3 (PMID:42185943), is recurrent FGFR1/2/4 kinase-domain-retaining fusions in six unclassified high-grade myogenic sarcomas — not GIST, so it cannot corroborate L2. It does, however, sharpen OQ6: it is direct evidence that FGFR fusions recur in KIT/PDGFRA-irrelevant mesenchymal tumours and that the rogaratinib basket (NCT04595747) has a genuine fusion arm distinct from its SDH-deficient arm. I open that as a separate lead for quadruple-WT, SDH-proficient GIST, where FGFR1 fusions are a known rare event [KNOWN] and are actionable with the same agent — with the explicit caveat that GIST-specific prevalence is unmeasured here.\n\nL4 strengthens and moves to CANDIDATE. Two independent 2025 reviews (PMID:40368739, PMID:40733131) and a GIST-specific editorial on kinase-inhibitor escape and ponatinib (PMID:42169879) converge on the same structural claim: each approved line (sunitinib exon 13/14-biased, regorafenib/ripretinib activation-loop-biased) covers a partial slice of the secondary mutation spectrum, so sequential monotherapy is chasing polyclonality. This is the exact hypothesis velzatinib frontline (NCT07585266) tests. Review-level corroboration only, hence 0.6 not higher. P4 (ponatinib analogues) is chemistry, not GIST — it does record that ponatinib's gatekeeper-agnostic potency is inseparable from a >60-kinase off-target profile including FGFR1 and SLK, which is why ponatinib will not be the broad-coverage answer; logged so the desk does not re-propose it.\n\nL1 retired. Two visits without a biallelic HR lesion, without a functional RAD51 assay, and without a second cohort; the G4 HRD signature remains single-cohort and plausibly transcriptional. Do not re-propose olaparib in GIST absent a genetic lesion.\n\nL6 weakened: olverembatinib's lipid effector remains unnamed; P2 lists it only as an investigational agent.\n\nNew pragmatic lead from P6 (PMID:41793262): 85.9% of oral anticancer drugs carry a DDI mechanism, CYP3A substrates 55.6%, acid-reducer victims 17.2%, and 17.4% of treated patients had a potential DDI. Imatinib exposure–response is real [KNOWN]; a fraction of \"primary imatinib resistance\" may be pharmacokinetic under-exposure, testable by trough monitoring in non-responders before genotype-based escalation.","leadChanges":[{"id":"L1","title":"PARP inhibition in the HRD-signature G4 (metabolic) GIST subtype","level":"LEAD","status":"RETIRED","confidence":0.1},{"id":"L4","title":"Frontline broad-spectrum KIT coverage to pre-empt polyclonal secondary resistance","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.6},{"id":"L7","title":"FGFR-fusion-directed therapy in quadruple-wild-type, SDH-proficient GIST","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L8","title":"Pharmacokinetic pseudo-resistance: exposure verification before declaring imatinib failure","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L6","title":"Lipid-metabolic / reductive-stress vulnerability of Complex II-null GIST","level":"LEAD","status":"WEAKENED","confidence":0.32}],"unverifiedCitations":0,"openQuestions":["Has the rogaratinib SDH-deficient GIST cohort (NCT04595747) reported its serial-biopsy WES, and do acquired FGFR1 gatekeeper (V561M-class) mutations, FGF ligand switching, or RAS/MAPK reactivation dominate at progression?","Has the belzutifan GIST cohort of NCT04924075 reported, and is HIF-2alpha dependency real in SDH-deficient GIST after FGFR-inhibitor failure?","Which lipid-metabolic enzyme does olverembatinib modulate in SDH-null GIST, and is the effect kinase-independent (last chance before L6 retires)?","What is the measured prevalence of FGFR1/2/3 and NTRK fusions specifically in quadruple-wild-type, SDH-proficient GIST, and has any fusion-positive GIST responded to a pan-FGFR or TRK inhibitor?","Do ctDNA studies after ripretinib/avapritinib failure show new secondary KIT mutations versus KIT-independent bypass (FGFR/AXL/MAPK/cell-cycle), and does PDGFRA D842V resistance follow a distinct route warranting its own lead?","What fraction of early imatinib failure in GIST is attributable to sub-therapeutic trough concentration or CYP3A/acid-reducer interactions rather than clonal evolution?"],"nextQueries":["(GIST OR \"gastrointestinal stromal\") AND (\"SDH-deficient\" OR SDHA OR SDHB) AND (rogaratinib OR belzutifan OR olverembatinib OR \"HIF-2\" OR lipid OR FASN OR SCD1) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(GIST OR \"gastrointestinal stromal\") AND (\"wild-type\" OR quadruple-wildtype OR fusion) AND (FGFR1 OR NTRK OR BRAF OR NF1 OR plixorafenib OR larotrectinib) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(GIST OR \"gastrointestinal stromal\") AND (ctDNA OR \"circulating tumor DNA\" OR \"secondary mutation\") AND (ripretinib OR avapritinib OR velzatinib OR bezuclastinib OR IDRX-42) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"40368739","doi":"10.1016/j.hoc.2025.04.006","year":2025,"isNew":true,"title":"Gastrointestinal Stromal Tumor: Current Approaches and Future Directions in the Treatment of Advanced Disease"},{"pmid":"40733131","doi":"10.3390/pharmaceutics17070923","year":2025,"isNew":true,"title":"Tyrosine Kinase Inhibitors for Gastrointestinal Stromal Tumor After Imatinib Resistance"},{"pmid":"42185943","doi":"10.1002/2056-4538.70094","year":2026,"isNew":true,"title":"A subset of high-grade sarcomas with myogenic differentiation are associated with recurrent FGFR fusions"},{"pmid":"42313448","doi":"10.1002/cmdc.202501007","year":2026,"isNew":true,"title":"Structure-Based Design, Synthesis, and Evaluation of Novel Ponatinib Derivatives With a Significantly Altered Selectivity Profile"},{"pmid":"42226293","doi":"10.1186/s44342-026-00074-7","year":2026,"isNew":true,"title":"Precision Medicine Gene Network Analyser: part I-cancer driver gene identification through network topology and ensemble machine learning"},{"pmid":"41793262","doi":"10.1002/cpt.70253","year":2026,"isNew":true,"title":"Pharmacokinetic Drug-Drug Interaction Potential of Oral Anticancer Drugs"},{"pmid":"42198465","doi":"10.3390/ph19050791","year":2026,"isNew":true,"title":"Multidimensional Predictors of Tirzepatide Efficacy: Clinical, Genetic, and Molecular Biomarkers for Glycemic, Weight, and Organ Protection"},{"pmid":"42196495","doi":"10.3390/ijms27104517","year":2026,"isNew":true,"title":"Integrated Genomic Profiling of Pediatric Acute Lymphoblastic Leukemia: Genomic Landscape, Risk Stratification and Association of RAS Pathway Mutations with Early Treatment Respons"},{"pmid":"42188588","doi":"10.3390/sports14050212","year":2026,"isNew":true,"title":"Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review"},{"pmid":"42169879","doi":"10.21037/jgo-2026-1-0120","year":2026,"isNew":true,"title":"Emerging mechanisms of kinase inhibitor escape and clinical implications of ponatinib in advanced gastrointestinal stromal tumor"}],"trialsShown":[{"nct":"NCT07585266","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Velzatinib Compared With Imatinib in Adult Participants With Previously Untreated Metastatic and/or Unresectable Gast"},{"nct":"NCT04557969","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Surgery in Gastrointestinal Stromal Tumors (GISTs) for Treatment, Tumor Modeling, and Genomic Analysis"},{"nct":"NCT07406633","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"KQB198 in Combination With Imatinib in Participants With Advanced/Metastatic GIST in 1st Line Setting (SynerGIST-1st Line)"},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT04595747","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing the Anti-cancer Drug, Rogaratinib (BAY 1163877), for Treatment of Advanced Sarcoma With Alteration in Fibroblast Growth Factor Recep"},{"nct":"NCT05503797","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations"},{"nct":"NCT06640361","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study of Olverembatinib in SDH-deficient GIST."},{"nct":"NCT05957367","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study of Inlexisertib (DCC-3116) in Combination With Anticancer Therapies in Participants With Advanced Malignancies"}],"usage":{"input":12357,"output":7533},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(GIST OR \"gastrointestinal stromal\") AND (rogaratinib OR \"FGFR1\" OR pemigatinib OR erdafitinib) AND (resistance OR \"gatekeeper\" OR V561 OR \"acquired mutation\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(GIST OR \"gastrointestinal stromal\") AND (ripretinib OR avapritinib OR sunitinib OR regorafenib) AND (resistance OR \"secondary mutation\" OR ctDNA OR bypass OR MAPK OR AXL) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:40368739","PMID:40733131","PMID:42185943","PMID:42313448","PMID:42226293","PMID:41793262","PMID:42198465","PMID:42196495","PMID:42188588","PMID:42169879","NCT07585266","NCT04557969","NCT07406633","NCT04924075","NCT04595747","NCT05503797","NCT06640361","NCT05957367"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787182195750","cycle":162,"visit":3,"ts":"2026-08-19T23:29:55.750Z","cancer":{"key":"synovial sarcoma","name":"synovial sarcoma","mondo":{"id":"MONDO:0010434","name":"synovial sarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"SUMO E1 inhibition (TAK-981) now has independent cross-tumour evidence that it restores antigen presentation, induces type-I IFN and depletes Tregs and synergises with checkpoint blockade — promoting the SS cBAF-restoration lead to CANDIDATE and opening a formal TAK-981-priming-before-CTA-TCR-T sequ","confidence":0.66,"notebook":"This visit's pack contains no synovial-sarcoma-specific primary data; the second query returned no afami-cel/lete-cel relapse-biopsy series, so Open Question 1 stays unanswered after two attempts — that absence is itself informative: as of this pack, the dominant resistance mechanism to CTA TCR-T in SS is unpublished, and L1 must not be promoted on reviews alone. P1 (PMID:39970827) and P2 (PMID:41843290) are competent syntheses that re-state MAGE-A4's testis/placenta-restricted expression, the ten-trial MAGE-A4 TCR-T landscape, and the generic solid-tumour resistance quartet (antigen heterogeneity/loss, hypoxia, Treg/MDSC/TAM-rich TME, on-target off-tumour toxicity). P1's explicit emphasis on off-target and on-target/off-tumour characterisation sharpens L1's window argument [INFERRED: cross-reactivity screening, not antigen density, is the safety-limiting step], but adds no SS-specific efficacy or paired-biopsy data. L1 therefore stays CANDIDATE with only a marginal confidence uptick; I am explicitly declining DOSSIER.\n\nThe substantive movement is on L5. Three independent new items converge on the immunologic arm of SUMOylation blockade: P8 (PMID:41340481) is in vivo mechanistic work showing SUMO E1 inhibition by TAK-981 reprogrammes an immunosuppressive TME, depletes FoxP3+CD4+ Tregs via innate-cell-mediated antibody-dependent elimination with type-I IFN involvement, and synergises with TIGIT blockade to prolong survival with protective memory in an orthotopic metastatic PDAC model, including a perioperative arm. P10 (PMID:42185884) and P4 (PMID:42142669) independently state that SUMOylation suppresses antigen presentation and immunopeptidome diversity and regulates PD-L1 and TIGIT, and that TAK-981/ML792 restore MHC-I-restricted presentation, type-I IFN and CD8 cytotoxicity. This partially answers Question 2 in the affirmative outside SS: SUMO E1 inhibition raises antigen presentation as a class effect, so the TAK-981-as-primer hypothesis for MAGE-A4/NY-ESO-1 TCR-T graduates from speculation to a testable lead (new L6), though whether MHC-I gain translates into higher MAGE-A4 peptide density in SS18::SSX cells is untested. L5 moves to CANDIDATE on this new, independent corroboration, with the caveat recorded that the SS-specific cBAF/SMARCE1-SUMO mechanism still rests on one abstract (PMID:41193430) and no sarcoma-inclusive TAK-981 trial appears in the pack.\n\nPack hygiene: P3, P5, P6, P7, P9 (pan-viral HDF, bacterial UBLs, TAM–NK, biomaterials, anti-MDA5 serology) are query drift from the \"SUMO/interferon\" arm and contribute nothing; next queries tighten to SS models and to TAK-981 trial registration. L4 (anlotinib) remains unconfirmed prospectively for a second consecutive visit and should be retired next visit absent randomised data.","leadChanges":[{"id":"L1","title":"Cancer-testis antigen TCR-T (MAGE-A4, NY-ESO-1/LAGE-1a) as the backbone therapy in SS18::SSX-driven synovial sarcoma","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.8},{"id":"L5","title":"TAK-981-mediated SUMOylation blockade to restore cBAF and collapse the SS18::SSX transcriptome, plus chemotherapy","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.65},{"id":"L6","title":"TAK-981 as an antigen-presentation priming lead-in before MAGE-A4/NY-ESO-1 TCR-T in synovial sarcoma","level":"LEAD","status":"NEW","confidence":0.45}],"unverifiedCitations":0,"openQuestions":["Do paired pre/post-relapse biopsies from afami-cel or lete-cel-treated SS show MAGE-A4/NY-ESO-1 downregulation, HLA-A*02 allelic LOH, TCR-T loss of persistence, or stromal exclusion — and is any mechanism dominant?","Does TAK-981 increase surface HLA-A*02 and MAGE-A4/NY-ESO-1 peptide density in SS18::SSX cells, and does a pulsed lead-in help or harm infused TCR-T fitness?","Is there any sarcoma-inclusive or SS-enrolling TAK-981/subasumstat trial, and what schedule and normal-tissue toxicity were reported in its dose-finding phases?","Does the PDAC TAK-981 + TIGIT design reproduce in an immunocompetent SS18::SSX GEMM, and is Treg depletion or MHC-I restoration the operative mechanism in SS?","Are SS18::SSX phase separation and PRC1 recruitment druggable with existing chemical matter, and do such agents phenocopy cBAF restoration and SMARCE1-SUMO loss?","Any prospective randomised data for anlotinib or pazopanib maintenance in lung-metastatic SS — if none appears next visit, retire L4."],"nextQueries":["(\"synovial sarcoma\" OR \"SS18-SSX\" OR \"SS18::SSX\") AND (\"TAK-981\" OR subasumstat OR SUMOylation OR SMARCE1 OR \"canonical BAF\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(afamitresgene OR letetresgene OR \"MAGE-A4 TCR\" OR \"NY-ESO-1 TCR\") AND (relapse OR progression OR \"paired biopsy\" OR \"antigen loss\" OR \"HLA loss\" OR persistence) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(subasumstat OR \"TAK-981\") AND (\"phase 1\" OR \"dose escalation\" OR \"first-in-human\" OR sarcoma OR \"solid tumor\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"39970827","doi":"10.1016/j.ctrv.2025.102891","year":2025,"isNew":true,"title":"Melanoma-associated antigen A4: A cancer/testis antigen as a target for adoptive T-cell receptor T-cell therapy"},{"pmid":"41843290","doi":"10.1007/s12672-026-04802-x","year":2026,"isNew":true,"title":"Efficacy and safety of approved cellular therapies and bispecific antibodies in solid tumors: the current state"},{"pmid":"42069597","doi":"10.1186/s12967-026-08197-9","year":2026,"isNew":true,"title":"A pan-viral map of host dependency factors from multi-omics integration and machine learning across influenza A, SARS-CoV-2, Zika, and dengue viruses"},{"pmid":"42142669","doi":"10.1016/j.bbcan.2026.189611","year":2026,"isNew":true,"title":"Reshaping tumor immunity by targeting SUMOylation: A novel immunotherapeutic strategy"},{"pmid":"42346086","doi":"10.3390/cells15121060","year":2026,"isNew":true,"title":"Molecular Functions of Ubiquitin-like Modifiers in Bacterial Infection"},{"pmid":"42236118","doi":"10.1136/jitc-2026-014840","year":2026,"isNew":true,"title":"Targeting macrophage-driven NK cell immunosuppression to improve cancer immunotherapy"},{"pmid":"42125258","doi":"10.1016/j.mtbio.2026.103167","year":2026,"isNew":true,"title":"Biomaterial-based strategies for postoperative residual tumors: From margin clearance to immune control and tissue repair"},{"pmid":"41340481","doi":"10.1158/1535-7163.mct-25-0129","year":2026,"isNew":true,"title":"Immunomodulation of Pancreatic Cancer via Inhibition of SUMOylation and the CD155/TIGIT Pathway"},{"pmid":"42194046","doi":"10.3390/biom16050698","year":2026,"isNew":true,"title":"Clinical Relevance and Methodological Comparison of Anti-MDA5 Antibody Detection: A Five-Year Retrospective and Exploratory Pilot Study"},{"pmid":"42185884","doi":"10.1186/s12943-026-02696-5","year":2026,"isNew":true,"title":"SUMOylation in cancer: molecular mechanisms and therapeutic implications"}],"trialsShown":[{"nct":"NCT05642455","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"SPEARHEAD-3 Pediatric Study"},{"nct":"NCT03967223","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Master Protocol to Assess the Safety and Antitumor Activity of Genetically Engineered T Cells in NY-ESO-1 and/or LAGE-1a Positive Solid Tumo"},{"nct":"NCT06239272","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhab"},{"nct":"NCT05711615","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Testing Low-Dose Common Chemotherapy (Liposomal Doxorubicin) in Combination With an Anti-Cancer Drug, Peposertib, in Advanced Sarcoma"},{"nct":"NCT06083883","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Phase I/Ib Study of NK Expressing an Affinity-enhanced T-cell Receptor (TCR) Against the NY-ESO-1"},{"nct":"NCT05227326","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"AOH1996 for the Treatment of Refractory Solid Tumors"},{"nct":"NCT02650986","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Gene-Modified T Cells With or Without Decitabine in Treating Patients With Advanced Malignancies Expressing NY-ESO-1"},{"nct":"NCT06625190","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors"}],"usage":{"input":11576,"output":5816},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(TAK-981 OR subasumstat OR \"SUMOylation inhibitor\" OR SAE1 OR UBA2) AND (sarcoma OR \"SS18-SSX\" OR \"SS18::SSX\" OR \"MHC class I\" OR \"type I interferon\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"synovial sarcoma\" AND (\"HLA-A*02\" OR \"loss of heterozygosity\" OR \"antigen loss\" OR \"MAGE-A4 expression\" OR relapse) AND (afamitresgene OR letetresgene OR \"TCR T\" OR biopsy) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:39970827","PMID:41843290","PMID:42069597","PMID:42142669","PMID:42346086","PMID:42236118","PMID:42125258","PMID:41340481","PMID:42194046","PMID:42185884","NCT05642455","NCT03967223","NCT06239272","NCT05711615","NCT06083883","NCT05227326","NCT02650986","NCT06625190"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787181998421","cycle":161,"visit":3,"ts":"2026-08-19T23:26:38.421Z","cancer":{"key":"chondrosarcoma","name":"chondrosarcoma","mondo":{"id":"MONDO:0008977","name":"chondrosarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Reframe the chondrosarcoma ICI+TKI lead as VEGFR-driven (not AXL-driven) and pursue patient-level chondrosarcoma cases from the eight published ICI+VEGFR-TKI sarcoma trials, since a chondrosarcoma complete response is documented (PMID:40927310) while pooled ORR is inflated by ASPS (PMID:41143677) an","confidence":0.42,"notebook":"This visit's pack was thin on chondrosarcoma-specific primary data, and the two most informative items cut in opposite directions on L5. The pooled single-arm meta-analysis of ICI + VEGFR-TKI in soft-tissue sarcoma (8 phase II trials, 332 patients) reports ORR 33% and median PFS 7.1 months, but the signal is carried by alveolar soft part sarcoma (ORR 73%), and grade ≥3 AEs occurred in 40% — hypothyroidism, diarrhoea, transaminitis (PMID:41143677). [INFERRED] Stripping ASPS out leaves a much more modest non-selected estimate, so the \"response rate exceeds chemotherapy\" argument for DDCS cannot be inherited from pooled STS data. Against that, the companion review of the same eight studies records complete responses in DSRCT, angiosarcoma **and chondrosarcoma**, while calling combination therapy less effective in bone sarcomas generally (PMID:40927310). A documented CS complete response is the first patient-level efficacy anchor this programme has for L5; it is one abstract-level datum without genotype, line or duration, so I am moving L5 to 0.55 rather than to CANDIDATE — the evidence is new but derivative of the same trial set, and the abstract does not say which CS subtype.\n\nMechanistically, the more important change is negative: a targeted query explicitly for chondrosarcoma AND (AXL OR GAS6 OR cabozantinib OR bemcentinib) returned no primary chondrosarcoma AXL data for the second consecutive visit (returned instead osteosarcoma, liver, lymphangiogenesis and paediatric reviews — P1, P2, P4, P6, P8). Open questions 2 and 3 are therefore answered in the negative for now: pAXL in primary CS tissue is undemonstrated, and the mechanism underlying any ICI+TKI activity should be attributed to VEGFR-driven vascular normalisation/immune entry, not AXL. I am rewriting L5 accordingly and demoting AXL/GAS6 to a [SPECULATIVE] correlative to be measured, not targeted. Notebook flag: if a third targeted query yields no primary pAXL/GAS6 chondrosarcoma data, retire the AXL component outright and keep cabozantinib only as a VEGFR/MET agent.\n\nCalibration datum for axial bone tumours: 57 advanced chordomas treated with off-label MTTs gave RECIST PR in 6.3% of 79 treatment courses with first-line PFS 6.5 months (PMID:42274206) — a reminder that single-agent TKI in slow-growing axial cartilage/notochord tumours produces stabilisation, not shrinkage [INFERRED for CS].\n\nNo readout for vismodegib (NCT01267955 still active, not recruiting), no new IDH data, nothing on REGγ/WDR6 or Grb10. Noted for future: HPK1 inhibitor NDI-101150 ± pembrolizumab is tolerable with on-target phospho-SLP76 suppression and increased intratumoural CD8/DC (PMID:42097144) — a potential priming backbone for immune-cold CS, but zero sarcoma data, so no lead yet.","leadChanges":[{"id":"L5","title":"AXL/VEGFR multikinase inhibition combined with PD-(L)1 blockade in dedifferentiated and high-grade chondrosarcoma","level":"LEAD","status":"STRENGTHENED","confidence":0.55}],"unverifiedCitations":0,"openQuestions":["Which specific chondrosarcoma subtype, line of therapy and TKI/ICI pairing produced the complete response reported in PMID:40927310, and what was its duration - can the individual patient-level data be recovered from the eight underlying ph","Is there ANY primary chondrosarcoma tissue evidence (IHC, phosphoproteomics, functional knockdown in endogenous CS lines) for AXL/GAS6 pathway activation? If a third targeted query fails, retire the AXL component of L5.","Do CRISPR-edited or endogenous IDH-MUT chondrosarcoma models respond to mutant-IDH inhibitors themselves, and does tumour D-2-HG concentration predict response in NCT04521686/NCT04340843?","Does the IDH-WT-2 high-CNV/high-grade methylome cluster (PMID:42575314) map onto CDKN2A-deleted, RB1-intact tumours suitable for abemaciclib selection in NCT04040205?","Is there any published readout for vismodegib in chondrosarcoma (NCT01267955, active-not-recruiting since years), and is EXT1/heparan-sulfate loss [GERMLINE] a maintenance dependency in secondary peripheral CS or purely predisposition?","Is T-cell priming (HPK1 inhibition, PMID:42097144; or other agonist backbones) worth testing in immune-cold chondrosarcoma, i.e. does any CS cohort show baseline CD8 infiltrate sufficient for a priming-plus-checkpoint strategy?"],"nextQueries":["(\"chondrosarcoma\" AND (\"complete response\" OR \"case report\" OR \"objective response\") AND (pembrolizumab OR nivolumab OR atezolizumab OR camrelizumab) AND SRC:MED AND PUB_YEAR:[2019 TO 2026])","(\"chondrosarcoma\" AND (AXL OR GAS6 OR \"TAM receptor\" OR MERTK) AND (immunohistochemistry OR knockdown OR siRNA OR phosphoproteom*) AND SRC:MED)","(\"chondrosarcoma\" AND (vismodegib OR \"hedgehog\" OR GLI1 OR SMO OR EXT1 OR \"heparan sulfate\") AND SRC:MED AND PUB_YEAR:[2015 TO 2026])"],"papersShown":[{"pmid":"40679695","doi":"10.1007/s12672-025-02208-9","year":2025,"isNew":true,"title":"Systemic strategies for osteosarcoma: advances and future directions"},{"pmid":"41997132","doi":"10.1016/j.cell.2026.03.001","year":2026,"isNew":true,"title":"Hallmarks of liver cancer: Therapeutic implications"},{"pmid":"41143677","doi":"10.1093/oncolo/oyaf337","year":2025,"isNew":true,"title":"Immune checkpoint inhibitors combined with tyrosine kinase inhibitors for soft-tissue sarcomas: a systematic review and single-arm meta-analysis"},{"pmid":"42064237","doi":"10.1177/18632521261444250","year":2026,"isNew":true,"title":"What's new in pediatric bone sarcomas and benign bone tumors"},{"pmid":"42274206","doi":"10.1002/cnr2.70596","year":2026,"isNew":true,"title":"Systemic Treatment of Advanced Chordoma With Molecular Targeted Therapies: A Large Multicentre European Retrospective Case Series"},{"pmid":"42159886","doi":"10.1007/s11912-026-01781-8","year":2026,"isNew":true,"title":"Sarcomas in Adolescents and Young Adults"},{"pmid":"42097144","doi":"10.1016/j.xcrm.2026.102789","year":2026,"isNew":true,"title":"HPK1 inhibitor NDI-101150 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: Phase 1/2 trial results"},{"pmid":"41971838","doi":"10.1016/j.fmre.2024.02.018","year":2026,"isNew":true,"title":"Molecular biology of targeting lymphangiogenesis in cancer: Therapeutic strategies and future promise"},{"pmid":"40927310","doi":"10.36401/jipo-25-10","year":2025,"isNew":true,"title":"Immunotherapy and Targeted Therapies in Sarcoma: Proposed Synergy with Combination Treatment"},{"pmid":"40909947","doi":"10.3389/fonc.2025.1418537","year":2025,"isNew":true,"title":"MAPK-targeted therapies in non-gastrointestinal stromal tumor soft tissue sarcomas: current landscape and future directions"}],"trialsShown":[{"nct":"NCT01267955","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Vismodegib in Treating Patients With Advanced Chondrosarcomas"},{"nct":"NCT06239272","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhab"},{"nct":"NCT04340843","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing the Combination of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional C"},{"nct":"NCT01659203","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Proton or Photon RT for Retroperitoneal Sarcomas"},{"nct":"NCT04458922","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing Atezolizumab in People 2-17 Years Old With Clear Cell Sarcoma or Advanced Chondrosarcoma"},{"nct":"NCT07734805","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Radiological Diagnosis of Pediatric Neck Swellings"},{"nct":"NCT04040205","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Abemaciclib for Bone and Soft Tissue Sarcoma With Cyclin-Dependent Kinase (CDK) Pathway Alteration"},{"nct":"NCT04521686","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations"}],"usage":{"input":12028,"output":5049},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"chondrosarcoma\" AND (AXL OR GAS6 OR cabozantinib OR bemcentinib OR \"multikinase\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026])","(\"chondrosarcoma\" AND (pembrolizumab OR nivolumab OR atezolizumab OR \"immune checkpoint\") AND (apatinib OR axitinib OR lenvatinib OR pazopanib OR regorafenib) AND SRC:MED)"],"evidenceIds":["PMID:40679695","PMID:41997132","PMID:41143677","PMID:42064237","PMID:42274206","PMID:42159886","PMID:42097144","PMID:41971838","PMID:40927310","PMID:40909947","NCT01267955","NCT06239272","NCT04340843","NCT01659203","NCT04458922","NCT07734805","NCT04040205","NCT04521686"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787181809056","cycle":160,"visit":3,"ts":"2026-08-19T23:23:29.056Z","cancer":{"key":"chordoma","name":"chordoma","mondo":{"id":"MONDO:0008978","name":"chordoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Palbociclib monotherapy in CDKN2A-lost/RB1-intact chordoma produces disease control but no objective responses (PMID:40627883), so CDK4/6 inhibition must move to combination (CDK2/7/9, EGFR-TKI, or brain-penetrant auceliciclib) while the newly validated EPHA2-LYN-OGT-Notch1 mechanoadaptation axis an","confidence":0.5,"notebook":"The decisive item this visit is P3 (PMID:40627883), the first prospective genotype-selected systemic trial in chordoma: palbociclib in p16/CDKN2A-lost, CDK4/6- and RB1-retained advanced disease gave DCR 39% (11 SD/28), **zero objective responses**, mPFS 5.6 months, OS 24.6 months, good tolerability. This answers open question 1 empirically and cuts both ways: the CDKN2A→CDK4/6→RB axis is real and selectable, but its blockade is purely cytostatic. L2 therefore stays CANDIDATE and is re-specified as combination-only — monotherapy CDK4/6i should not be re-proposed in chordoma; record that as a closed avenue. Mechanistic reading [INFERRED]: p16-null chordoma tolerates Rb-pathway arrest without apoptosis, implying a parallel survival input (CDK2/cyclin E, mTOR, or ISR buffering). P5 (PMID:42165630) is weak for chordoma (no chordoma line named) but flags SNS-032/CDK2-7-9 as a shared-sarcoma sensitivity worth pairing with CDK4/6i; P4 (PMID:41581338) supplies auceliciclib, a brain-penetrant selective CDK4/6i with no DLTs — the rational successor agent for clival/skull-base disease where palbociclib CNS exposure is poor [KNOWN].\n\nP7 (PMID:41632535) is the strongest new mechanism: recurrent chordoma inhabits a stiffer ECM, and stiffness drives ligand-independent EPHA2 phosphorylation → LYN → OGT (Y989/Y418) → NICD1 O-GlcNAcylation (T2063/T2090/S2162) → stemness/mechanoadaptive transcription. This is a druggable chain of approved or clinical-stage agents (dasatinib for LYN/SRC, OSMI-1/OGT tools, γ-secretase inhibition) and it explains post-surgical recurrence rather than bulk growth — new lead L7, with the honest caveat that OGT is essential in normal tissue, so the window argument must come from combination dosing or NICD1-site-selective readouts.\n\nP6 (PMID:41965872) grades EGF→EGFR and PDGF→PDGFR as the best-validated chordoma circuits (multi-modal, limited clinical activity), which corroborates L6 independently of the NGS prevalence figure; it also elevates IL-6→IL-6R→STAT3 to level A functional validation and defines an ERS-CAF IER2→GMFG→ITGB1 axis. P8 (PMID:41617967), in 126 chordoma cases, ties ERS-CAF programmes to fibrotic immune-excluded regions with independent prognostic value. Together these make stromal exclusion, not just SMARCB1 status, the likely reason chordoma checkpoint arms are silent — L3's immunotherapy arm weakens further; PD-L1 expression is confirmed but expression is not response. New lead L8: tocilizumab/siltuximab or a JAK-STAT3 inhibitor plus TGF-β or ITGB1 blockade as a stroma-normalising backbone. P1, P2, P9, P10 contain nothing chordoma-specific — non-evidence.","leadChanges":[{"id":"L2","title":"Copy-number cluster-directed therapy: CDK4/6 inhibition in chr9/CDKN2A-loss (C9), GLI/SHH blockade in chr2+chr7-gain (C2)","level":"CANDIDATE","status":"WEAKENED","confidence":0.55},{"id":"L7","title":"Stiffness-driven EPHA2-LYN-OGT-Notch1 mechanoadaptation as the recurrence-specific target","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L8","title":"Stromal-immune reprogramming: IL-6/STAT3 and ERS-CAF-ITGB1 blockade as the prerequisite for any immunotherapy in chordoma","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L6","title":"Genotype-selected EGFR (and PDGFR) TKI arms in chordoma","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.42},{"id":"L3","title":"SMARCB1/INI1-deficient (poorly differentiated) chordoma as a checkpoint-blockade subset","level":"LEAD","status":"WEAKENED","confidence":0.32}],"unverifiedCitations":0,"openQuestions":["Which combination converts CDK4/6i cytostasis into cytoreduction in p16-null chordoma — CDK2/cyclin E co-inhibition, EPRS/ISR amplification, mTOR, or EGFR-TKI — and does cyclin E1/CDK2 activity rise in the palbociclib-treated biopsies from ","Does auceliciclib or another brain-penetrant CDK4/6i achieve clival tumour exposure sufficient for pRB suppression, and can a chordoma cohort be appended to its phase IIa framework?","Is the EPHA2-LYN-OGT-NICD1 axis druggable with an acceptable window in vivo — does dasatinib or intermittent OGT inhibition reduce post-resection recurrence in orthotopic chordoma models, and is the dependency confined to recurrent/stiff-ad","Do ERS-CAF-high chordomas show quantitatively reduced intratumoural CD8 density, and does IL-6R or TGF-beta/ITGB1 blockade increase T-cell penetration into fibrotic zones in chordoma explants?","Is the chordoma ATF4-DDIT3/EPRS dependency reproducible with a second chemotype and orthogonal knockdown, and what halofuginone dose is tolerable with particle radiotherapy?","Are BRCA2/PALB2 alterations in chordoma germline or somatic, with functional HR deficiency (RAD51 foci/HRDetect) exploitable under LETd-escalated particle therapy?"],"nextQueries":["\"chordoma\" AND (OGT OR \"O-GlcNAc\" OR NOTCH1 OR EPHA2 OR dasatinib OR stiffness OR mechanotransduction)","\"chordoma\" AND (IL-6 OR STAT3 OR tocilizumab OR \"cancer-associated fibroblast\" OR TGF-beta OR ITGB1) AND PUB_YEAR:[2023 TO 2026]","\"chordoma\" AND (CDK2 OR \"cyclin E\" OR abemaciclib OR combination OR resistance) AND (\"cell line\" OR xenograft OR trial)"],"papersShown":[{"pmid":"41055792","doi":"10.1007/s00432-025-06316-5","year":2025,"isNew":true,"title":"From pathogenesis to the patient's bedside: a comprehensive review of extraskeletal myxoid chondrosarcoma"},{"pmid":"41097161","doi":"10.3390/nu17193085","year":2025,"isNew":true,"title":"Shikonin as a Dietary Phytochemical with Multi-Target Anti-Cancer Activities: From Molecular Mechanisms to Translational Applications"},{"pmid":"40627883","doi":"10.1016/j.esmoop.2025.105498","year":2025,"isNew":true,"title":"CDK4/6 inhibition in advanced chordoma: final results of the NCT PMO-1601 trial"},{"pmid":"41581338","doi":"10.1016/j.esmoop.2025.106035","year":2026,"isNew":true,"title":"A phase I/IIa study of auceliciclib in patients with advanced solid tumours and in combination with temozolomide in patients with recurrent/relapsed high-grade glioma"},{"pmid":"42165630","doi":"10.1158/2767-9764.crc-26-0142","year":2026,"isNew":true,"title":"Drug Screening of Sarcoma Cells: Finding Shared Sensitivities"},{"pmid":"41965872","doi":"10.1186/s13643-026-03183-0","year":2026,"isNew":true,"title":"Immune and stromal signaling networks in chordoma: an evidence-weighted review of ligand-receptor interactions and therapeutic implications"},{"pmid":"41632535","doi":"10.1172/jci194378","year":2026,"isNew":true,"title":"Notch1 O-GlcNAcylation drives tumor stemness and mechanoadaptation to a stiff microenvironment and promotes chordoma recurrence"},{"pmid":"41617967","doi":"10.1038/s41746-026-02388-w","year":2026,"isNew":true,"title":"Decoding the ERS-CAF immunoregulatory axis via multimodal AI and its pan-cancer prognostic and therapeutic predictive value"},{"pmid":"40498965","doi":"10.1002/1878-0261.70070","year":2025,"isNew":true,"title":"EACR 2025 Congress: Innovative Cancer Science, 16-19 June 2025"},{"pmid":"40862786","doi":"10.3390/curroncol32080417","year":2025,"isNew":true,"title":"Small-Molecule Drugs in Pediatric Neuro-Oncology"}],"trialsShown":[{"nct":"NCT03910465","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Children and Adults With Chordoma"},{"nct":"NCT01200680","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Genetic Clues to Chordoma Etiology: A Protocol to Identify Sporadic Chordoma Patients for Studies of Cancer-Susceptibility Genes"},{"nct":"NCT05286801","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors"},{"nct":"NCT04416568","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of Nivolumab and Ipilimumab in Children and Young Adults With INI1-Negative Cancers"},{"nct":"NCT06625190","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors"},{"nct":"NCT01346124","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"High Dose Intensity Modulated Proton Radiation Treatment +/- Surgical Resection of Sarcomas of the Spine, Sacrum and Base of Skull"},{"nct":"NCT02834013","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Nivolumab and Ipilimumab in Treating Patients With Rare Tumors"},{"nct":"NCT00496119","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Proton Beam Therapy for Chordoma Patients"}],"usage":{"input":11881,"output":7598},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chordoma\" AND (halofuginone OR EPRS OR ATF4 OR DDIT3 OR \"integrated stress response\") AND SRC:MED","\"chordoma\" AND (CDKN2A OR RB1 OR palbociclib OR abemaciclib OR ribociclib) AND (xenograft OR \"cell line\" OR response) AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41055792","PMID:41097161","PMID:40627883","PMID:41581338","PMID:42165630","PMID:41965872","PMID:41632535","PMID:41617967","PMID:40498965","PMID:40862786","NCT03910465","NCT01200680","NCT05286801","NCT04416568","NCT06625190","NCT01346124","NCT02834013","NCT00496119"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787181590306","cycle":159,"visit":3,"ts":"2026-08-19T23:19:50.306Z","cancer":{"key":"uveal melanoma","name":"uveal melanoma","mondo":{"id":"MONDO:0006486","name":"uveal melanoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Sorafenib's randomised-discontinuation PFS benefit (5.5 vs 1.9 mo, PMID:41362626) plus a tolerable chemosaturation+immunotherapy window (PMID:41795199, PMID:41834299) make RAF/VEGFR maintenance and melphalan-based immunogenic debulking the two highest-value new combination arms to test against the d","confidence":0.62,"notebook":"This visit's pack contains one genuinely new randomised result and a cluster of locoregional-delivery data; it contains nothing on ASS1 despite a targeted query.\n\nSTREAM (PMID:41362626) is the first placebo-controlled randomised signal for an oral agent in treatment-naive mUM: after a 56-day sorafenib run-in, randomised discontinuation gave mPFS 5.5 vs 1.9 months (HR 0.53). Caveats are structural — only the 78/147 patients with stable disease were randomised, so this measures maintenance benefit in an enriched population, not first-line ORR or OS. Mechanistically sorafenib hits CRAF/VEGFR2/PDGFR-β [KNOWN], i.e. both the RAF node downstream of Gq→PKC→RASGRP3 and hepatic angiogenesis, which the liver-TME review (PMID:41160198) argues is a distinct compartment sustaining LMUM. That makes sorafenib a plausible rational partner for, not a competitor to, PKC inhibition — and a cheap one. The same paper reports baseline GNAQ/GNA11-mutant ctDNA predicting inferior outcome, which converges with the tebentafusp week-12 ctDNA-clearance thread: ctDNA is becoming a cross-modality stratifier, not a tebentafusp-specific one. New lead L7, confidence held at 0.45 pending OS and a non-enriched cohort.\n\nDYP688 gained only pharmacology, not efficacy: PMID:39690276 shows the FR900359 Gq-inhibitor payload undergoes on-antibody inactivation in plasma, so a short antibody half-life is deliberately optimal, with AUC above a tumourostatic concentration as the efficacy driver, and interim clinical PK matching prediction. This supports the DYP688 arm of L1 as developable but leaves open question 5 unanswered — no response rate, no ocular/pigmentary toxicity data yet.\n\nLocoregional integration is where the practical movement is. A small retrospective series (PMID:41795199) gave ICI or tebentafusp within ±40 days of chemosaturation in 10 patients: hepatic control in all, 7 PR, with pancytopenia the dominant toxicity; PHP thrombocytopenia is transient and, by ROTEM, not functionally coagulopathic (PMID:41834299), with structured peri-procedural care now codified (PMID:42555789). Together these define a real haematologic window for combining hepatic melphalan with a systemic agent — new lead L8 (melphalan as immunogenic debulking plus engager/ICI), and a bounded rather than fatal constraint on L5's regional-melphalan plus pegargiminase design, which is why L5 moves only marginally. PMID:42317800's Bayesian hybrid-control design (28% fewer patients for a 50% hazard reduction, borrowing six BAC PFS sources) is the enabling statistical vehicle for both in a rare disease.\n\nL5's biology remains uncorroborated: a dedicated ASS1/arginine query returned nothing beyond PMID:42322017. If the next targeted query is again empty, L5 should be retired rather than carried. Bel-sar (NCT06007690/NCT07338968) still has no readout; P5, P9 are off-target for this programme.","leadChanges":[{"id":"L1","title":"PKC inhibition (darovasertib) as the obligate backbone in GNAQ/GNA11/CYSLTR2-mutant uveal melanoma, with rational partners against MAPK rebound and YAP/TAZ outp","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.7},{"id":"L2","title":"Next-generation ImmTAC/T-cell engagers plus innate priming for HLA-A*02:01-negative and post-tebentafusp metastatic UM","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.7},{"id":"L5","title":"Arginine auxotrophy (ASS1 loss) as a liver-directed synthetic lethality: pegargiminase plus hepatic melphalan via Fanconi-anaemia pathway suppression","level":"LEAD","status":"STRENGTHENED","confidence":0.42},{"id":"L7","title":"Sorafenib (CRAF/VEGFR/PDGFR) as a repurposed maintenance backbone in mUM, with GNAQ/GNA11 ctDNA stratification","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L8","title":"Hepatic melphalan (PHP/chemosaturation) as immunogenic debulking combined with systemic immunotherapy, enabled by hybrid-Bayesian trial design","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["Does STREAM show any OS benefit or ITT (pre-randomisation) PFS advantage for sorafenib, and is the GNAQ/GNA11 ctDNA-poor-prognosis subgroup the one that benefits or the one that fails?","Is there any efficacy or ocular/pigmentary toxicity readout for DYP688 (PMEL17-FR900359 ADC) in humans, and does the short-half-life design translate into responses after darovasertib?","In paired pre/post-hepatic-perfusion biopsies, does melphalan raise MHC-I and gp100/PRAME expression and T-cell infiltration — i.e. is 'immunogenic debulking' real or just burden reduction?","Does any independent dataset beyond PMID:42322017 report ASS1 loss frequency or arginine-deprivation sensitivity in UM organoids or metastases (kill/keep decision for L5)?","In post-tebentafusp progression biopsies, what is the relative frequency of HLA-haplotype loss vs B2M/antigen-presentation defects vs gp100 downregulation, and does week-12 ctDNA non-clearance flag it prospectively?","Has the CoMpass phase 3 (NCT06007690) or its long-term follow-up (NCT07338968) reported any metastasis-free-survival signal for bel-sar primary ablation?"],"nextQueries":["\"uveal melanoma\" AND (sorafenib OR lenvatinib OR \"multikinase inhibitor\" OR antiangiogenic OR VEGFR) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"uveal melanoma\" OR \"ocular melanoma\") AND (\"percutaneous hepatic perfusion\" OR chemosaturation OR \"hepatic perfusion\") AND (tebentafusp OR immunotherapy OR \"checkpoint inhibitor\" OR \"immunogenic cell death\") AND SRC:ME","(\"uveal melanoma\" OR \"metastatic uveal melanoma\") AND (DYP688 OR \"FR900359\" OR PMEL17 OR ASS1 OR \"arginine deiminase\" OR pegargiminase) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"40380030","doi":"10.1007/s11912-025-01684-0","year":2025,"isNew":true,"title":"State-of-the-art in Metastatic Uveal Melanoma Treatment: A 2025 Update : How to treat Metastatic Uveal Melanoma in 2025"},{"pmid":"39690276","doi":"10.1007/s10928-024-09956-1","year":2024,"isNew":true,"title":"QSP modeling of a transiently inactivating antibody-drug conjugate highlights benefit of short antibody half life"},{"pmid":"41160198","doi":"10.1007/s10555-025-10298-8","year":2025,"isNew":true,"title":"Functions and clinical implications of the liver microenvironment in hepatic uveal melanoma metastases"},{"pmid":"41362626","doi":"10.1016/j.isci.2025.114045","year":2025,"isNew":true,"title":"Sorafenib as first-line therapy for metastatic uveal melanoma: A multicenter, placebo-controlled randomized discontinuation study (STREAM)"},{"pmid":"42254311","doi":"10.1016/j.ajoc.2026.102601","year":2026,"isNew":true,"title":"Acral lentiginous melanoma metastases to the vitreous masquerading as uveitis: A case report"},{"pmid":"42555789","doi":"10.1188/26.cjon.283-290","year":2026,"isNew":true,"title":"Percutaneous Hepatic Perfusion: Continuum of Nursing Care and Safety Implications for Managing Patients With Metastatic Uveal Melanoma"},{"pmid":"41795199","doi":"10.1002/ijc.70418","year":2026,"isNew":true,"title":"Tolerability and efficacy of chemosaturation in combination with systemic therapy for metastatic uveal melanoma"},{"pmid":"42317800","doi":"10.1016/j.conctc.2026.101653","year":2026,"isNew":true,"title":"The design of a small Bayesian hybrid-controlled trial utilizing time-to-event data from six published sources that used best alternative care to treat liver-predominant metastasis"},{"pmid":"42278562","doi":"10.3390/ijms27115038","year":2026,"isNew":true,"title":"An Exploratory Study of High-Concentration Trace Amine Effects and Adrenoceptor Expression Patterns in SH-SY5Y Cells and Neuroblastoma"},{"pmid":"41834299","doi":"10.1097/cmr.0000000000001093","year":2026,"isNew":true,"title":"Percutaneous hepatic perfusion with melphalan in liver metastatic uveal melanoma and viscoelastic hemostatic assays guided coagulation assessment for thrombocytopenia"}],"trialsShown":[{"nct":"NCT07338968","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"A Long-Term Follow-Up Study of Subjects Completing the AU-011-301(CoMpass) for Early Choroidal Melanoma"},{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT03025256","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Intravenous and Intrathecal Nivolumab in Treating Patients With Leptomeningeal Disease"},{"nct":"NCT04588662","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Prospective Natural History Study in Uveal Melanoma"},{"nct":"NCT04855435","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Safety and Preliminary Efficacy of MBS8(1V270) in Cancer Patients With Advanced Solid Tumours"},{"nct":"NCT01979523","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Trametinib With or Without GSK2141795 in Treating Patients With Metastatic Uveal Melanoma"},{"nct":"NCT06007690","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Phase 3 Randomized, Masked, Controlled Trial to Evaluate Efficacy and Safety of Belzupacap Sarotalocan (AU-011) Treatment Compared to Sham"},{"nct":"NCT01587352","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Vorinostat in Treating Patients With Metastatic Melanoma of the Eye"}],"usage":{"input":12444,"output":9297},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"uveal melanoma\" AND (ASS1 OR \"arginine deprivation\" OR ADI-PEG20 OR pegargiminase OR melphalan) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"uveal melanoma\" AND (DYP688 OR PMEL17 OR \"antibody-drug conjugate\" OR brenetefusp OR PRAME) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:40380030","PMID:39690276","PMID:41160198","PMID:41362626","PMID:42254311","PMID:42555789","PMID:41795199","PMID:42317800","PMID:42278562","PMID:41834299","NCT07338968","NCT07636785","NCT03025256","NCT04588662","NCT04855435","NCT01979523","NCT06007690","NCT01587352"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787181351746","cycle":158,"visit":3,"ts":"2026-08-19T23:15:51.746Z","cancer":{"key":"juvenile myelomonocytic leukemia","name":"juvenile myelomonocytic leukemia","mondo":{"id":"MONDO:0011908","name":"juvenile myelomonocytic leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"RAS-pathway genotype is associated with poor GvL response to donor lymphocyte infusion in myeloid malignancy, so JMML post-HSCT relapse strategies should test clone-directed pharmacology (MEK inhibitor or HMA immune priming) layered onto DLI/immunosuppression withdrawal rather than T-cell pressure a","confidence":0.45,"notebook":"Thin pack for JMML proper: both queries returned adult CMML/MDS surrogates and no primary JMML data, so open questions 1–2 (trametinib VAF kinetics, infant mucosal toxicity rates) and 3 (pacritinib on GM-CSF-independent CFU) remain unanswered. Record the retrieval failure: \"pacritinib OR IRAK1\" against JMML/CMML yields nothing mechanistic — the agent has no published myelomonocytic preclinical read-out beyond the running trial, so L6 rests on NCT07033598 (T4) plus [KNOWN] pharmacology and must not drift upward on trial existence alone.\n\nWhat genuinely changed. P7 (PMID:42258587) is the highest-value item: in 62 alloHSCT recipients salvaged with DLI, KRAS/NRAS/JAK2 (and TP53/RUNX1) mutations tracked with adverse outcome, and therapeutic DLI achieved CR/CRi in only 29% with median OS 6 months. JMML relapse after HSCT is managed with immunosuppression withdrawal/DLI [KNOWN]; this is the first pack evidence that RAS-pathway genotype specifically blunts GvL, which argues that the JMML relapse problem is not solvable by T-cell pressure alone and needs pharmacologic co-treatment of the clone (MEK inhibition, or HMA) layered onto DLI/taper strategies (NCT07302776 tests targeted tacrolimus cessation). New lead L8. Caveat: only 3 CMML patients, retrospective, adult, RAS mutations not separated from complex karyotype/TP53 — association, not mechanism [INFERRED].\n\nP2 (PMID:41908667) gives a second, immune rationale for HMA choice: low-dose decitabine alone raised peripheral NKT-like cells (3.5→4.25%, p=0.035) with no change in Tregs or CD8 — n=12, one CMML, so hypothesis-generating only. It reframes L3 from \"which agent debulks better\" to \"which agent debulks and primes the graft,\" and it is orthogonal to L1's Treg-remodelling axis (no Treg shift seen here, arguing HMA does not fix the niche). L3 nudged up but stays low-confidence.\n\nP1 (PMID:41894646) makes the adult surrogate usable: 3,013+516 patients resolve into nine genomic CMML entities, so I can now ask which cluster the \"advanced proliferative\" pacritinib population maps to and whether it is the RAS-pathway-enriched, JMML-like one — a prerequisite for reading T4 across to JMML at all. Modest strengthening of L6's surrogate logic, not its mechanism.\n\nP3 (PMID:42305129) is pure enablement: a validated thaw protocol preserving >80% viability and CFU function in fragile monocyte-rich CMML/AML mononuclear cells — the exact sample type L2's BH3 profiling and L6's CFU assays require. Feasibility, not biology; L2 moves 0.42→0.44 on that basis only.\n\nNext I need JMML-restricted relapse/DLI/azacitidine-maintenance data, serial VAF on MEK inhibitors, and any allele-resolved PTPN11 inflammasome read-out.","leadChanges":[{"id":"L8","title":"RAS-genotype-blunted graft-versus-leukemia: pharmacologically augmented DLI/immunosuppression-withdrawal for post-HSCT JMML relapse","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L3","title":"Hypomethylating agent selection (decitabine vs azacitidine) as a modifiable pre-HSCT variable in JMML","level":"LEAD","status":"STRENGTHENED","confidence":0.38},{"id":"L6","title":"Pacritinib as a dual GM-CSF/JAK2-STAT5 and IL-1R/IRAK1 node inhibitor in JMML","level":"LEAD","status":"STRENGTHENED","confidence":0.42},{"id":"L2","title":"Monocytic/RAS-driven BCL2-family rewiring predicts venetoclax failure in JMML; MCL-1/BCL-xL-directed priming plus MAPK blockade","level":"LEAD","status":"STRENGTHENED","confidence":0.44}],"unverifiedCitations":0,"openQuestions":["In JMML-only cohorts, does response to immunosuppression withdrawal or DLI differ by somatic genotype (PTPN11/NRAS/KRAS/NF1/CBL), and does pre- or post-HSCT azacitidine/decitabine or trametinib exposure change DLI response?","Does trametinib monotherapy in JMML reduce mutant VAF or only suppress counts, and what is the rebound risk on taper/discontinuation?","What is the quantified mucosal/airway toxicity rate of MEK inhibitors in RASopathy infants, and can MEK be staggered rather than combined with post-HSCT immunotherapy?","Which of the nine molecular CMML entities corresponds to the RAS-pathway/proliferative, JMML-like cluster, and is that the population enrolled in NCT07033598?","Which PTPN11 alleles beyond E76K carry the NLRP3/IL-1beta/PTGS2 signature, and do germline Noonan MPD alleles differ from somatic JMML alleles?","Is venetoclax resistance in JMML MCL-1/BCL-xL-driven, and does MEK or SHP2 pre-treatment re-prime BCL2 dependence in primary samples?"],"nextQueries":["\"juvenile myelomonocytic leukemia\" AND (relapse OR \"donor lymphocyte\" OR \"immunosuppression withdrawal\" OR \"second transplant\" OR azacitidine maintenance) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(trametinib OR selumetinib) AND (\"juvenile myelomonocytic\" OR RASopathy) AND (\"variant allele frequency\" OR \"molecular response\" OR chimerism OR discontinuation) AND SRC:MED","PTPN11 AND (E76K OR D61Y OR allele OR variant) AND (NLRP3 OR \"IL-1\" OR inflammasome OR PTGS2 OR macrophage) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"papersShown":[{"pmid":"41894646","doi":"10.1200/jco-25-02116","year":2026,"isNew":true,"title":"Molecular-Based Ecosystem to Improve Personalized Medicine in Chronic Myelomonocytic Leukemia"},{"pmid":"41908667","doi":"10.1016/j.cpt.2026.01.002","year":2026,"isNew":true,"title":"Low-dose decitabine increases peripheral NKT-like cell proportions in patients with chronic myeloid neoplasms"},{"pmid":"42305129","doi":"10.21769/bioprotoc.5720","year":2026,"isNew":true,"title":"A Reliable Method for Thawing Primary AML and CMML Mononuclear Cells to Preserve Viability and Function"},{"pmid":"42299353","doi":"10.11613/bm.2026.020504","year":2026,"isNew":true,"title":"Proteomics in myelodysplastic syndromes: towards novel prognostic and diagnostic biomarkers"},{"pmid":"42279423","doi":"10.3390/cancers18111841","year":2026,"isNew":true,"title":"SNP-Based Chromosomal Microarray Analysis in the Era of Optical Genome Mapping: An Enriched Case-Series Evaluating Copy-Neutral Events"},{"pmid":"42277437","doi":"10.1038/s43856-026-01599-2","year":2026,"isNew":true,"title":"Optimized post-GWAS analysis identifies therapeutic targets for essential thrombocythemia and polycythemia vera"},{"pmid":"42258587","doi":"10.1159/000552196","year":2026,"isNew":true,"title":"Comparative Efficacy of Donor Lymphocyte Infusions in Augmenting Graft-versus-Leukemia Effect after Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Myeloid Mal"},{"pmid":"42146026","doi":"10.14740/jmc5297","year":2026,"isNew":true,"title":"Isolated Neutropenia as a Sentinel of High-Risk Clonal Evolution: Acute Myeloid Leukemia With Myelodysplasia-Related Changes Harboring &lt;i&gt;TP53&lt;/i&gt; Deletion via Isochrom"}],"trialsShown":[{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"},{"nct":"NCT07302776","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"TACrolimus Targeted Immunosuppression Cessation in ALlogeneic HCT"},{"nct":"NCT07143669","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Screening Study for KIT D816V Mutated Mast Cell Disease in Select Populations"},{"nct":"NCT04708054","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS"}],"usage":{"input":11961,"output":6544},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"juvenile myelomonocytic leukemia\" OR \"chronic myelomonocytic leukemia\") AND (pacritinib OR IRAK1 OR \"JAK2\" OR \"GM-CSF hypersensitivity\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(trametinib OR \"MEK inhibitor\") AND (RASopathy OR \"Noonan syndrome\" OR \"juvenile myelomonocytic\") AND (toxicity OR mucositis OR \"adverse event\" OR discontinuation OR rebound OR \"variant allele frequency\") AND SRC:MED AND"],"evidenceIds":["PMID:41894646","PMID:41908667","PMID:42305129","PMID:42299353","PMID:42279423","PMID:42277437","PMID:42258587","PMID:42146026","NCT06904066","NCT06566742","NCT05600894","NCT07033598","NCT06001385","NCT07302776","NCT07143669","NCT04708054"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787181143787","cycle":157,"visit":3,"ts":"2026-08-19T23:12:23.787Z","cancer":{"key":"atypical teratoid rhabdoid tumor","name":"atypical teratoid rhabdoid tumor","mondo":{"id":"MONDO:0020560","name":"atypical teratoid rhabdoid tumor"}},"control":false,"modelLabel":"SCIENCE","summary":"Fresh chromatin evidence favours the 'lethal derepression' axis in SWI/SNF-deficient cells — CHD3/NuRD depletion kills via PARD3B derepression (PMID:42174139) — so open a NuRD-ATPase degradation lead for SMARCB1-null ATRT, weaken PHIP (leukaemogenic PHF6/PHIP loss, PMID:40721297), and pair EZH2 degr","confidence":0.5,"notebook":"This visit's pack is chromatin-mechanistic, not ATRT-clinical, but it splits the L1/L6 polarity question I set myself.\n\nPMID:42174139 [NEW] is the most consequential item: in dual SMARCA4/SMARCA2-null cancers, CHD3/NuRD is an \"epigenetic brake\" whose depletion causes hyper-accessibility and toxic derepression of PARD3B, attenuated MYC output, and tumour regression in xenografts. That is the same directional logic as corin (L1): in SWI/SNF-crippled cells, *removing* a repressor is lethal, not protective. It is the opposite of L6's model (PMID:41946722), where PHIP loss lets NuRD silence promoters lethally. Both cannot be the general rule; the genotype differs (dual ATPase loss vs SMARCB1 loss with retained SMARCA4), so I treat the CHD3 result as [INFERRED] extrapolation to ATRT and open a new lead (L7) to test NuRD-ATPase (CHD3/CHD4) degradation in SMARCB1-null ATRT with PARD3B and MYC-signature readouts — attractive because ATRT-MYC is the worst subgroup.\n\nPMID:40721297 [NEW] damages L6 from a second direction: PHIP is the obligate chromatin-loading partner of PHF6, and PHIP loss phenocopies PHF6 loss — i.e. derepresses a myeloid stemness network. PHF6/PHIP loss converts Flt3-ITD CMML into AML. So systemic PHIP degradation in an infant carries a plausible leukaemogenic liability on top of the Chung-Jansen neurodevelopmental floor, and PHIP's \"activator-cooperating with SWI/SNF\" role is at minimum context-dependent. L6 weakened (0.42→0.34); it now needs ATRT-specific dependency data plus a haematopoietic safety readout before any chemistry argument.\n\nPMID:42358575 [NEW] (rhabdoid tumour of kidney) independently states that EZH2 inhibition and CDK4/6 blockade give proof of principle with modest single-agent activity and no predictive biomarkers, and that immunotherapy's role is undefined. That corroborates L5's core claim that catalytic EZH2 inhibition is insufficient (motivating degraders) and adds CDK4/6 blockade — mechanistically rational given SMARCB1-loss-driven p16 repression [KNOWN] — as a clinic-ready combination partner (abemaciclib for CNS exposure [KNOWN]). It also reinforces the L3 weakening; no ERV/interferon data appeared again.\n\nNotebook records: NCT06465199 (DFMO+AMXT 1501, CNS tumours) is recruiting, but the retired polyamine lead stays retired — trial existence is not ATRT dependency evidence. PMID:41312722 (SALL4 loads BAF at neural-crest enhancers) and PMID:41791709 (SWI/SNF–GLS1/OXPHOS metabolic coupling) are parked as unbuilt hypotheses: no rhabdoid data. P4/P5/P7/P9/P10 contribute nothing actionable to ATRT.\n\nNo promotion to CANDIDATE this visit: every new item is either a different genotype or a different tissue.","leadChanges":[{"id":"L1","title":"CoREST complex inhibition (corin; bifunctional LSD1/HDAC1-2) to restore differentiation programmes in SMARCB1-deficient ATRT","level":"LEAD","status":"STRENGTHENED","confidence":0.58},{"id":"L5","title":"DCAF5 degradation to restore residual SWI/SNF assembly in SMARCB1-deficient ATRT, with EZH2-degrader/MDM2/SINE combinations","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55},{"id":"L6","title":"PHIP inhibition as SWI/SNF-loss synthetic lethality: weaponising NuRD-mediated promoter silencing in SMARCB1-null ATRT","level":"LEAD","status":"WEAKENED","confidence":0.34},{"id":"L7","title":"NuRD-ATPase (CHD3/CHD4) degradation as toxic-derepression synthetic lethality in SMARCB1-null ATRT","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["In isogenic SMARCB1-null ATRT lines, does CHD3/CHD4 depletion phenocopy corin (shared hyper-accessibility, PARD3B induction, MYC-output loss) or is it additive — and does either state resemble or oppose PHIP loss?","Is PARD3B derepression a lethal effector in SMARCB1-null (SMARCA4-retained) cells at all, or does residual SWI/SNF activity abolish the CHD3 brake dependency?","Does PHIP depletion in ATRT models transform or expand normal murine HSPCs (PHF6-network stemness derepression), i.e. is there any survivable therapeutic window for PHIP degradation in infants?","Does an EZH2 degrader plus CNS-penetrant CDK4/6 inhibitor (abemaciclib) combination outperform either agent in orthotopic ATRT PDX, and is it tolerable in infant-equivalent models?","What is quantitative B7-H3 surface density across ATRT subgroups versus TME myeloid/endothelial B7-H3, and do differentiation-inducing epigenetic agents raise or lower it?","Does corin (or any CoREST/NuRD-directed agent) achieve pharmacologically active CNS exposure in orthotopic ATRT?"],"nextQueries":["(CHD4 OR CHD3 OR NuRD) AND (degrader OR PROTAC OR \"chemical probe\") AND PUB_YEAR:[2023 TO 2026] AND SRC:MED","(\"atypical teratoid\" OR rhabdoid) AND (EZH2 AND (degrader OR \"CDK4/6\" OR abemaciclib OR palbociclib)) AND PUB_YEAR:[2023 TO 2026] AND SRC:MED","(B7-H3 OR CD276) AND (\"atypical teratoid\" OR rhabdoid OR \"intracerebroventricular\") AND PUB_YEAR:[2024 TO 2026] AND SRC:MED"],"papersShown":[{"pmid":"40721297","doi":"10.1101/gad.352602.125","year":2025,"isNew":true,"title":"Leukemia mutated proteins PHF6 and PHIP form a chromatin complex that represses acute myeloid leukemia stemness"},{"pmid":"42174139","doi":"10.1038/s41698-026-01499-7","year":2026,"isNew":true,"title":"Targeting the CHD3 chromatin remodeler exploits a synthetic lethal vulnerability in dual SMARCA4/SMARCA2-deficient cancers via derepression of PARD3B"},{"pmid":"41791709","doi":"10.1016/j.jbc.2026.111342","year":2026,"isNew":true,"title":"The SWI/SNF complex in tumor metabolism: Mechanisms and therapeutic implications"},{"pmid":"42145909","doi":"10.3892/ol.2026.15636","year":2026,"isNew":true,"title":"Next-generation sequencing elucidates the distinct mutational landscape of SMARCA4-deficient lung cancer"},{"pmid":"41664213","doi":"10.1186/s13048-026-02010-3","year":2026,"isNew":true,"title":"Exploring the optimal cutoff point and genomic characteristics for PARP inhibitor maintenance therapy in early recurrence of ovarian cancer"},{"pmid":"42358575","doi":"10.3389/fped.2026.1861712","year":2026,"isNew":true,"title":"Current treatment landscape and translational priorities in malignant rhabdoid tumor of the kidney"},{"pmid":"41789425","doi":"10.3389/fcimb.2026.1774929","year":2026,"isNew":true,"title":"SWI/SNF-associated molecular subtypes reshape tumor microenvironmental features and inform precision therapeutic strategies in bladder cancer"},{"pmid":"41312722","doi":"10.1242/dev.205248","year":2025,"isNew":true,"title":"Neural crest induction requires SALL4-mediated BAF recruitment to lineage specific enhancers"},{"pmid":"42072710","doi":"10.3390/biom16040589","year":2026,"isNew":true,"title":"Chromatin Remodeling, DNA Double-Strand Break Repair, and Human Disease: How a Breakup Changes You"},{"pmid":"41278204","doi":"10.3389/fcell.2025.1690350","year":2025,"isNew":true,"title":"Chromatin remodeling complexes: architects influencing breast cancer progression"}],"trialsShown":[{"nct":"NCT06465199","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Eflornithine (DFMO) and AMXT 1501 for Neuroblastoma, CNS Tumors, and Sarcomas"},{"nct":"NCT03959800","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Molecular Basis of Pediatric Liver Cancer"},{"nct":"NCT04715191","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors"},{"nct":"NCT03793166","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, T"},{"nct":"NCT06622941","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Study to ONO-4538 in Patients With Rhabdoid Tumor"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT04099797","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"C7R-GD2.CAR T Cells for Patients With GD2-expressing Brain Tumors (GAIL-B)"},{"nct":"NCT03911388","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"HSV G207 in Children With Recurrent or Refractory Cerebellar Brain Tumors"}],"usage":{"input":12694,"output":6930},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(DCAF5 OR \"DDB1-CUL4\") AND (\"rhabdoid\" OR SMARCB1) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(PHIP OR NuRD OR CHD4) AND (SMARCB1 OR \"SWI/SNF\" OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:40721297","PMID:42174139","PMID:41791709","PMID:42145909","PMID:41664213","PMID:42358575","PMID:41789425","PMID:41312722","PMID:42072710","PMID:41278204","NCT06465199","NCT03959800","NCT04715191","NCT03793166","NCT06622941","NCT04320888","NCT04099797","NCT03911388"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787180934076","cycle":156,"visit":15,"ts":"2026-08-19T23:08:54.076Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Retire CD26-directed LSC killing (no depleting construct exists after a dedicated query) and open a new CML-primary lead on FBXO3–DUSP9–MAPK as a kinase-independent LSC dependency combinable with imatinib.","confidence":0.62,"notebook":"This visit's two targeted queries were designed to fire prespecified decisions, and both did.\n\nThe CD26/DPP4 query returned no depleting construct against primary CML LSCs — no antibody, ADC, immunotoxin, CAR-T or CAR-M, and no surface-density comparison against activated T cells or same-donor CD34+ HSPCs. The only DPP4 material remains enzymatic and haematopoiesis-supportive (PMID:42053786), and the standing counter-evidence that CD26+ burden does not track molecular relapse in TFR is unchanged (PMID:40116978). **L15 is retired** on its own prespecified condition: CD26 stays a validated discrimination marker for BCR::ABL1+ LSCs (PMID:39503729) and nothing more. Recorded so the desk does not re-propose CD26-directed killing without primary depletion data.\n\nThe randomised de-escalation query returned no prospective randomised dose-reduction trial with MR4.0/MR4.5, TFR and PRO endpoints — the tier-limiting gap of **L7** for a sixth pass. L7's mechanistic base (floor-plus-plateau exposure–response, the dasatinib 50 vs 100 mg toxicity separation) is untouched, but I mark it weakened for evidential silence rather than let a DOSSIER coast; the immortal-time re-analysis of PMID:41668074 is still the only tractable next step.\n\nThe substantive novelty is off-query: FBXO3 in CML LSCs (PMID:41850237). Agnostic scRNA-seq of CD34+ cells from TKI-resistant patients nominates FBXO3 as upregulated and as an LSC marker; FBXO3 loss induces apoptosis in lines and primary LSCs in vitro and in vivo with minimal effect on normal CD34+ HSCs; mechanistically FBXO3 ubiquitinates DUSP9, and DUSP9 depletion partially rescues, placing the dependency on relief of a MAPK phosphatase — i.e. FBXO3 sustains MAPK output in the persistent clone. This is BCR-ABL1-kinase-independent by construction and directly answers part of open question 5 with a primary-cell-supported node rather than an atlas correlation. Caveats stated plainly: single laboratory, abstract only, the \"FBXO3 inhibitor\" is unnamed (BC-1215 is the obvious class tool [KNOWN]), and FBXO3 has normal roles in innate inflammatory signalling and cardiac/neuronal proteostasis [KNOWN], so the window claim rests entirely on the same-donor HSC comparison. New LEAD at 0.3, above L3/L14 because the data are CML-primary rather than extrapolated.\n\nControl calibration: the desk's highest tier remains the known solved axis — BCR::ABL1 [SOMATIC] fusion blocked at the ATP site, with the allosteric myristoyl pocket as non-cross-resistant salvage (L8, PMID:42463944) and dose as a therapeutic-window variable (L7).\n\nNext I need FBXO3/DUSP9 independent replication and the identity of the tool inhibitor, plus the mutation-resolved asciminib-failure spectrum.","leadChanges":[{"id":"L16","title":"FBXO3-mediated DUSP9 degradation sustains MAPK output in the persistent CML LSC: FBXO3 inhibition plus ATP-site TKI","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L15","title":"CD26 (DPP4) as a CML-restricted surface antigen for antibody- or cell-mediated eradication of the persistent BCR::ABL1+ LSC","level":"LEAD","status":"RETIRED","confidence":0.08},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"DOSSIER","status":"WEAKENED","confidence":0.74}],"unverifiedCitations":0,"openQuestions":["Is FBXO3 dependence in CML LSCs reproducible in an independent laboratory, which pharmacological FBXO3 inhibitor was used in PMID:41850237, and does DUSP9 protein stabilisation with p-ERK loss serve as an on-target pharmacodynamic marker in","Does the FBXO3-DUSP9-MAPK dependency persist in T315I, compound-mutant and asciminib-resistant backgrounds, and is it additive with the L11 ISR/MCL-1 axis?","Does any prospective randomised CML trial, or a matched-exposure re-analysis of PMID:41668074, test dose de-escalation with MR4.0/MR4.5, TFR and PRO co-primary endpoints, and does the MR4.5 gap at 50 mg dasatinib survive adjustment for uneq","What is the mutation-resolved kinase-domain spectrum at asciminib failure beyond A337V/P465S, and which ATP-site agent rescues each genotype?","Has the IL-6/MCP-1 plus CD8dim/NK clonality discontinuation decision tree been replicated in an independent DMR cohort adjusted for TKI duration and prior interferon, and do cytotoxic CD4+ effectors (PMID:41803090) contribute measurably to ","Does TDM-guided dosing beat a flat halved dose for DMR attainment once adherence and relative dose intensity are deconfounded?"],"nextQueries":["(FBXO3 OR \"F-box protein 3\" OR BC-1215) AND (leukemia OR \"leukaemia\" OR \"stem cell\" OR DUSP9) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"chronic myeloid leukemia\" OR CML) AND (asciminib) AND (\"kinase domain\" OR mutation OR resistance) AND (sequencing OR NGS OR spectrum) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"chronic myeloid leukemia\" OR CML) AND (\"treatment-free remission\" OR discontinuation) AND (IL-6 OR MCP-1 OR CCL2 OR \"CD8dim\" OR \"NK cell\" OR \"cytotoxic CD4\") AND (cohort OR validation OR independent) AND SRC:MED AND PU"],"papersShown":[{"pmid":"41803090","doi":"10.1038/s41392-025-02533-z","year":2026,"isNew":true,"title":"Cytotoxic CD4&lt;sup&gt;+&lt;/sup&gt; T cells: origin, biological functions, diseases and therapeutic targets"},{"pmid":"41862812","doi":"10.1186/s11658-026-00895-y","year":2026,"isNew":true,"title":"Targeting dormant cancer cells: ferroptosis as a precision therapeutic strategy"},{"pmid":"41850237","doi":"10.1016/j.xcrm.2026.102686","year":2026,"isNew":true,"title":"FBXO3-mediated DUSP9 ubiquitination promotes leukemia stem cell maintenance and tyrosine kinase inhibitor resistance in chronic myeloid leukemia"},{"pmid":"41789071","doi":"10.3389/fimmu.2026.1741794","year":2026,"isNew":true,"title":"Understanding hairy cell leukemia in the context of mature B-cell neoplasms: tumor microenvironment and extracellular vesicle contribution to disease pathogenesis"},{"pmid":"41493844","doi":"10.1111/cas.70254","year":2026,"isNew":true,"title":"Abstracts of the 84&lt;sup&gt;th&lt;/sup&gt; Annual Meeting of the Japanese Cancer Association"},{"pmid":"41955967","doi":"10.1016/j.neo.2026.101306","year":2026,"isNew":false,"title":"Targeting tumor dormancy: the next frontier in gastrointestinal stromal tumor therapy"},{"pmid":"41861100","doi":"10.1002/advs.202600027","year":2026,"isNew":false,"title":"Tumor-Induced Splenic Remodeling: Mechanisms of Systemic Immunosuppression and Emerging Therapeutic Opportunities"},{"pmid":"42053786","doi":"10.1007/s00277-026-07036-7","year":2026,"isNew":false,"title":"Low dose of sitagliptin: effectively prevent liver aGVHD and accelerate neutrophil engraftment"},{"pmid":null,"doi":null,"year":2020,"isNew":false,"title":"Abstract Book: 25th Congress of the European Hematology Association Virtual Edition, 2020"},{"pmid":null,"doi":null,"year":2019,"isNew":false,"title":"47° Congress of the Italian Society of Hematology Rome, Italy, October 7-9, 2019"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":15007,"output":5483},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"chronic myeloid leukemia\" OR CML) AND (CD26 OR DPP4) AND (CAR OR \"chimeric antigen\" OR antibody OR immunotoxin OR \"antibody-drug conjugate\") AND (\"leukemic stem cell\" OR CD34) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"chronic myeloid leukemia\") AND (\"dose reduction\" OR de-escalation OR \"half dose\" OR \"low dose\") AND (randomized OR randomised OR \"phase 3\" OR \"phase III\" OR prospective) AND (\"treatment-free remission\" OR MR4 OR \"quali"],"evidenceIds":["PMID:41803090","PMID:41862812","PMID:41850237","PMID:41789071","PMID:41493844","PMID:41955967","PMID:41861100","PMID:42053786","untracked","untracked","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787180743745","cycle":155,"visit":3,"ts":"2026-08-19T23:05:43.745Z","cancer":{"key":"rhabdomyosarcoma","name":"rhabdomyosarcoma","mondo":{"id":"MONDO:0005212","name":"rhabdomyosarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Two isotype/linker-controlled preclinical ADC datasets — vobramitamab duocarmazine against B7-H3 and 3A11-exatecan against FGFR4 — make ADCs, not CAR-T, the fastest RMS route, and the next decisive experiment is a matched orthotopic RMS PDX head-to-head with calibrated antigen density, internalisati","confidence":0.55,"notebook":"Two ADC datasets arrived this visit and they reorganise the programme's centre of gravity from cellular to non-cellular targeting.\n\nFirst, B7-H3. Vobramitamab duocarmazine (DAR ~2.7, duocarmycin payload) produced objective responses across paediatric solid tumour xenografts including rhabdomyosarcoma after a single 6 mg/kg dose, with a linker/payload-matched anti-CD20 control ADC (SYD988) failing — the isotype-controlled specificity my visit-2 lead lacked (PMID:41941262). This converts the MGA271-IRDye800 biodistribution argument (tumour:background 5.6 in RH30) from \"delivery precondition\" to demonstrated antigen-dependent efficacy [INFERRED], and it partly answers open question 1: whatever RMS B7-H3 density and internalisation kinetics are, they suffice for a DNA-alkylating payload with bystander capacity. The B7-H3 ADC axis is also clinically maturing independently — ifinatamab deruxtecan sits in the late-stage commercial pipeline (PMID:41560619) — and a second paediatric workshop again ranks B7-H3 as advantageous for both CAR-T and ADC formats (PMID:42426296). L4 moves to CANDIDATE. Non-internalising/extracellular-release linker chemistry (PMID:41866709) is the fallback if calibrated flow shows slow RMS internalisation.\n\nSecond, and possibly larger: FGFR4-targeted ADCs using the 3A11 binder already in a CAR-T trial for relapsed/refractory RMS (NCT06865664) were rapidly internalised, FGFR4-dependently cytotoxic, and active in fusion-negative RMS559, fusion-positive RH4 CDX and one PDX, with the exatecan (TOP1) conjugate outperforming MMAE and delivering durable control (PMID:42447867). New lead L6. FGFR4 is an RMS lineage-restricted receptor tyrosine kinase; its normal-tissue role is hepatic FGF19-driven bile-acid homeostasis [KNOWN], so hepatotoxicity/bile-acid readouts, not marrow, are the window argument.\n\nThird, payload logic is now a lead in its own right: exatecan's superiority over MMAE in RMS aligns with TOP1-payload determinants — SLFN11, Ki67, ABCG2/BCRP efflux, HRD — and with the mechanistic case for TTTi plus ATR/CHK1/PARP1 combination (PMID:42092629). RMS is TP53-altered and proliferative [KNOWN]; whether it is SLFN11-high is unknown and testable. L7 created as the biomarker/combination arm feeding both L4 and L6.\n\nL1 (L1CAM CAR) is weakened again: a third fielded pass returned no new RMS L1CAM data, while two competing antigens now have controlled in vivo ADC efficacy. It survives only as the B7-H3-low/FGFR4-low contingency and I will retire it next visit absent matched-model data. The RMS immune-cold/PAX3-FOXO1 antigen-presentation review (PMID:41007114) is consistent with L2 but adds no primary data, so L2 holds. I am dropping the SSTR2/Lu-177 question — two visits, no RMS expression data, dead ground for now. Temsirolimus (NCT02567435) still unposted.","leadChanges":[{"id":"L4","title":"B7-H3/CD276 antibody-drug conjugate and antibody-guided delivery in RMS","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.62},{"id":"L6","title":"FGFR4-targeted ADC (3A11-exatecan) for fusion-positive and fusion-negative RMS","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L7","title":"Payload-and-biomarker layer: TOP1-payload ADCs plus ATR/CHK1/PARP1 inhibition, stratified by SLFN11 and ABCG2 in RMS","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L1","title":"CD28-costimulated L1CAM-CAR T cells for moderate-/low-antigen-density, fusion-positive RMS","level":"LEAD","status":"WEAKENED","confidence":0.3}],"unverifiedCitations":1,"openQuestions":["In one matched orthotopic RMS PDX panel (fusion-positive and fusion-negative), how do vobramitamab duocarmazine, a B7-H3-TOP1 ADC, and 3A11-exatecan rank on EFS, and does ranking track calibrated antigen molecules/cell or internalisation ha","Are RMS lines/PDXs SLFN11-high or SLFN11-low, and does SLFN11/ABCG2 status predict exatecan- or DXd-payload ADC response — i.e. is a companion Dx feasible for RMS ADC trials?","What is the hepatobiliary/bile-acid and skeletal-muscle toxicity profile of FGFR4-directed ADCs at efficacious doses, given normal FGF19-FGFR4 signalling, and does it differ from FGFR4 CAR-T (NCT06865664)?","Does FGFR4 surface density differ systematically between PAX3/PAX7-FOXO1-positive and fusion-negative RMS, and is FGFR4 a direct fusion target gene?","Does ADC pretreatment lower B7-H3 or FGFR4 surface density enough to compromise subsequent CAR-T against the same antigen (sequencing question for L2 and the FGFR4 programme)?","Any posted readout for temsirolimus plus VAC/VI in intermediate-risk RMS (NCT02567435) — if negative, formally close mTOR-plus-chemotherapy as dead ground?"],"nextQueries":["(rhabdomyosarcoma OR \"soft tissue sarcoma\") AND (SLFN11 OR ABCG2 OR \"schlafen 11\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","FGFR4 AND (rhabdomyosarcoma OR sarcoma) AND (toxicity OR hepatotoxicity OR \"bile acid\" OR \"antigen density\" OR internalization) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"B7-H3\" OR CD276 OR FGFR4) AND (rhabdomyosarcoma) AND (\"molecules per cell\" OR quantitative OR \"antigen density\" OR \"CAR T\" AND ADC) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"41560619","doi":"10.1080/19420862.2026.2614669","year":2026,"isNew":true,"title":"Antibodies to watch in 2026"},{"pmid":"41866709","doi":"10.1080/10717544.2026.2645769","year":2026,"isNew":true,"title":"Extracellular payload release from non-internalizing antibody-drug conjugates: mechanisms and linker technologies"},{"pmid":"42326738","doi":"10.1016/j.bonr.2026.101930","year":2026,"isNew":true,"title":"Genomic landscape and tumor immune microenvironment of osteosarcoma: Bridging mechanistic insights to precision therapeutics"},{"pmid":"42092629","doi":"10.1016/j.jmb.2026.169841","year":2026,"isNew":true,"title":"Molecular Determinants of Response and Rational Drug Combinations for Antibody-Drug Conjugates (ADCs) with Topoisomerase I (TOP1) Inhibitor Payloads"},{"pmid":"42426296","doi":"10.1038/s41416-026-03533-8","year":2026,"isNew":true,"title":"Paediatric therapeutic development workshop on medulloblastoma"},{"pmid":"41941262","doi":"10.1158/1078-0432.ccr-25-4767","year":2026,"isNew":true,"title":"Preclinical Activity of the B7-H3-Targeting Antibody-Drug Conjugate Vobramitamab Duocarmazine in Pediatric Solid Tumors"},{"pmid":"42341116","doi":"10.1126/sciadv.aef0121","year":2026,"isNew":true,"title":"FOLR1-targeted actinium-225-based alpha-particle therapy eliminates ovarian cancer"},{"pmid":"42447867","doi":"10.1016/j.xcrm.2026.102922","year":2026,"isNew":true,"title":"Targeted antibody-drug conjugates for rhabdomyosarcoma and other FGFR4-expressing cancers"},{"pmid":"41007114","doi":"10.3390/children12091249","year":2025,"isNew":true,"title":"Tumor-Immune Interactions in Pediatric Oral Rhabdomyosarcoma: A Narrative Review on Immuno-Oncology and Emerging Therapies"},{"pmid":"41749943","doi":"10.3390/cancers18040690","year":2026,"isNew":true,"title":"The Development of Novel Treatment Strategies for Rhabdomyosarcoma"}],"trialsShown":[{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"},{"nct":"NCT05210374","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Disulfiram With Copper Gluconate and Liposomal Doxorubicin in Treatment-Refractory Sarcomas"},{"nct":"NCT04715191","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors"},{"nct":"NCT06441331","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Phase I Trial to Determine the Dose and Evaluate the PK and Safety of Lutetium Lu 177 Edotreotide Therapy in Pediatric Participants With SST"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT06239272","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhab"},{"nct":"NCT02567435","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma"},{"nct":"NCT07628634","phase":"EARLY_phase 1","status":"RECRUITING","isNew":false,"title":"Feasibility Study on the Effect of a Methionine-Reduced Diet on Serum Levels in Pts w/ Solid Tumors"}],"usage":{"input":12222,"output":7063},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"B7-H3\" OR CD276) AND (\"antibody-drug conjugate\" OR ADC OR MGA271 OR vobramitamab OR ifinatamab) AND (sarcoma OR rhabdomyosarcoma OR pediatric) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","rhabdomyosarcoma AND (FGFR4 AND (degrader OR \"CAR T\" OR \"antibody-drug conjugate\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41560619","PMID:41866709","PMID:42326738","PMID:42092629","PMID:42426296","PMID:41941262","PMID:42341116","PMID:42447867","PMID:41007114","PMID:41749943","NCT07172958","NCT05210374","NCT04715191","NCT06441331","NCT04320888","NCT06239272","NCT02567435","NCT07628634"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787180530768","cycle":154,"visit":3,"ts":"2026-08-19T23:02:10.768Z","cancer":{"key":"ewing sarcoma","name":"Ewing sarcoma","mondo":{"id":"MONDO:0012817","name":"Ewing sarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Ewing sarcoma's SLFN11-high, B7-H3-positive phenotype makes antigen-directed TOP1-payload ADCs (with SLFN11/ABCG2 selection and ATR-inhibitor potentiation) the most actionable new axis, while the cabozantinib and PARPi-autophagy leads weaken for lack of any ES-specific corroboration.","confidence":0.45,"notebook":"This visit's two targeted queries were designed to close open questions 2 and 4 and both came back empty of ES-specific content: no 2022–2026 paper links cabozantinib/VEGFR2/AXL/MET to Ewing sarcoma, and no paper couples ES with ATG5/ATG7/hydroxychloroquine plus PARP inhibition. NCT02243605 remains ACTIVE_NOT_RECRUITING with no posted ES ORR/PFS. So L5 takes a decrement (0.40→0.35) and L2 takes one (0.30→0.27) — the autophagy-resistance claim of PMID:42215796 is still a single correlative report with no genetic ablation anywhere in the literature I can reach; the Beclin-1 review (PMID:39650649) is generic, non-ES, and does not count as corroboration, only as a menu of tractable nodes (VPS34/Beclin-1 scaffold, ATG5-dependent autophagy-ferroptosis coupling) should the causal experiment ever be done.\n\nL1 is left at 0.55 rather than strengthened: PMID:42092629 and PMID:40859871 restate the ATR/CHK1/WEE1 synthetic-lethality and TOP1-combination logic generically, but neither replicates fusion-induced ATM hypofunction, which remains a single-report mechanism (PMID:41811428).\n\nThe genuinely new content is biomarker-shaped. PMID:42092629 lays out the response determinants for TOP1-poison payloads — surface-epitope density, Ki67, SLFN11 expression, HRD, and ABCG2/BCRP-mediated efflux — plus explicit rationale for pairing them with PARP/ATR/CHK1/ATM inhibitors. Ewing sarcoma is the archetypal SLFN11-high, irinotecan-sensitive paediatric tumour [KNOWN], and it already has a validated high-density surface antigen in B7-H3 from L3. That intersection is a new lead: antigen-directed TOP1 payload delivery in ES, selected by SLFN11 and screened for ABCG2, with VAL-413/temozolomide (NCT04337177) as the free-drug comparator and ATR inhibition as the potentiating partner. Second new lead from PMID:40138251: BET inhibitors specifically disrupt fusion-driven transcriptional programmes and DDR in sarcoma and combine with CHK1 inhibitors — a route to attack EWSR1::FLI1 output indirectly and then harvest the resulting replication stress, which is mechanistically continuous with L1 rather than a separate bet.\n\nL3 gains a feasibility citation rather than an efficacy one: PMID:42241897 shows autologous mononuclear apheresis succeeds across paediatric solid-tumour diagnoses at ALC ≥300/µL and CD3 ≥150/µL, addressing the practical objection that heavily pretreated ES patients cannot supply CAR starting material. Antigen density in metastases is still unanswered.\n\nOperationally, PMID:42590965 reports 100% sensitivity and NPV for FDG-PET/CT for marrow involvement in 128 ES patients, arguing BMAT is redundant for staging — relevant to the correlative burden written into NCT06820957, whose arms remain unlisted in this pack.","leadChanges":[{"id":"L7","title":"Antigen-directed TOP1-payload ADCs in SLFN11-high Ewing sarcoma, ABCG2-screened and ATR-potentiated","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L8","title":"BET inhibition to collapse EWSR1::FLI1 transcriptional output, combined with CHK1/ATR inhibition","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L3","title":"B7-H3 CAR T cells armoured against TGF-beta signalling for relapsed/refractory Ewing sarcoma","level":"LEAD","status":"STRENGTHENED","confidence":0.43},{"id":"L5","title":"Cabozantinib as an approved multikinase backbone in relapsed Ewing sarcoma, to be combined rather than escalated alone","level":"LEAD","status":"WEAKENED","confidence":0.35},{"id":"L2","title":"PARP inhibitor monotherapy is dead in Ewing sarcoma; only autophagy-blockade combinations are worth revisiting","level":"LEAD","status":"WEAKENED","confidence":0.27}],"unverifiedCitations":0,"openQuestions":["What is the distribution of SLFN11, ABCG2/BCRP and B7-H3 protein expression across matched Ewing sarcoma primaries and metastases, and does SLFN11-high status predict TOP1-payload ADC or irinotecan benefit?","Are there any registered TOP1-payload ADC trials (B7-H3, GD2, LINGO1, HER3 directed) that enrol Ewing sarcoma or paediatric bone sarcoma cohorts?","Has any BET inhibitor been tested clinically in EWSR1-fusion sarcoma, and does BETi lower measured EWSR1::FLI1 target-gene output in ES models at tolerable exposures?","Which agents constitute the arms of NCT06820957 in newly diagnosed metastatic ES, and can fusion-dose, SLFN11 and pCHK1 correlatives be embedded now that FDG-PET/CT (PMID:42590965) frees up marrow-sampling burden?","Has fusion-induced ATM hypofunction (PMID:41811428) been replicated independently, and has any ATR-inhibitor cohort actually enrolled ES patients?","Does genetic ATG5/ATG7/Beclin-1 ablation restore PARPi killing in ES, and does the same axis blunt ATR inhibitors?"],"nextQueries":["(\"Ewing sarcoma\" OR EWSR1) AND (SLFN11 OR ABCG2 OR \"antibody-drug conjugate\" OR deruxtecan OR exatecan) AND PUB_YEAR:[2021 TO 2026] AND SRC:MED","(\"Ewing sarcoma\" OR \"EWSR1-FLI1\" OR \"EWS-FLI1\") AND (BRD4 OR \"BET inhibitor\" OR JQ1 OR ZEN-3694 OR mivebresib) AND SRC:MED","(\"Ewing sarcoma\") AND (B7-H3 OR CD276) AND (immunohistochemistry OR \"antigen density\" OR metastasis) AND SRC:MED"],"papersShown":[{"pmid":"39650649","doi":"10.3389/fimmu.2024.1506426","year":2024,"isNew":true,"title":"Beclin-1: a therapeutic target at the intersection of autophagy, immunotherapy, and cancer treatment"},{"pmid":"40806481","doi":"10.3390/ijms26157350","year":2025,"isNew":true,"title":"Combination Therapy Using Phytochemicals and PARP Inhibitors in Hybrid Nanocarriers: An Optimistic Approach for the Management of Colon Cancer"},{"pmid":"40138251","doi":"10.1158/1535-7163.mct-24-1027","year":2025,"isNew":true,"title":"Therapeutic Targeting of BET Proteins in Sarcoma"},{"pmid":"40859871","doi":"10.1111/jcmm.70756","year":2025,"isNew":true,"title":"Synthetic Lethality-Based Targets and Their Exploration in Tumour Combination Strategies"},{"pmid":"42590965","doi":"10.1002/1545-5017.70618","year":2026,"isNew":true,"title":"Reassessing Bone Marrow Aspirate and Trephine Biopsies in Staging for Paediatric and Young Adult Patients With Ewing Sarcoma and Rhabdomyosarcoma"},{"pmid":"42317522","doi":"10.1016/j.mtbio.2026.103316","year":2026,"isNew":true,"title":"Advances in oncolytic virus delivery strategies and challenges in clinical translation"},{"pmid":"42241897","doi":"10.1016/j.jcyt.2026.102907","year":2026,"isNew":true,"title":"Successful autologous T cell apheresis in pediatric patients with hematologic malignancies, solid tumors, and brain tumors"},{"pmid":"42214318","doi":"10.1016/j.identj.2026.109662","year":2026,"isNew":true,"title":"Pharmacovigilance Analysis of Drug-Induced Stomatitis: Insights From Twenty-One Years of Real-World Data"},{"pmid":"42092629","doi":"10.1016/j.jmb.2026.169841","year":2026,"isNew":true,"title":"Molecular Determinants of Response and Rational Drug Combinations for Antibody-Drug Conjugates (ADCs) with Topoisomerase I (TOP1) Inhibitor Payloads"},{"pmid":"42064237","doi":"10.1177/18632521261444250","year":2026,"isNew":true,"title":"What's new in pediatric bone sarcomas and benign bone tumors"}],"trialsShown":[{"nct":"NCT02243605","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Cabozantinib S-malate in Treating Patients With Relapsed Osteosarcoma or Ewing Sarcoma"},{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"},{"nct":"NCT06465199","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Eflornithine (DFMO) and AMXT 1501 for Neuroblastoma, CNS Tumors, and Sarcomas"},{"nct":"NCT05210374","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Disulfiram With Copper Gluconate and Liposomal Doxorubicin in Treatment-Refractory Sarcomas"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT07628634","phase":"EARLY_phase 1","status":"RECRUITING","isNew":false,"title":"Feasibility Study on the Effect of a Methionine-Reduced Diet on Serum Levels in Pts w/ Solid Tumors"},{"nct":"NCT04337177","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With Temozolomide for Treatment of Recurrent Pediatric Solid Tumors"},{"nct":"NCT06820957","phase":"phase 2/phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing a New Combination of Anti-cancer Drugs in Patients Newly Diagnosed With Ewing Sarcoma Who Have Cancer That Has Spread to Other Parts"}],"usage":{"input":11907,"output":7154},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"Ewing sarcoma\" OR \"EWSR1\") AND (cabozantinib OR \"VEGFR2\" OR AXL OR MET) AND PUB_YEAR:[2022 TO 2026] AND SRC:MED","(\"Ewing sarcoma\") AND (ATG5 OR ATG7 OR autophagy OR hydroxychloroquine) AND (olaparib OR PARP) AND SRC:MED"],"evidenceIds":["PMID:39650649","PMID:40806481","PMID:40138251","PMID:40859871","PMID:42590965","PMID:42317522","PMID:42241897","PMID:42214318","PMID:42092629","PMID:42064237","NCT02243605","NCT07172958","NCT06465199","NCT05210374","NCT04320888","NCT07628634","NCT04337177","NCT06820957"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787180317042","cycle":153,"visit":3,"ts":"2026-08-19T22:58:37.042Z","cancer":{"key":"osteosarcoma","name":"osteosarcoma","mondo":{"id":"MONDO:0009807","name":"osteosarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Functional ALT — present in ~63% of osteosarcomas but poorly predicted by ATRX/DAXX/TOP3A genotype — should become the desk's primary stratification variable, prioritising SMARCAL1/replication-stress synthetic lethality and demoting unstratified PARPi-radiosensitisation.","confidence":0.58,"notebook":"The pack pivots the programme toward telomere biology. Three convergent new inputs establish alternative lengthening of telomeres (ALT) as the dominant, under-exploited dependency axis in this disease: a systematic review of 342 patient tumours across seven studies finds functional ALT in 62.9% of osteosarcomas while ATRX/DAXX mutation and TOP3A amplification together explain only a minority — a statistically significant discrepancy (PMID:42330800); a DNA-repair-centric review confirms ALT enrichment in paediatric osteosarcoma and enumerates the exploitable factors (PMID:41480636); and a glioma study delivers the concrete druggable node, showing SMARCAL1 as a highly specific CRISPR synthetic-lethal vulnerability in ATRX-deficient ALT cells, localising to APBs, validated in patient-derived lines and xenografts (PMID:41520142). The osteosarcoma-relevant consequence is a selection rule, not a genotype: sequencing cannot identify these patients, so C-circle/APB functional assays must be the enrolment biomarker [INFERRED]. New lead L8 opens at moderate confidence — the mechanism is osteosarcoma-plausible and the dependency is cross-tissue, but the SMARCAL1 data are glioma-derived, and the ATRX-wildtype ALT majority (PMID:42330800) may or may not retain the dependency; that is the falsification test. Normal-tissue window caveat logged: regenerating zebrafish fin tissue maintains telomeres via ALT (PMID:41120592), so ALT is not strictly tumour-exclusive in proliferating regenerative compartments [INFERRED].\n\nThis same evidence undercuts L7. ALT-positive tumours are classically described as resistant to DNA-damaging therapy despite high replication stress (PMID:41148828), and osteosarcoma is majority ALT-positive (PMID:42330800). A PARPi/carbon-ion strategy therefore cannot be proposed disease-wide; it must be stratified by functional ALT status, with ALT-negative/telomerase-positive tumours the primary hypothesis and ALT-positive tumours a resistance arm. L7 weakened accordingly. Conversely PMID:41148828 offers a secondary hypothesis: ALT-driven instability may raise immunogenicity in immune-quiescent tumours — a bridge to L3/attIL12 worth testing as an ALT-status biomarker for immunotherapy response rather than a new lead.\n\nL6 gains mechanistic support for its central inference: a review of non-internalising ADCs details extracellular linker chemistries that deliver payload by diffusion/bystander effect precisely to defeat antigen heterogeneity and impaired endocytosis (PMID:41866709) — the plausible route to activity in the ~45% of low-H-score lesions. L2 gains only operational support: autologous apheresis feasibility data across paediatric solid tumours (PMID:42241897) define a manufacturing constraint (ALC ≥300/µL, CD3 ≥150/µL) for any B7-H3 CAR-T arm in heavily pretreated relapsed osteosarcoma; no new antigen-density data, so it stays CANDIDATE. L3 gains a usable endpoint: quantitative MRI histogram features outperformed RECIST 1.1 for necrosis-rate response after neoadjuvant immunotherapy in 55 osteosarcoma patients (PMID:42273091).","leadChanges":[{"id":"L8","title":"ALT-directed synthetic lethality (SMARCAL1, replication-stress DDR nodes) selected by functional C-circle/APB assay, not ATRX genotype, in osteosarcoma","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L7","title":"PARP inhibition as radiosensitiser (including high-LET) in unresectable/axial osteosarcoma with STING-mediated immune conversion","level":"LEAD","status":"WEAKENED","confidence":0.22},{"id":"L6","title":"B7-H3 antibody-drug conjugate (vobramitamab duocarmazine) as antigen-directed cytotoxic delivery in osteosarcoma","level":"LEAD","status":"STRENGTHENED","confidence":0.5},{"id":"L2","title":"B7-H3 (CD276) antigen-density-stratified targeting with companion immunoPET selection","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.64},{"id":"L3","title":"Locally delivered IL-12 via membrane-anchored tumour-targeted T/TIL cells against the immunosuppressive osteosarcoma TME","level":"LEAD","status":"STRENGTHENED","confidence":0.45}],"unverifiedCitations":0,"openQuestions":["Do ATRX-wildtype but functionally ALT-positive osteosarcoma models retain SMARCAL1 dependency, or is the synthetic lethality restricted to ATRX-loss genotypes (PMID:41520142 vs PMID:42330800)?","What is the sensitivity of ALT+ osteosarcoma PDX to ATR inhibitors, and does ALT status predict resistance to doxorubicin/cisplatin/radiation as PMID:41148828 implies?","Can a C-circle or APB assay be standardised on FFPE osteosarcoma biopsies to serve as a clinical stratification biomarker, given sequencing's failure to call ALT?","Does duocarmycin payload from a B7-H3 ADC produce measurable bystander killing in mosaic low/high-H-score osteosarcoma models, and would an extracellular-release linker outperform the internalising design?","What fraction of relapsed osteosarcoma patients meet ALC/CD3 apheresis thresholds for autologous B7-H3 CAR-T, and does prior chemotherapy intensity predict failure?","Is ALT positivity associated with greater immune infiltration or immunotherapy response in osteosarcoma, as the glioblastoma/chondrosarcoma paradox suggests?"],"nextQueries":["(\"osteosarcoma\" OR \"bone sarcoma\") AND (SMARCAL1 OR FANCM OR SLX4 OR BLM OR \"C-circle\" OR \"ALT-associated PML\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"osteosarcoma\" AND (\"ATR inhibitor\" OR berzosertib OR ceralasertib OR \"replication stress\" OR \"telomere maintenance\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"osteosarcoma\" OR \"bone sarcoma\") AND (\"B7-H3\" OR CD276) AND (\"antigen density\" OR bystander OR \"CAR T\" OR apheresis) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"41520142","doi":"10.1093/neuonc/noaf300","year":2026,"isNew":true,"title":"SMARCAL1 is a targetable synthetic lethal therapeutic vulnerability in ATRX-deficient gliomas that use alternative lengthening of telomeres"},{"pmid":"41480636","doi":"10.1093/narcan/zcaf056","year":2025,"isNew":true,"title":"The alternative lengthening of telomeres pathway through a DNA repair lens: mechanism and therapeutic opportunities"},{"pmid":"41866709","doi":"10.1080/10717544.2026.2645769","year":2026,"isNew":true,"title":"Extracellular payload release from non-internalizing antibody-drug conjugates: mechanisms and linker technologies"},{"pmid":"41148828","doi":"10.3390/cells14201613","year":2025,"isNew":true,"title":"Alternative Lengthening of Telomeres: A Prognostic Paradox in Cancer"},{"pmid":"41120592","doi":"10.1038/s44319-025-00602-6","year":2025,"isNew":true,"title":"Telomerase and alternative lengthening of telomeres coexist in the regenerating zebrafish caudal fins"},{"pmid":"42093837","doi":"10.1016/j.bioactmat.2026.04.031","year":2026,"isNew":true,"title":"A 'three-axis synergy' immunotherapeutic strategy for malignant bone tumors based on natural bioactives and bioactive materials"},{"pmid":"42241897","doi":"10.1016/j.jcyt.2026.102907","year":2026,"isNew":true,"title":"Successful autologous T cell apheresis in pediatric patients with hematologic malignancies, solid tumors, and brain tumors"},{"pmid":"42281807","doi":"10.1093/noajnl/vdag080","year":2026,"isNew":true,"title":"Focused ultrasound for enhancing cell-based immunotherapies in neuro-oncology"},{"pmid":"42273091","doi":"10.21037/qims-2025-1-2568","year":2026,"isNew":true,"title":"Magnetic resonance imaging signal variation for the effective quantitative evaluation of treatment response to neoadjuvant immunotherapy of osteosarcoma: a comparative study with R"},{"pmid":"42330800","doi":"10.1016/j.cancergen.2026.06.001","year":2026,"isNew":true,"title":"Beyond ATRX: The heterogeneous basis of Alternative Lengthening of Telomeres in osteosarcoma"}],"trialsShown":[{"nct":"NCT06859801","phase":"n/a","status":"RECRUITING","isNew":false,"title":"A Multi-Center Observational Trial of Symptomatic, High-Risk Bone Metastases Treated With Percutaneous Ablation and Palliative Radiation The"},{"nct":"NCT07774533","phase":"EARLY_phase 1","status":"RECRUITING","isNew":false,"title":"68Ga-B7-H3 Nanobody ImmunoPET in Osteosarcoma"},{"nct":"NCT06474676","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"T Cell Membrane-Anchored Tumor-Targeted IL12 -Modified TIL Cell Therapy (attIL12-TIL) for Advanced/Metastatic Soft Tissue and Bone Sarcoma P"},{"nct":"NCT06737172","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Functional and Structural Outcomes Following Childhood Bone or Soft Tissue Sarcomas of the Lower Extremity"},{"nct":"NCT06743958","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Prehabilitation in Childhood Soft Tissue or Bone Sarcomas"},{"nct":"NCT02243605","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Cabozantinib S-malate in Treating Patients With Relapsed Osteosarcoma or Ewing Sarcoma"},{"nct":"NCT05621668","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A First-In-Human Phase 1 Trial of T-Cell Membrane-Anchored Tumor Targeted Il12 (Attil12)- T-Cell Therapy in Subjects With Advanced/Metastati"},{"nct":"NCT03900793","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Losartan + Sunitinib in Treatment of Osteosarcoma"}],"usage":{"input":12711,"output":7797},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"osteosarcoma\" OR \"bone sarcoma\") AND (\"B7-H3\" OR CD276) AND (\"antibody-drug conjugate\" OR \"CAR T\" OR immunoPET OR radioligand) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"osteosarcoma\" AND (KIF18A OR \"whole genome doubling\" OR polyploid* OR \"alternative lengthening of telomeres\" OR ATRX OR \"ATR inhibitor\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41520142","PMID:41480636","PMID:41866709","PMID:41148828","PMID:41120592","PMID:42093837","PMID:42241897","PMID:42281807","PMID:42273091","PMID:42330800","NCT06859801","NCT07774533","NCT06474676","NCT06737172","NCT06743958","NCT02243605","NCT05621668","NCT03900793"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787180098786","cycle":152,"visit":3,"ts":"2026-08-19T22:54:58.786Z","cancer":{"key":"wilms tumor","name":"Wilms tumor","mondo":{"id":"MONDO:0006058","name":"Wilms tumor"}},"control":false,"modelLabel":"SCIENCE","summary":"B7-H3 is now the best-validated surface target in Wilms tumor after a duocarmycin ADC (vobramitamab duocarmazine) produced antigen-dependent responses in WT xenografts, so the desk should pursue B7-H3 ADC and CAR-T in parallel while opening a TP53-mutant/1q-gain chemoresistant stratum for WEE1/ATR s","confidence":0.44,"notebook":"Two items in this pack matter; the rest is off-target retrieval (urothelial Nectin-4, TNBC αvβ6, lung IHC, Hippo in brain tumours, AI review) and should not be mistaken for WT evidence.\n\nFirst real advance: PMID:41941262 tests vobramitamab duocarmazine, a B7-H3 ADC (DAR ~2.7, duocarmycin payload), across pediatric solid-tumour xenografts *including Wilms tumor*, with objective responses versus an isotype-matched control ADC (SYD988) carrying identical linker/payload — the control arm is what makes this antigen-dependent rather than payload-dependent. This is the first in vivo WT-specific validation of B7-H3 as a targetable surface antigen in this programme, and it partially answers open question 3 by proxy (functional antigen sufficiency), though it still does not give me B7-H3 IHC prevalence by WT histologic component in primary human pathology. L2 therefore moves up: the antigen is credible enough that the CAR-T/dTβRII construct in NCT07172958 is no longer resting on pan-pediatric inference alone. I also open a separate modality lead: a B7-H3 ADC is a faster, less logistically fragile route into relapsed WT than autologous cell therapy, with a different resistance profile (payload efflux/ABCB1, antigen-low escape, no TGF-β shielding requirement) and different normal-tissue risk (B7-H3 is low but non-zero in normal epithelium; duocarmycin toxicity is haematologic/mucosal [KNOWN]). By contrast, HER2 (L7) and GPC3 (L1) still have zero WT prevalence data after two dedicated IHC-targeted searches — both trimmed. If the desk must pick one ADC hypothesis, the evidence now favours B7-H3 over HER2.\n\nSecond: PMID:42254928, a single bilateral blastemal-predominant WT with somatic TP53 p.R273H, 1q gain and 16q deletion that progressed through CCCG-WT-2019 VAD, staged nephron-sparing surgery, radiotherapy and oral targeted therapy. Anecdotal, but it is the first concrete case in the programme anchoring open question 6: TP53-mutant/1q-gain WT behaves as intrinsically chemoresistant and is a separable therapeutic stratum. Mechanistically, G1/S checkpoint loss shifts dependence onto the G2/M and replication-stress checkpoints [INFERRED], making WEE1 (adavosertib) or ATR inhibition plus a topo-I backbone the rational synthetic-lethal probe [KNOWN paradigm]; window issue is myelosuppression in heavily pretreated children.\n\nL6 (cabozantinib) does not move — no NCT02867592 stratum readout for a second visit — but PMID:41977363 records that cabozantinib's multikinase breadth buys modest efficacy at real toxicity cost, with MET-mediated bypass; RET-selective selpercatinib (NCT04320888) is only relevant to WT if a RET fusion is documented, which nothing here shows.","leadChanges":[{"id":"L2","title":"B7-H3 CAR-T combined with TGF-beta-insensitive (dTbetaRII) antigen-specific T cells for relapsed embryonal WT","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.5},{"id":"L8","title":"B7-H3-directed antibody-drug conjugate (vobramitamab duocarmazine) as the fastest B7-H3 route into relapsed Wilms tumor","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L9","title":"TP53-mutant / 1q-gain chemoresistant Wilms tumor as a separable stratum for replication-stress (WEE1 or ATR) synthetic lethality","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L1","title":"IL-15/IL-21-armored GPC3 CAR-T against onco-fetal GPC3 in Wilms tumor","level":"LEAD","status":"WEAKENED","confidence":0.32},{"id":"L7","title":"Trastuzumab deruxtecan as antigen-anchored topoisomerase-I payload delivery in relapsed WT (not HER2 addiction)","level":"LEAD","status":"WEAKENED","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["Which Wilms tumor PDX model(s) responded to vobramitamab duocarmazine in PMID:41941262, at what B7-H3 IHC/protein level, and is there a pediatric expansion cohort of NCT03729596?","What is B7-H3 protein prevalence and intensity across WT blastemal, epithelial, stromal and anaplastic components in primary human pathology series?","What is the frequency of somatic TP53 mutation and 1q gain in relapsed/blastemal-predominant WT, and do TP53-mutant WT models show WEE1/ATR inhibitor sensitivity?","What is the Wilms tumor stratum outcome (ORR, PFS, MET/AXL/VEGFR correlates) of cabozantinib in NCT02867592 — still unretrieved after two visits?","Does NCT04616560 report a HER2 IHC/ISH entry threshold or any WT responses, and is HER2 protein detectable at all in primary WT?","Do TRIM28-, DIS3L2- or CTR9-mutant WT define a distinct dependency, and are the reported cases germline or somatic?"],"nextQueries":["(\"Wilms tumor\" OR nephroblastoma) AND (\"B7-H3\" OR CD276) AND (immunohistochemistry OR \"antibody-drug conjugate\" OR xenograft)","(\"Wilms tumor\" OR nephroblastoma) AND (TP53 OR \"1q gain\") AND (chemoresistance OR relapse OR WEE1 OR ATR OR adavosertib)","cabozantinib AND (\"Wilms tumor\" OR nephroblastoma OR \"rare tumors\") AND (\"phase 2\" OR \"objective response\" OR NCT02867592)"],"papersShown":[{"pmid":"40571752","doi":"10.1007/s00428-025-04164-9","year":2026,"isNew":true,"title":"Nectin-4 expression in upper and lower tract urothelial carcinoma: correlation with early-stage disease and prognostic relevance"},{"pmid":"41977363","doi":"10.3390/ijms27073180","year":2026,"isNew":true,"title":"RET Signaling Pathway in Human Cancer: Oncogenic Mechanisms, Selective Inhibitors, and Emerging Resistance Strategies"},{"pmid":"42222867","doi":"10.3892/ol.2026.15656","year":2026,"isNew":true,"title":"Rare &lt;i&gt;BRCA1&lt;/i&gt; c.3418_3419insTGACTACT:p.S1140Mfs*18 germline mutation in a family with breast and ovarian cancer"},{"pmid":"41941262","doi":"10.1158/1078-0432.ccr-25-4767","year":2026,"isNew":true,"title":"Preclinical Activity of the B7-H3-Targeting Antibody-Drug Conjugate Vobramitamab Duocarmazine in Pediatric Solid Tumors"},{"pmid":"42287329","doi":"10.1007/s10555-026-10349-8","year":2026,"isNew":true,"title":"The Hippo signaling pathway in pediatric brain tumors: molecular mechanisms and therapeutic opportunities"},{"pmid":"42147259","doi":"10.14740/wjon2757","year":2026,"isNew":true,"title":"Immunohistochemistry as a Cornerstone in Lung Cancer Diagnosis: Subtyping Based on the 2021 World Health Organization Classification and Its Practical Application"},{"pmid":"41517891","doi":"10.1158/1535-7163.mct-25-0450","year":2026,"isNew":true,"title":"Identification of CADM1 as an Immunotherapeutic Target and Evaluation of a Novel CADM1-Targeting Antibody-Drug Conjugate in Preclinical Osteosarcoma Models"},{"pmid":"42194054","doi":"10.3390/biom16050706","year":2026,"isNew":true,"title":"Immunohistochemical Evaluation of Integrin β6 Expression in Triple-Negative Breast Cancer as a Predictive Biomarker for Therapeutic and Diagnostic Radionuclides"},{"pmid":"42192906","doi":"10.3390/cancers18101543","year":2026,"isNew":true,"title":"Artificial Intelligence in Oncology: A Comprehensive Cross-Cancer Translational Readiness Analysis Across 18 Malignancies"},{"pmid":"42254928","doi":"10.3389/fsurg.2026.1759786","year":2026,"isNew":true,"title":"Case Report: Bilateral Wilms tumor with TP53 mutation: a case-based review of clinical challenges"}],"trialsShown":[{"nct":"NCT07645469","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"FH-WT1-E50 TCR T Cells With Azacitidine for the Treatment of Minimal Residual Disease Positive Acute Myeloid Leukemia"},{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"},{"nct":"NCT04616560","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Trastuzumab Deruxtecan (DS-8201a) for the Treatment of Recurrent or Refractory Osteosarcoma, Wilms Tumor, and Desmoplastic Small Round Cell "},{"nct":"NCT04715191","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT03155620","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin L"},{"nct":"NCT02867592","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumor"},{"nct":"NCT04284774","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Trea"}],"usage":{"input":12851,"output":6595},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"Wilms tumor\" OR nephroblastoma) AND (immunohistochemistry OR \"protein expression\") AND (GPC3 OR \"glypican-3\" OR CD276 OR B7-H3 OR HER2 OR ERBB2) AND SRC:MED","(\"Wilms tumor\" OR nephroblastoma) AND (cabozantinib OR MET OR AXL OR VEGFR2 OR \"receptor tyrosine kinase\") AND (xenograft OR \"phase 2\" OR response) AND SRC:MED"],"evidenceIds":["PMID:40571752","PMID:41977363","PMID:42222867","PMID:41941262","PMID:42287329","PMID:42147259","PMID:41517891","PMID:42194054","PMID:42192906","PMID:42254928","NCT07645469","NCT07172958","NCT04616560","NCT04715191","NCT04320888","NCT03155620","NCT02867592","NCT04284774"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787179892988","cycle":151,"visit":3,"ts":"2026-08-19T22:51:32.988Z","cancer":{"key":"retinoblastoma","name":"retinoblastoma","mondo":{"id":"MONDO:0008380","name":"retinoblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise TRIP13+Aurora A co-targeting as the leading RB1-loss synthetic lethality for retinoblastoma (PMID:42013305), test it head-to-head against CDK7 inhibition in RB1-null WERI-Rb1/Y79 and RB1-/- cone-precursor organoids, and retire the sunitinib organoid lead.","confidence":0.42,"notebook":"This visit's pack is mostly noise for the programme (optogenetics review, lung/urological metastasis, uveal-melanoma deep learning, pancreatic TAMs; PMID:42061029 is a withdrawn/retracted CDK4/6→CDK2 review and is unusable — notebook rule: never cite it). Three items matter.\n\nFirst, the highest-value item answers open question 1 from an unexpected direction: PMID:42013305 shows that co-targeting TRIP13 and Aurora A kills RB-deficient cancer cells by prolonging AURKAi-induced mitotic arrest, generating mitotic DNA damage and concurrent apoptotic plus GSDME-mediated pyroptotic death, with in vivo efficacy using a clinically relevant Aurora A inhibitor plus inducible TRIP13 degradation. This is a genotype-anchored synthetic lethality for RB loss with animal data — the first such in this programme. Caveat from abstract alone: the models are \"Rb-deficient cancers\", not stated to include WERI-Rb1/Y79 or RB1−/− cone-precursor organoids [INFERRED that retinoblastoma is untested]. Mechanistically it is coherent with RB1 loss: unrestrained E2F output shortens G1 and increases mitotic load, and TRIP13 (AAA+ ATPase that recycles MAD2 to silence the spindle checkpoint [KNOWN]) becomes the brake whose removal converts arrest into death. New lead L5, confidence 0.4, above L1.\n\nConsequently L1 (CDK7) weakens again: a third consecutive sweep with zero primary transcriptional-CDK data in any RB1-null retinoblastoma model, while a competing RB1-loss synthetic lethality now has in vivo support. Drop to 0.20 and pre-commit: retire at visit 4 unless a primary CDK7/9/12 experiment in an RB1-null retinoblastoma model appears. L4 (sunitinib) is retired as pre-committed — the single review abstract never yielded target attribution.\n\nSecond, open question 3 is now partially answered. PMID:42187581 maps the retinoblastoma immune microenvironment including PD-1/PD-L1/CTLA-4 and notes chemotherapy-induced changes in infiltration and checkpoint expression; PMID:41238845 (scRNA-seq, 10 primaries) defines cone-precursor subpopulations enriched in invasive disease, increased fibroblast–CP crosstalk, TGF-β–high CP4, and a bulk subtype 1 with an immunosuppressive TME. For L2 this cuts both ways: it establishes that immune cells do enter these tumours (supporting trafficking feasibility) while flagging TGF-β/fibroblast-mediated suppression as a headwind for any cell product; neither paper reports GPC2. L2 held at 0.35 with citations added; the antigen-frequency gap remains the rate-limiter and NCT05650749 stays invitation-only.\n\nNext I need retinoblastoma-specific TRIP13/AURKA expression and dependency data, a tractable TRIP13 pharmacology answer, GSDME status in retinoblastoma lines, and whether alisertib-class agents reach tumoricidal vitreous exposure.","leadChanges":[{"id":"L5","title":"TRIP13 + Aurora A co-inhibition as mitotic synthetic lethality in RB1-null retinoblastoma","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L1","title":"CDK7 / transcriptional-CDK inhibition as synthetic lethality with RB1 loss and MYCN amplification in retinoblastoma","level":"LEAD","status":"WEAKENED","confidence":0.2},{"id":"L2","title":"GPC2-directed CAR T cells for metastatic/extraocular retinoblastoma","level":"LEAD","status":"STRENGTHENED","confidence":0.38},{"id":"L4","title":"Sunitinib repurposing (multi-RTK inhibition) validated in CRISPR retinal organoid retinoblastoma models","level":"LEAD","status":"RETIRED","confidence":0.05}],"unverifiedCitations":0,"openQuestions":["Were any retinoblastoma models (WERI-Rb1, Y79, RB1-/- cone-precursor organoids) included in the TRIP13/Aurora A Rb-deficient panel, and what were the AURKAi IC50s relative to other Rb-null lineages?","What are TRIP13, AURKA and GSDME expression levels in retinoblastoma primaries and vitreous seeds, and is GSDME silenced (which would abolish the pyroptotic arm)?","Is there any clinical-grade TRIP13 inhibitor or degrader, or must the combination be reformulated as AURKAi plus an alternative SAC-prolonging partner (e.g. MPS1 or KIF11 modulation)?","What intravitreal or intra-arterial exposure is achievable for alisertib-class Aurora A inhibitors relative to melphalan/topotecan, and is ocular toxicity to proliferating retinal tissue prohibitive?","What is the measured GPC2 surface density and positivity frequency in retinoblastoma primaries, vitreous seeds and CSF deposits, and does it track with MYCN amplification?","Does the TGF-beta-high, immunosuppressive invasive-RB subtype (PMID:41238845) predict failure of unarmoured CAR T or checkpoint blockade, and is HLA class I retained in these tumours?"],"nextQueries":["(\"TRIP13\" OR \"AURKA\" OR \"Aurora A\" OR \"alisertib\") AND (\"retinoblastoma\" OR \"RB1\" OR \"Rb-deficient\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"retinoblastoma\") AND (\"GPC2\" OR \"glypican-2\" OR \"B7-H3\" OR \"GD2\" OR \"surfaceome\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"retinoblastoma\") AND (\"intravitreal pharmacokinetics\" OR \"intra-arterial chemotherapy\" OR \"vitreous concentration\" OR \"ocular pharmacokinetics\") AND SRC:MED AND PUB_YEAR:[2015 TO 2026]"],"papersShown":[{"pmid":"42058626","doi":"10.1016/j.bioactmat.2026.04.019","year":2026,"isNew":true,"title":"Illuminating cancer therapy: The translational path of optogenetics"},{"pmid":"42246161","doi":"10.3892/mmr.2026.13924","year":2026,"isNew":true,"title":"Beyond the primary site: Molecular insights and clinical implications of cancer metastatic overlap between lung and urological organ cancers (Review)"},{"pmid":"42061029","doi":"10.1016/j.breast.2026.104791","year":2026,"isNew":true,"title":"WITHDRAWN: From CDK4/6 to CDK2 and KAT: Evolving therapeutic approaches in HR+/HER2- breast cancer"},{"pmid":"42138187","doi":"10.3892/mmr.2026.13903","year":2026,"isNew":true,"title":"Emerging role of DYRK1A as a target in cardiovascular diseases (Review)"},{"pmid":"42013305","doi":"10.1158/1078-0432.ccr-25-4712","year":2026,"isNew":true,"title":"Dual Inhibition of TRIP13 and Aurora A Induces Mitotic DNA Damage and Concurrent Pyroptotic-Apoptotic Cell Death in Rb-Deficient Cancer Cells"},{"pmid":"41615646","doi":"10.1007/s12094-025-04187-3","year":2026,"isNew":true,"title":"Deep learning for early diagnosis of uveal melanoma: a systematic review and meta-analysis"},{"pmid":"42358772","doi":"10.1021/cbmi.5c00279","year":2026,"isNew":true,"title":"pH-Responsive Materials for Therapy and Precision Biomedical Imaging"},{"pmid":"42187581","doi":"10.3390/curroncol33050264","year":2026,"isNew":true,"title":"Retinoblastoma and Its Tumor Microenvironment"},{"pmid":"42210511","doi":"10.1111/jcmm.71212","year":2026,"isNew":true,"title":"Single-Cell RNA-Seq Combined With Bulk RNA-Seq Revealed the Involvement of Pancreatic Cancer Tissue-Resident Macrophages in Tumour Progression and the Immunotherapy Response"},{"pmid":"41238845","doi":"10.1038/s41598-025-23779-1","year":2025,"isNew":true,"title":"Comprehensive analysis of single-cell and bulk RNA sequencing uncover tumor microenvironment diversity in invasive Retinoblastoma"}],"trialsShown":[{"nct":"NCT05650749","phase":"phase 1","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"GPC2 CAR T Cells for Relapsed or Refractory Neuroblastoma and Metastatic Retinoblastoma"},{"nct":"NCT01109394","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Comprehensive Omics Analysis of Pediatric and Adult Solid Tumors and Establishment of a Repository for Related Biological Studies"},{"nct":"NCT07633756","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Phase 1b, Open-Label Study Of REC-617, A Selective CDK7 Inhibitor, In Patients With Metastatic Or Unresectable RB1-Negative Leiomyosarcoma"},{"nct":"NCT04040205","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Abemaciclib for Bone and Soft Tissue Sarcoma With Cyclin-Dependent Kinase (CDK) Pathway Alteration"},{"nct":"NCT03567642","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of the Combination of Osimertinib, Platinum and Etoposide for Patients With Metastatic EGFR Mutant Lung Cancers"},{"nct":"NCT03655223","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Early Check: Expanded Screening in Newborns"},{"nct":"NCT01783535","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":10270,"output":5627},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"WERI-Rb1\" OR \"Y79\" OR \"retinoblastoma\") AND (\"CRISPR screen\" OR \"dependency\" OR \"essential gene\" OR \"DepMap\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","\"retinoblastoma\" AND (\"HLA class I\" OR \"tumor microenvironment\" OR \"tumour microenvironment\" OR \"immune infiltrate\" OR \"single-cell RNA\") AND SRC:MED AND PUB_YEAR:[2019 TO 2026]"],"evidenceIds":["PMID:42058626","PMID:42246161","PMID:42061029","PMID:42138187","PMID:42013305","PMID:41615646","PMID:42358772","PMID:42187581","PMID:42210511","PMID:41238845","NCT05650749","NCT01109394","NCT07633756","NCT04040205","NCT03567642","NCT03655223","NCT01783535","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787179699129","cycle":150,"visit":3,"ts":"2026-08-19T22:48:19.129Z","cancer":{"key":"medulloblastoma","name":"medulloblastoma","mondo":{"id":"MONDO:0007959","name":"medulloblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"CDK9 (with CDK7 co-inhibition) is now the best-evidenced druggable dependency in MYC-amplified medulloblastoma — supported by eight pooled CRISPR screens, primary-tumour Hi-C and xenograft activity — and should be tested head-to-head against TOP1/replication-stress agents in the same orthotopic Myc-","confidence":0.47,"notebook":"CDK9 is the most consequential new fact this visit. P6 (PMID:40372972) pools eight independent CRISPR-Cas9 screens across three labs and recovers CDK9 as a conserved dependency in MYC-amplified MB, anchors it to primary-patient Hi-C enhancer–promoter architecture, and shows CDK9i activity in vitro and in xenografts with synergy on co-inhibition of CDK7. That is genetic + structural + in vivo evidence in the correct subgroup, and it answers OQ2 asymmetrically: transcription-CDK targeting now has primary MB data, whereas the replication-stress arm (L1) still rests only on trial registrations (NCT06161519, NCT04337177). L1 is therefore weakened rather than abandoned — the amplification-gated PLX038 design remains the most interpretable clinical readout available, and P7 (PMID:40759474) supplies a general rationale for ATR/CHK1/WEE1 in TP53-mutant disease that is relevant to TP53-mutant SHH-MB but contains no MB data. The head-to-head in the same orthotopic model still does not exist; that is now the single highest-value experiment on the desk. Window caveat for the new lead: CDK9/P-TEFb is required for productive transcription in all dividing tissue [KNOWN], so tumour selectivity must come from Myc-driven core-regulatory-circuit addiction and from MCL1 dependence, not from target absence in normal cerebellum.\n\nP8 (PMID:41729336) converts the MET half of L7 from a prevalence guess into an expression/dependency claim: c-MET and HGF are highest in SHH-α/SHH-β, and siRNA knockdown reduces proliferation. But the same abstract undercuts its own pharmacology — tivantinib kills via prolonged mitotic block, while the genuinely selective inhibitors crizotinib and foretinib only produce mitotic slippage. Tivantinib's antimitotic/tubulin off-target activity is well documented [KNOWN], so the best-performing drug is probably not acting through MET. I therefore open a separate SHH-MB MET/HGF lead at modest confidence with an explicit falsification test (savolitinib/capmatinib in orthotopic SHH models), and weaken L7 to what it always was: an unquantified RET prevalence question, with no new data this visit.\n\nL5 is retired. Two visits of targeted querying produced no MB-specific paired plasma/tumour exposure or subgroup-stratified permeability data, and P1 (PMID:41168621) states directly that BBB penetration and absent pediatric PK data remain unresolved obstacles — confirmation of a gap, not of the hypothesis.\n\nNull results worth recording: the ELP1 query returned no MB-specific proteostasis data for a second visit (only the generic tRNA-modification review P10, PMID:41501031); OQ1 gets one final query before closure. P5 (PMID:41271695) shows 23.3% germline P/LP prevalence with somatic second hits in 830 pediatric CNS tumours but gives no gene-level MB breakdown — needed before any germline-DDR/PARP hypothesis in MB.","leadChanges":[{"id":"L8","title":"CDK9 (P-TEFb) inhibition, synergistic with CDK7, collapses the Myc core regulatory circuit in MYC-amplified Group 3 MB","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L1","title":"TOP1-directed replication-stress payloads in MYC/MYCN-amplified Group 3/4 MB","level":"LEAD","status":"WEAKENED","confidence":0.4},{"id":"L9","title":"c-MET/HGF autocrine signalling in SHH-alpha/beta medulloblastoma - real dependency, misleading pharmacology","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L7","title":"Genotype-matched kinase inhibition at MB relapse: RET and MET as screenable but unquantified alterations","level":"LEAD","status":"WEAKENED","confidence":0.12},{"id":"L5","title":"Subgroup-differential BBB integrity as the determinant of CNS drug exposure in MB","level":"LEAD","status":"RETIRED","confidence":0.08}],"unverifiedCitations":0,"openQuestions":["In the same orthotopic MYC-amplified MB model, does CDK9 (+/- CDK7) inhibition outperform TOP1/ATR-directed replication-stress agents, and is any CDK9 inhibitor CNS-penetrant at active exposures?","Is MCL1 loss the proximal effector of CDK9i in Myc-MB, and does BCL2L1/MCL1 rebalancing or ABCB1 efflux drive resistance?","Does selective MET inhibition (savolitinib/capmatinib) reproduce the anti-SHH-MB effect of tivantinib in vivo, or is tivantinib's activity tubulin-mediated and MET-independent?","Final attempt: any primary data that ELP1 loss in SHH-MB creates a measurable ISR/GCN2/PERK or tRNA-modification vulnerability?","In the PBTA germline cohort, which cancer-predisposition genes are P/LP in medulloblastoma specifically, and is BRCA2/DDR carriage frequent enough to justify a PARP/platinum stratum?","Does DFMO/ODC1 dependency in MB have primary mechanistic support via eIF5A hypusination, and what is the polyamine-transport salvage route?"],"nextQueries":["\"medulloblastoma\" AND (CDK9 OR \"P-TEFb\" OR AZD4573 OR enitociclib OR MCL1)","\"medulloblastoma\" AND (ELP1 OR Elongator OR \"integrated stress response\" OR GCN2 OR hypusination OR eIF5A)","(\"medulloblastoma\" AND (germline OR \"cancer predisposition\") AND (BRCA2 OR PARP OR \"second hit\"))"],"papersShown":[{"pmid":"41168621","doi":"10.1007/s40291-025-00817-2","year":2026,"isNew":true,"title":"Advancing Medulloblastoma Treatment: Molecular Mechanisms, Drug Repurposing, and Precision Therapies"},{"pmid":"41692895","doi":"10.1186/s43556-026-00411-w","year":2026,"isNew":true,"title":"Tumor cell cycle regulation: integrated perspective of stage characteristics, regulatory networks, and signaling pathway intervention strategies"},{"pmid":"41291966","doi":"10.1186/s40478-025-02140-7","year":2025,"isNew":true,"title":"Recurrent genetic alterations in epigenetically defined pineoblastoma subtypes"},{"pmid":"41468145","doi":"10.1093/clinchem/hvaf154","year":2025,"isNew":true,"title":"The Mutational Epidemiology of Childhood Cancer"},{"pmid":"41271695","doi":"10.1038/s41467-025-65190-4","year":2025,"isNew":true,"title":"Germline pathogenic variation impacts somatic alterations and patient outcomes in pediatric central nervous system tumors"},{"pmid":"40372972","doi":"10.1093/neuonc/noaf121","year":2025,"isNew":true,"title":"Targeting processive transcription for Myc-driven circuitry in medulloblastoma"},{"pmid":"40759474","doi":"10.14791/btrt.2025.0017","year":2025,"isNew":true,"title":"Therapeutic Targeting of DNA Damage Response Pathways in &lt;i&gt;TP53&lt;/i&gt;- and &lt;i&gt;ATM&lt;/i&gt;-Mutated Tumors"},{"pmid":"41729336","doi":"10.1007/s12672-026-04717-7","year":2026,"isNew":true,"title":"Distinct cMET inhibitors uncover pharmacological heterogeneity in SHH medulloblastoma cell lines"},{"pmid":"41602819","doi":"10.1177/20503121251386139","year":2026,"isNew":true,"title":"Exploring the prognostic molecular mechanisms of medulloblastoma through methylation-transcriptome integration"},{"pmid":"41501031","doi":"10.1038/s41419-025-08234-3","year":2026,"isNew":true,"title":"Emerging roles of tRNA modification-mediated codon-specific translational reprogramming in cancer biology"}],"trialsShown":[{"nct":"NCT06161519","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"PLX038 in Primary Central Nervous System Tumors Containing MYC or MYCN Amplifications"},{"nct":"NCT04696029","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"DFMO as Maintenance Therapy for Molecular High/Very High Risk and Relapsed Medulloblastoma"},{"nct":"NCT05057702","phase":"NA","status":"RECRUITING","isNew":false,"title":"Individualized Treatment Plan in Children and Young Adults With Relapsed Medulloblastoma and Ependymoma"},{"nct":"NCT06514898","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Adoptive T Cell Therapy, DC Vaccines, and Hematopoietic Stem Cells Combined With Immune checkPOINT Blockade in Patients With Medulloblastoma"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT06624371","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Atovaquone Combined With Radiation in Children With Malignant Brain Tumors"},{"nct":"NCT04337177","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With Temozolomide for Treatment of Recurrent Pediatric Solid Tumors"},{"nct":"NCT03598244","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Savolitinib in Treating Patients With Recurrent or Refractory Primary CNS Tumors"}],"usage":{"input":11673,"output":6914},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"medulloblastoma\" AND ELP1","\"medulloblastoma\" AND (\"replication stress\" OR CDK7 OR CDK9 OR ATR OR CHK1)"],"evidenceIds":["PMID:41168621","PMID:41692895","PMID:41291966","PMID:41468145","PMID:41271695","PMID:40372972","PMID:40759474","PMID:41729336","PMID:41602819","PMID:41501031","NCT06161519","NCT04696029","NCT05057702","NCT06514898","NCT04320888","NCT06624371","NCT04337177","NCT03598244"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787179485619","cycle":149,"visit":3,"ts":"2026-08-19T22:44:45.619Z","cancer":{"key":"neuroblastoma","name":"neuroblastoma","mondo":{"id":"MONDO:0005072","name":"neuroblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Lorlatinib produces responses in ALK-aberrant neuroblastoma but appears to fail fast in MYCN-amplified tumours, so ALK inhibition should be pursued as a combination — with anti-GD2/NK exploiting its ALK/USP7/SOX9/MFAP2-mediated M2-to-M1 myeloid reprogramming — while METTL3 inhibition (STM2457) is te","confidence":0.55,"notebook":"Visit 3 delivered the first real clinical answer to open question 1. P5 (PMID:42499277) is a five-patient off-label lorlatinib series in relapsed/refractory ALK-aberrant neuroblastoma: three partial responses across F1174L, R1275Q, BEND5::ALK and ALK amplification, but the two rapid progressors were MYCN-amplified, and the longest PFS (6.7 months) was in an F1174L/MYCN-non-amplified tumour. n=5, uncontrolled, no sequencing of progression biopsies, so acquired-mutation data remain absent — but the direction is consistent with MYCN amplification [SOMATIC] acting as a dominant modifier that uncouples ALK-kinase inhibition from tumour regression [INFERRED]. This makes ALK a lead in this programme for the first time, and specifically a combination lead, not a monotherapy one.\n\nP3 (PMID:42603656) supplies a non-cell-autonomous mechanism that partly explains why: ALK signalling stabilises SOX9 via USP7, driving MFAP2 transcription, glycolysis and lactate export, which polarises TAMs to M2; lorlatinib flips M1/M2 markers in vivo and MFAP2 overexpression rescues tumour growth. So lorlatinib is also a myeloid-conditioning agent, which folds open question 5 into the ALK lead: in ALK-aberrant disease, ALK inhibition is a candidate partner for anti-GD2/NK (L1) rather than a competitor. Expected resistance: compound ALK mutations (G1202R/L1196M class [KNOWN]), MYCN-driven RAS/MEK and MDM2 bypass, MFAP2/lactate restoration.\n\nP10 (preprint, DOI:10.21203/rs.3.rs-10306203/v1) is the most consequential mechanistic item: HMGA2, reinforced by IGF2BP2/m6A and cooperating with FOSL1, maintains the MES state and suppresses GD2, and METTL3 inhibition with STM2457 raises GD2 and re-sensitises MES cells to cisplatin. That is a druggable handle on the exact antigen-escape axis L1/L2/L5 are built around, and it is epitranscriptomic rather than PRC2-mediated — a parallel route to L3, not a confirmation of it. Preprint status caps confidence; METTL3 is required for HSC self-renewal [KNOWN], so marrow toxicity bounds the window.\n\nP4 (PMID:42587334) strengthens L2 on the T-cell side: linsitinib, or selective FECH inhibition, lowers intracellular heme, reduces activation/exhaustion markers and pushes GD2.CAR T cells toward central memory with better persistence — a repurposable clinical-stage conditioning agent applicable to GPC2/B7-H3 constructs. P2 adds only that GPC2 is high in MYCN-amplified tumours. P1, P6, P8, P9 are off-indication; P7 has no content.\n\nNext: acquired-resistance genotyping at lorlatinib progression; whether ALK inhibition raises GD2/MHC-I; whether STM2457-induced GD2 is sufficient for dinutuximab ADCC.","leadChanges":[{"id":"L6","title":"Lorlatinib in ALK-aberrant neuroblastoma stratified by MYCN status, combined with anti-GD2 to exploit ALK-driven myeloid reprogramming","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L7","title":"METTL3/IGF2BP2-HMGA2-FOSL1 blockade to reverse MES-state GD2 suppression and restore anti-GD2/CAR sensitivity","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L2","title":"Multi-antigen CAR-T against GPC2/B7-H3 with TGF-beta blockade for MHC-I-low MYCN-amplified disease","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55}],"unverifiedCitations":0,"openQuestions":["What acquired ALK resistance genotypes (compound mutations, MYCN/MDM2 or RAS-MEK bypass) appear at lorlatinib progression in neuroblastoma, and is the MYCN-amplified failure pattern in PMID:42499277 reproduced in larger series such as NANT/","Does ALK inhibition itself alter GD2 density, MHC-I and TAM M1/M2 ratio in ALK-aberrant neuroblastoma in vivo, i.e. is lorlatinib a legitimate immunotherapy partner rather than just a cytoreductor?","Is METTL3- or IGF2BP2-driven GD2 restoration in MES cells quantitatively sufficient for dinutuximab ADCC and GD2.CAR lysis, and how does it compare head-to-head with EZH2/DNMT re-differentiation (L3)?","Can FECH/heme-directed metabolic conditioning (linsitinib, N-methyl protoporphyrin IX) be applied ex vivo during CAR manufacture, and does it also improve NK-cell persistence relevant to L1?","Is the ALK/USP7/SOX9/MFAP2 lactate-TAM axis druggable downstream of ALK — USP7 inhibitors, MCT1/4 or lactate-export blockade — for ALK-wild-type MYCN-amplified tumours?","Are LIN28B, LMO1, HACE1 or PHOX2B tractable beyond lineage/predisposition markers, and which are germline versus somatic in neuroblastoma?"],"nextQueries":["(neuroblastoma AND (lorlatinib OR \"ALK inhibitor\") AND (resistance OR \"compound mutation\" OR MYCN)) AND (FIRST_PDATE:[2024-01-01 TO 2026-12-31])","neuroblastoma AND (METTL3 OR IGF2BP2 OR HMGA2 OR FOSL1) AND (\"cell state\" OR mesenchymal OR GD2)","neuroblastoma AND (USP7 OR SOX9 OR MFAP2 OR lactate OR \"tumor-associated macrophage\") AND (\"anti-GD2\" OR dinutuximab OR CAR)"],"papersShown":[{"pmid":"42282123","doi":"10.1016/j.jncc.2025.11.003","year":2026,"isNew":true,"title":"Study of the blood-brain barrier-penetrating KRAS G12C inhibitor JMKX1899 in KRAS G12C-mutated NSCLC with brain metastases"},{"pmid":"41750126","doi":"10.3390/brainsci16020125","year":2026,"isNew":true,"title":"Exosomes as Specific Vehicles for Delivery of Combination Therapies for Inhibiting Autophagy and Inducing Apoptosis in MYCN-Amplified Neuroblastoma Displaying Gut Dysbiosis: Curren"},{"pmid":"42603656","doi":"10.1016/j.cellsig.2026.112824","year":2026,"isNew":true,"title":"ALK regulates macrophage polarization via the USP7/SOX9/MFAP2-mediated glycolytic pathway to promote neuroblastoma progression"},{"pmid":"42587334","doi":"10.1186/s40364-026-00979-z","year":2026,"isNew":true,"title":"FECH, a novel metabolic target influencing CAR T-cell phenotype and function"},{"pmid":"42499277","doi":"10.1002/1545-5017.70511","year":2026,"isNew":true,"title":"Feasibility and Efficacy of Lorlatinib in Japanese Patients With Relapsed/Refractory ALK-Aberrant Neuroblastoma"},{"pmid":"42303626","doi":"10.1038/s41392-026-02729-x","year":2026,"isNew":true,"title":"Non-receptor tyrosine kinase signaling pathways and therapeutic implications"},{"pmid":null,"doi":null,"year":2026,"isNew":true,"title":"Publication Only"},{"pmid":"42221857","doi":"10.1093/pcmedi/pbag014","year":2026,"isNew":true,"title":"Protein modification systems as cancer biomarkers and therapeutic targets"},{"pmid":"41955968","doi":"10.1016/j.neo.2026.101304","year":2026,"isNew":true,"title":"Midkine and pleiotrophin in glioma: From mechanistic insights to therapeutic potential"},{"pmid":null,"doi":"10.21203/rs.3.rs-10306203/v1","year":2026,"isNew":true,"title":"The IGF2BP2/HMGA2/FOSL1 Axis Controls Cell Plasticity and Therapy Resistance in Neuroblastoma"}],"trialsShown":[{"nct":"NCT06172296","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Dinutuximab With Chemotherapy, Surgery and Stem Cell Transplantation for the Treatment of Children With Newly Diagnosed High Risk Neuroblast"},{"nct":"NCT07767630","phase":"EARLY_phase 1","status":"RECRUITING","isNew":false,"title":"Safety, Tolerability, and Preliminary Efficacy of [211At]MABG in Patients With Relapsed or Refractory Neuroblastoma"},{"nct":"NCT06479811","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"[212Pb]VMT-Alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive Gastrointestinal Neuroendocrine Tumors, Pheochromocytoma/Par"},{"nct":"NCT04755205","phase":"n/a","status":"RECRUITING","isNew":false,"title":"A Natural History Study of Children and Adults With Olfactory Neuroblastoma"},{"nct":"NCT01005654","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Prospective Comprehensive Molecular Analysis of Endocrine Neoplasms"},{"nct":"NCT07549321","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"A Safety and Efficacy Study of hu14 in High-Risk Neuroblastoma Patients"},{"nct":"NCT05650749","phase":"phase 1","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"GPC2 CAR T Cells for Relapsed or Refractory Neuroblastoma and Metastatic Retinoblastoma"},{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"}],"usage":{"input":11203,"output":6536},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(neuroblastoma AND lorlatinib) OR (neuroblastoma AND \"ALK inhibitor\" AND resistance)","neuroblastoma AND (\"mesenchymal\" OR \"adrenergic\") AND (\"GD2\" OR \"antigen escape\")"],"evidenceIds":["PMID:42282123","PMID:41750126","PMID:42603656","PMID:42587334","PMID:42499277","PMID:42303626","untracked","PMID:42221857","PMID:41955968","DOI:10.21203/rs.3.rs-10306203/v1","NCT06172296","NCT07767630","NCT06479811","NCT04755205","NCT01005654","NCT07549321","NCT05650749","NCT07172958"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787179280700","cycle":148,"visit":3,"ts":"2026-08-19T22:41:20.700Z","cancer":{"key":"adrenocortical carcinoma","name":"adrenocortical carcinoma","mondo":{"id":"MONDO:0006639","name":"adrenal cortex carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"ACC should be triaged by molecular subtype: prioritise CDK4/6 inhibition in the CDK4-amplified/CDKN2A-deleted cell-cycle-altered subtype, restrict checkpoint-combination expectations to the immunomodulatory subtype, and demote tumour cortisol from general to subtype-specific immune-evasion mechanism","confidence":0.46,"notebook":"Two ACC-specific datasets landed and they reorganise the programme's architecture around subtype rather than around cortisol.\n\nPMID:42550593 (n=61, WES+RNA+CNV) partitions ACC into cortisol-driven (14%), immune-suppressed (40%, TCR-pathway downregulation, worst DFS), cell-cycle-altered (22%, chromosomal instability), and immunomodulatory (24%, favourable). Focal TERT and CDK4 amplification and HLA class II deletions are named. This is the first independent transcriptomic partition the desk has seen that separates steroidogenic from immune-cold biology — and it argues against cortisol being the dominant immune-evasion axis: the largest, worst-prognosis subtype is defined by TCR downregulation and antigen-presentation loss, not steroid output. L3 is therefore weakened (still CANDIDATE; the glucocorticoid axis remains real for the 14% CD subtype and for iatrogenic exposure in L4, but it cannot be the general explanation of MSS-ACC checkpoint failure). Conversely, the IM subtype gives L2 a prespecifiable enrichment biomarker, and PMID:42106259 records that SWOG DART nivolumab/ipilimumab produced durable unselected benefit in rare histologies including ACC — subset benefit without biomarker selection is exactly what a 24% immune-hot fraction predicts [INFERRED]. HLA-II deletion becomes a candidate resistance route to add to L2's list.\n\nPMID:42265438 (9 patients, 29 matched primary/relapse WGS) shows truncal global LOH followed by whole-genome doubling in 7/9 — a single catastrophic event conserved across all lesions per patient. Combined with the CCA subtype, this converts L1 from an isolated OTSSP167/RSK1 report into a subtype-anchored replication-stress/CIN hypothesis: WGD and copy-neutral LOH plus TP53 loss predict dependence on G2/M restraint (WEE1, PKMYT1) and on ATR, and predict KIF18A vulnerability in aneuploid cells [KNOWN]. Still no ACC WEE1 dependency data, so confidence rises only modestly. New lead: CDK4/6 inhibition in the CCA/CDK4-amplified, CDKN2A-deleted subtype — the cleanest repurposing signal in this pack, with the practical caveat that mitotane's CYP3A4 induction will collapse exposure of CYP3A4-cleared CDK4/6 inhibitors [KNOWN].\n\nPMID:42236114 contradicts a working assumption: ZNRF3 loss → Wnt activation → SCD repression *increased* T-cell infiltration and synergised with checkpoint blockade in non-ACC models. If transferable, ZNRF3-mutant ACC (10% here) may be immunologically favourable rather than excluded, and SCD becomes a target in ZNRF3-intact tumours. Logged as a new low-confidence lead and as a retraction of \"WNT = T-cell exclusion\" boilerplate in L2/L3 until ACC-specific data exist. Still no tractable ACC WNT-targeting agent evidence (OQ3 unresolved).","leadChanges":[{"id":"L1","title":"Adaptive WEE1 induction as the actionable vulnerability of TP53-mutant ACC after RSK1/multikinase inhibition","level":"LEAD","status":"STRENGTHENED","confidence":0.44},{"id":"L2","title":"VEGFR/MET TKI plus PD-1 blockade as the practical immunotherapy backbone in advanced ACC","level":"LEAD","status":"STRENGTHENED","confidence":0.46},{"id":"L3","title":"Tumour-derived cortisol as a targetable immune-evasion axis: GR antagonism to enable checkpoint therapy","level":"CANDIDATE","status":"WEAKENED","confidence":0.42},{"id":"L5","title":"CDK4/6 inhibition in the CDK4-amplified / CDKN2A-deleted cell-cycle-altered ACC subtype","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L6","title":"ZNRF3-Wnt-SCD lipid axis as an immune-metabolic modifier in ACC, with SCD inhibition in ZNRF3-intact tumours","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Do responders in NCT02721732, NCT03333616 and NCT06900595 concentrate in the immunomodulatory subtype of PMID:42550593, and is HLA class II copy loss enriched in non-responders?","Is hypercortisolism predictive of ICI failure independently of molecular subtype, or was the prior cortisol signal confounded by the immune-suppressed subtype?","Does whole-genome doubling / copy-neutral LOH status (PMID:42265438) co-segregate with the cell-cycle-altered subtype, and does it predict WEE1/PKMYT1/ATR/KIF18A sensitivity in ACC models?","What fraction of CDK4-amplified or CDKN2A-deleted ACC retains RB1, and can CDK4/6-inhibitor exposure be sustained on concurrent mitotane?","In ZNRF3-mutant ACC specifically, is the tumour immune microenvironment T-cell-enriched (consistent with PMID:42236114) or excluded, and is SCD expression correspondingly low?","Are on-treatment biopsies from NCT06900595 yielding any evidence of MET/AXL bypass or Treg re-expansion after cabozantinib plus cemiplimab?"],"nextQueries":["(\"adrenocortical carcinoma\" AND (CDK4 OR CDK6 OR palbociclib OR ribociclib OR abemaciclib OR CDKN2A)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"adrenocortical carcinoma\" AND (\"whole genome doubling\" OR aneuploidy OR \"chromosomal instability\" OR WEE1 OR PKMYT1 OR KIF18A OR ATR)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"adrenocortical carcinoma\" AND (\"HLA class II\" OR \"antigen presentation\" OR \"immune subtype\" OR \"tumor microenvironment\" OR \"single-cell\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41535994","doi":"10.1186/s40364-026-00892-5","year":2026,"isNew":true,"title":"Peripheral blood biomarkers for predicting response to PD-1/PD-L1 inhibitors"},{"pmid":"41945753","doi":"10.1182/bloodadvances.2025018830","year":2026,"isNew":true,"title":"DLK1 is a GATA1s-driven dependency and therapeutic target in Down syndrome-associated myeloid leukemia"},{"pmid":"42550593","doi":"10.1530/erc-25-0342","year":2026,"isNew":true,"title":"Molecular subtyping of adrenocortical carcinoma reveals distinct subtypes with prognostic and therapeutic implications"},{"pmid":"42265438","doi":"10.1007/s12022-026-09922-2","year":2026,"isNew":true,"title":"Genomic Catastrophe Defines the Evolutionary Trajectory of Adrenocortical Carcinoma"},{"pmid":"42254722","doi":"10.1016/j.iliver.2026.100237","year":2026,"isNew":true,"title":"Histone delactylation shapes epigenetic landscapes and therapeutic stratification in hepatocellular carcinoma"},{"pmid":"42236114","doi":"10.1136/jitc-2026-014927","year":2026,"isNew":true,"title":"Glucose restriction reprograms lipid metabolism and enhances immunotherapy through ZNRF3-Wnt-SCD signaling axis"},{"pmid":"42017034","doi":"10.3892/mco.2026.2948","year":2026,"isNew":true,"title":"Advances in the molecular mechanisms and clinical applications of LEMD1 in tumor development and progression (Review)"},{"pmid":"41930481","doi":"10.3892/mmr.2026.13869","year":2026,"isNew":true,"title":"Emerging roles of POLR2L of RNA polymerase II dynamics and disease mechanisms (Review)"},{"pmid":"42106259","doi":"10.1016/j.ejca.2026.116784","year":2026,"isNew":true,"title":"The case for tumour-agnostic reimbursement of dual immunotherapy"},{"pmid":"41792526","doi":"10.1007/s11934-026-01325-4","year":2026,"isNew":true,"title":"Sarcomatoid Renal Cell Carcinoma: Biological Features and Therapeutic Implications-A Narrative Review"}],"trialsShown":[{"nct":"NCT06487481","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Study of Preoperative Radiation Therapy in Participants With Resectable Recurrent Abdominal Adrenocortical Carcinoma"},{"nct":"NCT03604198","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Extension Study to Evaluate the Safety of Long-Term Use of Relacorilant in Patients With Cushing Syndrome"},{"nct":"NCT06900595","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing the Addition of an Anti-Cancer Drug, Cabozantinib to the Immunotherapy Drug Cemiplimab (REGN2810), in Adolescents and Adults With Ad"},{"nct":"NCT03333616","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Nivolumab Combined With Ipilimumab for Patients With Advanced Rare Genitourinary Tumors"},{"nct":"NCT02867592","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumor"},{"nct":"NCT02721732","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Pembrolizumab in Treating Patients With Rare Tumors That Cannot Be Removed by Surgery or Are Metastatic"},{"nct":"NCT03583710","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Mitotane With or Without Cisplatin and Etoposide After Surgery in Treating Patients With Stage I-III Adrenocortical Cancer With High Risk of"},{"nct":"NCT05286814","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"PDS01ADC in Combination With Hepatic Artery Infusion Pump (HAIP) and Systemic Therapy for Subjects With Metastatic Colorectal Cancer, Intrah"}],"usage":{"input":11918,"output":7704},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"adrenocortical carcinoma\" AND (ZNRF3 OR CTNNB1 OR \"Wnt\" OR porcupine OR tankyrase OR beta-catenin)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"adrenocortical carcinoma\" AND (pembrolizumab OR nivolumab OR avelumab OR cemiplimab) AND (cohort OR \"response rate\" OR retrospective OR biomarker)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41535994","PMID:41945753","PMID:42550593","PMID:42265438","PMID:42254722","PMID:42236114","PMID:42017034","PMID:41930481","PMID:42106259","PMID:41792526","NCT06487481","NCT03604198","NCT06900595","NCT03333616","NCT02867592","NCT02721732","NCT03583710","NCT05286814"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787179062130","cycle":147,"visit":3,"ts":"2026-08-19T22:37:42.130Z","cancer":{"key":"head and neck squamous cell carcinoma","name":"head and neck squamous cell carcinoma","mondo":{"id":"MONDO:0010150","name":"head and neck squamous cell carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"b-AP15-type DUB/proteasome inhibition induces DR5 via ROS/JNK and is required for TRAIL sensitisation in HNSCC (PMID:42069980), making 'DR5 induction + DR5 agonism, stratified by CASP8/FADD/cFLIP status' the programme's new testable axis, while ING1 is retired as an anchor.","confidence":0.42,"notebook":"This visit finally moved the oldest dead weight in the programme. Q3 splits: TNFRSF10B is now citable in disease context — b-AP15, a USP14/UCHL5 (19S proteasome DUB) inhibitor, upregulates DR5 in HNSCC cells via ROS→JNK, and that DR5 induction is *required* for TRAIL sensitisation; the same agent inhibits NF-κB and previously sensitised HNSCC to TNFα and to TNF-inducing radiation (PMID:42069980). That converts the Monarch anchor from an orphan gene name into a mechanistic node with a licensing strategy: HNSCC is not intrinsically TRAIL-sensitive, so the therapeutic unit is *induce DR5 + agonise it*, not agonist monotherapy. New lead L6. The druggability context is broader than one tool compound — DUB/proteostasis targeting is an active medicinal-chemistry space (PMID:41891958, PMID:42259777), and clinically approved proteasome inhibitors are an obvious repurposing surrogate for b-AP15 [KNOWN]. Caveats stated plainly: single paper, in vitro only, abstract gives no xenograft, no CASP8 or cFLIP status. HNSCC carries recurrent CASP8 loss-of-function and 11q13 FADD amplification [KNOWN], which should be the stratifier and the kill-test. ING1, by contrast, remains citation-free after three visits with no HNSCC dependency evidence — I retire it from the anchor set rather than keep generating queries against it.\n\nL3 gains real drug-side substance. The antibody-pipeline survey places petosemtamab, an EGFR×LGR5 bispecific with enhanced Fc-effector function [KNOWN], in the late-stage commercial pipeline (PMID:41560619), and an NK review reframes ADCC/bispecific-engager platforms as a complementary effector axis to T cells (PMID:42193922, NPC-focused, review-level). So the lead is no longer just CD47–SIRPα plus two phase 1s: the Fc-effector arm has a molecule likely to reach registration, and correlatives (FcγR polymorphism, CD16 NK density, CD47/SIRPα IHC) apply across both. Confidence 0.35→0.42, still rationale-level because no efficacy readout is in the pack.\n\nQ5 is answered only in the negative sense that matters: the two pack items on the perioperative backbone are an editorial on concurrent vs sequential immunotherapy with chemoradiation (PMID:41815177) and a commentary on KEYNOTE-689/NIVOPOSTOP redefining resectable-disease standards (PMID:41352978) — no acquired-resistance biology. Practical consequence for L1 and L5: they must now be designed as add-ons to perioperative pembrolizumab, not R/M salvage. Q4 stays open — AZD6750, ABBV-711 and BI 765179 targets remain undisclosed in the registry text; the only new detail is that AZD6750 is partnered with rilvegostomig (PD-1/TIGIT bispecific [KNOWN]), which does not identify it.\n\nL2 and L4 unchanged; nothing in this pack touches PI3K/platinum or IRF9.","leadChanges":[{"id":"L6","title":"Pharmacological DR5 (TNFRSF10B) induction by DUB/proteasome inhibition to license TRAIL/DR5-agonist apoptosis in HNSCC","level":"LEAD","status":"NEW","confidence":0.38},{"id":"L3","title":"Macrophage/innate-checkpoint potentiation of cetuximab-mediated ADCP in R/M HNSCC","level":"LEAD","status":"STRENGTHENED","confidence":0.42}],"unverifiedCitations":0,"openQuestions":["Does DR5 induction by b-AP15/VLX1570 or by an approved proteasome inhibitor plus a multivalent DR5 agonist produce in vivo activity in HNSCC xenografts/PDX, and is that activity abolished in CASP8-mutant or cFLIP-high models?","Is 11q13 FADD/CCND1 amplification (frequent in HPV-negative HNSCC) a positive predictor of death-receptor-pathway sensitivity, and does CASP8 mutation status segregate HNSCC responders from non-responders in any published dataset?","Has petosemtamab reported response rate, duration and Fc-effector/FCGR3A correlatives in HNSCC, and is any innate-checkpoint or NK-engager combination with it in registries?","What are the disclosed targets of AZD6750 (NCT07115043), ABBV-711 (NCT07241039) and BI 765179 (NCT04958239), and do any sit on the myeloid/innate axis L3 depends on?","Are there mechanistic (not commentary) data on acquired resistance and relapse biology after perioperative pembrolizumab in HNSCC - JAK/B2M/MHC-I loss, IFN-signature exhaustion, myeloid re-infiltration - given that L1, L3, L5 and L6 all lay","Does any HNSCC or HPV+ model show that EP2/EP4 or COX-2 blockade increases cDC1 cross-presentation or vaccine-induced CD8 responses (L5), and does an E6*(aa49-110)-directed TCR-T/TCR-mimic programme exist anywhere (L1)?"],"nextQueries":["(\"head and neck squamous cell carcinoma\" OR HNSCC) AND (DR5 OR TRAIL OR TNFRSF10B) AND (agonist OR \"caspase-8\" OR CASP8 OR cFLIP OR FADD) AND (xenograft OR \"in vivo\" OR PDX) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(petosemtamab OR (EGFR AND LGR5 AND bispecific) OR \"ADCC-enhanced\") AND (\"head and neck\" OR HNSCC) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"head and neck\" OR HNSCC) AND (\"acquired resistance\" OR relapse) AND (pembrolizumab OR \"PD-1\") AND (B2M OR JAK1 OR JAK2 OR \"MHC class I\" OR \"interferon signature\" OR myeloid) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41560619","doi":"10.1080/19420862.2026.2614669","year":2026,"isNew":true,"title":"Antibodies to watch in 2026"},{"pmid":"41891958","doi":"10.3892/ijmm.2026.5807","year":2026,"isNew":true,"title":"USP10 deubiquitinase: Physiological function, diseases and therapeutic target (Review)"},{"pmid":"42074066","doi":"10.3390/ijms27083420","year":2026,"isNew":true,"title":"The Therapeutic Potential of Dihydroartemisinin in Cancer Treatment"},{"pmid":"42259777","doi":"10.1038/s41392-026-02714-4","year":2026,"isNew":true,"title":"Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases"},{"pmid":"42143016","doi":"10.1016/j.crmeth.2026.101422","year":2026,"isNew":true,"title":"Improved expansion of peripheral blood and iPSC-derived natural killer cells for clinical applications"},{"pmid":"42193922","doi":"10.3390/cells15100913","year":2026,"isNew":true,"title":"Natural Killer (NK) Cells in Tumor Immunity: Limitations and Therapeutic Potential with a Focus on Nasopharyngeal Carcinoma and Comparison with T-Cell-Based Therapies"},{"pmid":"42069980","doi":"10.1038/s41417-026-01038-3","year":2026,"isNew":true,"title":"b-AP15 enhances TRAIL-induced cell death in HNSCC via the induction of ROS/JNK/DR5 signalling"},{"pmid":"42123607","doi":"10.3390/ijms27094033","year":2026,"isNew":true,"title":"Sulforaphane-Activated Functional Nucleic Acids for Cancer Therapy: Mechanisms, Delivery Strategies, and Nanomedicine Advances"},{"pmid":"41815177","doi":"10.21037/tcr-2025-1-2616","year":2026,"isNew":true,"title":"Timing matters: concurrent &lt;i&gt;vs.&lt;/i&gt; sequential immunotherapy in combination with chemoradiation in head and neck cancer"},{"pmid":"41352978","doi":"10.1093/oncolo/oyaf404","year":2026,"isNew":true,"title":"Re-defining standards of care in resectable head and neck squamous cell carcinoma-lessons from KEYNOTE-689 and NIVOPOSTOP"}],"trialsShown":[{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT06508606","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"AK117 (Anti-CD47 mAb) Plus Cetuximab or AK104 (Anti-PD-1/CTLA-4 bsAb) as Second-Line Therapy in Recurrent/Metastatic Head and Neck Squamous "},{"nct":"NCT04958239","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Test BI 765179 Alone and in Combination With Ezabenlimab in Patients With Advanced Cancer (Solid Tumors) and BI 765179 in Combina"},{"nct":"NCT07241039","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Study to Assess the Adverse Events, Change in Disease Activity, and How Oral ABBV-711 Tablets Move Through the Body as a Monotherapy and i"},{"nct":"NCT02734537","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Radiation Therapy With or Without Cisplatin in Treating Patients With Stage III-IVA Squamous Cell Carcinoma of the Head and Neck Who Have Un"},{"nct":"NCT06995508","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Olanzapine for Managing Anorexia in Head and Neck Cancer Patients Undergoing Chemoradiation, MACRO Trial"},{"nct":"NCT05136196","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"BiCaZO: A Study Combining Two Immunotherapies (Cabozantinib and Nivolumab) to Treat Patients With Advanced Melanoma or Squamous Cell Head an"},{"nct":"NCT06806852","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Test Whether Treatment With BI 770371 in Combination With Pembrolizumab With or Without Cetuximab Helps People With Head and Neck"}],"usage":{"input":11384,"output":6546},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"head and neck squamous cell carcinoma\" OR HNSCC) AND (TNFRSF10B OR \"DR5\" OR \"TRAIL receptor\" OR ING1) AND (agonist OR apoptosis OR caspase-8) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"head and neck\" OR oropharyngeal) AND (\"neoadjuvant pembrolizumab\" OR KEYNOTE-689 OR \"resistance to PD-1\") AND (biomarker OR relapse OR \"acquired resistance\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41560619","PMID:41891958","PMID:42074066","PMID:42259777","PMID:42143016","PMID:42193922","PMID:42069980","PMID:42123607","PMID:41815177","PMID:41352978","NCT07115043","NCT06508606","NCT04958239","NCT07241039","NCT02734537","NCT06995508","NCT05136196","NCT06806852"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787178853854","cycle":146,"visit":3,"ts":"2026-08-19T22:34:13.854Z","cancer":{"key":"mesothelioma","name":"mesothelioma","mondo":{"id":"MONDO:0005065","name":"mesothelioma"}},"control":false,"modelLabel":"SCIENCE","summary":"TEAD palmitoylation inhibition now has independent mesothelioma efficacy data (AZ'4331) and a defined adaptive resistance route (promoter reinforcement), while VSIG4/CRIg+ cavity-resident macrophages plus site-dependent ICT failure are independently replicated — making intracavitary CSF1R blockade +","confidence":0.55,"notebook":"Fresh pack finally breaks the single-source problem, and it does so on both flanks — but not on the join between them.\n\nPharmacology (L1): AZ'4331, a pan-TEAD auto-palmitoylation inhibitor, blocks TEAD1–4 palmitoylation, reduces YAP–TEAD binding and TEAD transcription in NCI-H226 (Hippo-altered mesothelioma [KNOWN NF2-null]) and gives monotherapy xenograft activity in mesothelioma (PMID:42525965); a medicinal-chemistry review confirms three mature modalities — PPI disruptors, palmitoylation-pocket ligands, TEAD PROTACs — with mesothelioma named as an indication (PMID:42603497). This is independent, non-42208538 support for tumour-cell-intrinsic TEAD dependency in mesothelioma, so L1 moves to CANDIDATE (0.60). Caveat stated plainly: nothing in the pack tests whether TEAD inhibition remodels the cavity myeloid niche, so the CAR-T-resistance-reversal half of L1 remains single-source. Still no first-in-human TEAD trial in the pack (Q4 unanswered).\n\nNiche (L3): VSIG4 is CRIg [KNOWN]. Human peritoneal single-cell data define abundant C1Q+VSIG4+ and SPP1+VSIG4+ resident macrophages present even at homeostasis, losing antigen-presentation genes and gaining IL10/VEGF in tumour, and intraperitoneal anti-CSF1R + anti-PD1 reduces burden and extends survival (PMID:40246872). Independently, identical mesothelioma cell lines are ICT-responsive subcutaneously and refractory intraperitoneally, with low IFN/TNF/STAT tone (PMID:41735480) — replicating the site-dependence claim in mesothelioma from a second lab. L3 → CANDIDATE (0.50), and the actionable node shifts from unidentified chemokine/RAR to CSF1R, where repurposable agents exist [KNOWN]. Q3 partially answered; RAR isoform and chemokine still unknown.\n\nNew (L5): mesothelioma cells acquire pan-TEAD-inhibitor resistance via \"promoter reinforcement\" — enhancer–promoter contacts lost, promoter activity and target expression restored by promoter-biased resistance TFs (PMID:42410069). Resistance is therefore transcriptional-adaptive, not necessarily palmitoylation-site mutational; this predicts up-front combination with promoter/pause-release machinery (CDK7, CDK9, BET) or TEAD degraders rather than dose escalation [SPECULATIVE beyond the abstract's own \"promoter-associated vulnerabilities\"].\n\nNotebook entries: peritoneal mesothelioma is a distinct immunologic compartment, not a variant of pleural — do not pool them in ICT trials (PMID:41735480, NCT05001880). Post-ICI relapse can be driven by 9p24 amplification plus ARG1/PLA2G7-high TAMs and LAG3+ exhausted T cells in a single lesion (PMID:41986072, n=1) — supports collecting myeloid endpoints in NCT07234058. Broader resistance architecture reviewed in PMID:42040767, PMID:41514125. L2 untouched: third visit without primary BAP1/EZH2 synthetic-lethality data.\n\nL4 gains a mandate: stratify correlative sampling by cavity (pleural vs peritoneal) and score VSIG4/CRIg, SPP1, C1Q, ARG1 alongside NF2 copy number and BAP1/B2M IHC.","leadChanges":[{"id":"L1","title":"TEAD inhibition to reverse NF2-loss-driven resistance to mesothelin CAR T cells in pleural mesothelioma","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.6},{"id":"L3","title":"CRIg+ macrophage / retinoic-acid niche as a cavity-specific immunosuppression target","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.5},{"id":"L5","title":"Pre-empt promoter-reinforcement resistance to TEAD inhibitors with transcriptional-machinery combinations or TEAD degradation","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L4","title":"Human correlative platform in BAP1 germline carriers to test the NF2/myeloid resistance model before building drug combinations on it","level":"LEAD","status":"STRENGTHENED","confidence":0.5}],"unverifiedCitations":0,"openQuestions":["Does TEAD palmitoylation inhibition (AZ'4331-class, VT3989, IK-930) change the VSIG4/CRIg+ cavity macrophage compartment in vivo, or is its mesothelioma activity purely tumour-cell-intrinsic?","Is any TEAD palmitoylation-site inhibitor in first-in-human trials in NF2-altered disease, with reported dose, schedule and renal safety signal?","Do pleural resident macrophages share the C1Q+VSIG4+/SPP1+VSIG4+ ontogeny and CSF1R dependence demonstrated for peritoneal resident macrophages, and does intracavitary CSF1R blockade deplete or merely reprogramme them?","In human pleural mesothelioma cohorts, are NF2 copy-number loss and BAP1 loss co-occurring or mutually exclusive, and does BAP1 status track with MHC-I/B2M loss?","Which promoter-biased transcription factors mediate promoter reinforcement after TEAD inhibition in mesothelioma, and are they druggable (CDK7/9, BET, or the TF itself)?","Does the LAG-3 trial NCT07234058 collect myeloid endpoints (ARG1, VSIG4, SPP1) that could discriminate T-cell-intrinsic from macrophage-mediated ICI resistance, as the sarcomatoid relapse case report implies is needed?"],"nextQueries":["(\"VT3989\" OR \"IK-930\" OR \"TEAD inhibitor\") AND (\"phase 1\" OR \"first-in-human\" OR \"clinical trial\") AND (\"NF2\" OR \"mesothelioma\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"VSIG4\" OR \"CRIg\") AND (\"pleural\" OR \"pleura\" OR \"cavity macrophage\" OR \"resident macrophage\") AND (\"CSF1R\" OR \"depletion\" OR \"immunotherapy\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"mesothelioma\" AND (\"NF2\" AND \"BAP1\") AND (\"co-occurrence\" OR \"mutually exclusive\" OR \"copy number\" OR \"HLA\" OR \"B2M\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"papersShown":[{"pmid":"40246872","doi":"10.1038/s41467-025-58999-6","year":2025,"isNew":true,"title":"Peritoneal resident macrophages constitute an immunosuppressive environment in peritoneal metastasized colorectal cancer"},{"pmid":"41735480","doi":"10.1038/s41598-026-41431-4","year":2026,"isNew":true,"title":"Mesothelioma location influences the tumour microenvironment and immune checkpoint therapy response in preclinical models"},{"pmid":"41514125","doi":"10.1038/s44321-025-00363-8","year":2026,"isNew":true,"title":"Pathobiology and clinical significance of malignant pleural effusions"},{"pmid":"42603497","doi":"10.1016/j.ejmech.2026.119217","year":2026,"isNew":true,"title":"Recent advances in TEAD modulators: A medicinal chemistry perspective"},{"pmid":"42525965","doi":"10.1158/1535-7163.mct-25-1267","year":2026,"isNew":true,"title":"AZ'4331 is a novel pan-TEAD auto-palmitoylation inhibitor for the treatment of Hippo pathway-altered cancers"},{"pmid":"42410069","doi":"10.1038/s41594-026-01829-0","year":2026,"isNew":true,"title":"Promoter reinforcement supports transcriptional resilience in drug-resistant cancer"},{"pmid":"42138205","doi":"10.3892/ijmm.2026.5853","year":2026,"isNew":true,"title":"Rab27: Molecular switch of tumor exosome secretion (Review)"},{"pmid":"42287329","doi":"10.1007/s10555-026-10349-8","year":2026,"isNew":true,"title":"The Hippo signaling pathway in pediatric brain tumors: molecular mechanisms and therapeutic opportunities"},{"pmid":"41986072","doi":"10.1136/jitc-2025-014516","year":2026,"isNew":true,"title":"Regional immunosuppression and associated systemic markers in focally relapsed sarcomatoid mesothelioma: case report"},{"pmid":"42040767","doi":"10.20517/cdr.2025.215","year":2026,"isNew":true,"title":"Immunotherapy resistance and strategies in malignant pleural mesothelioma"}],"trialsShown":[{"nct":"NCT04104776","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas"},{"nct":"NCT00242723","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Evaluation of Cell Changes in Blood and Tissue in Cancers of the Lung, Esophagus and Lung Lining"},{"nct":"NCT03830229","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Long Term Follow-Up of Patients With Mesothelioma and Individuals With Germline Mutations in BAP1"},{"nct":"NCT05001880","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Chemotherapy With or Without Immunotherapy for Peritoneal Mesothelioma"},{"nct":"NCT04431024","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Prospective Evaluation of High Resolution Dual Energy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and Minimally Invasive Su"},{"nct":"NCT00715611","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Pleurectomy/Decortication (Neo) Adjuvant Chemotherapy and Intensity Modulated Radiation Therapy to the Pleura in Patients With Locally Advan"},{"nct":"NCT07234058","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Trial Assessing Fianlimab Plus Cemiplimab Plus Chemotherapy or Cemiplimab Plus Chemotherapy in Patients With Pleural Mesothelioma"},{"nct":"NCT06885697","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Anti-Mesothelin TNaive/SCM hYP218 (TNhYP218) CAR T Cells in Participants With Mesothelin-Expressing Solid Tumors Including Mesothelioma"}],"usage":{"input":11376,"output":7807},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"mesothelioma\" OR \"NF2-mutant\") AND (\"TEAD inhibitor\" OR \"VT3989\" OR \"IK-930\" OR \"palmitoylation\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"mesothelioma\" AND (\"macrophage\" OR \"myeloid\" OR \"CRIg\" OR \"VSIG4\") AND (\"pleural\" OR \"cavity\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:40246872","PMID:41735480","PMID:41514125","PMID:42603497","PMID:42525965","PMID:42410069","PMID:42138205","PMID:42287329","PMID:41986072","PMID:42040767","NCT04104776","NCT00242723","NCT03830229","NCT05001880","NCT04431024","NCT00715611","NCT07234058","NCT06885697"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787178636169","cycle":145,"visit":3,"ts":"2026-08-19T22:30:36.169Z","cancer":{"key":"hepatocellular carcinoma","name":"hepatocellular carcinoma","mondo":{"id":"MONDO:0007256","name":"hepatocellular carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"AXIN1-mutant HCC is a low-Wnt/YAP-TAZ-high subtype distinct from CTNNB1ex3 tumours, so test clinical-stage TEAD palmitoylation inhibitors in AXIN1-mutant organoids/PDX while using CTNNB1ex3 status (immune-cold) as a stratification covariate in IO+VEGF and PD-L1xVEGF bispecific trials.","confidence":0.44,"notebook":"Visit 3 pack was Wnt/FLC-directed and it delivered on open question 3, though not the way L4 assumed. Four independent new datasets now split \"Wnt-activated HCC\" into two therapeutically distinct entities. AXIN1-mutant tumours engineered into liver-derived organoids show *low* Wnt/β-catenin output — including alternative translation of N-terminally truncated AXIN1 retaining partial suppressor activity — yet grow Wnt/R-spondin-independently and carry inversely correlated, elevated YAP/TAZ activity (PMID:41550750). Pathology corroborates: only 11/18 AXIN1 tumours showed Wnt activation and it was weak, versus 15/17 CTNNB1, and tertiary lymphoid structures were rare outside CTNNB1-plus-second-Wnt-hit cases (PMID:41804058). Multi-omic classification of 529+807 HCC keeps AXIN1/IRF2 (11%) as a separate subtype from CTNNB1ex3/APC (25%) (PMID:42156413) — although its transcriptomic score reports AXIN1 mutation *increasing* β-catenin activity, directly contradicting PMID:41550750/41804058; that discordance (score-based versus IHC/organoid readout) is unresolved and decides whether Wnt-directed agents have any place in AXIN1 disease. [INFERRED] The actionable consequence is a YAP/TAZ-TEAD dependency in AXIN1-mutant HCC, testable with clinical-stage TEAD palmitoylation-site inhibitors [KNOWN: VT3989, IK-930, VT103]. New lead L8. [SPECULATIVE] TEAD requires S-palmitoylation for function, so ABHD17C (L1) and TEAD lipidation may intersect — cheap to test in the acyl-RAC experiment already planned for L1.\n\nSeparately, two reviews consolidate the Wnt-high/immune-cold axis: CTNNB1 or AXIN1/APC/ZNRF3 alterations in up to 50% of HCC drive CD8 exclusion, DC repression, MDSC recruitment, plus sorafenib/lenvatinib resistance via ferroptosis evasion and stemness (PMID:42237887, PMID:41142820). Reviews are not primary evidence, but combined with CTNNB1 at 20% of refractory HCC in a prospective multicentre sequencing initiative where 59% of HCC had an actionable alteration yet only 3/31 matched treatments were ESCAT I–II (PMID:41865801), the practical deliverable is exclusion/stratification, not a new drug: L9 opens as a Wnt-status stratification hypothesis for IO-containing first line, and L4's VETC covariate must now be crossed with CTNNB1ex3 status (a cold, VEGF-independent phenotype would confound VETC enrichment).\n\nFLC remains unserved: the pack's FLC material is a management review restating DNAJB1-PRKACA (PMID:42595050) plus two case reports; no PKA-catalytic, Aurora or mTOR pharmacology. Question 2 stays open with a broader query. PMID:42352927 reports HDAC6 *down* in HCC with worse survival — recorded as a discouraging signal against HDAC6 inhibition here (bioinformatic only). L7 (plectin/plecstatin) is retired per its own probation clause: no independent confirmation, single line, and normal-tissue essentiality unaddressed.","leadChanges":[{"id":"L8","title":"AXIN1-mutant HCC as a YAP/TAZ-TEAD-dependent subtype for TEAD palmitoylation inhibitors","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L9","title":"CTNNB1ex3/Wnt-high status as an exclusion-stratification biomarker for IO-containing first-line HCC","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L4","title":"PD-L1xVEGF bispecific (pumitamig) +/- ipilimumab as first-line HCC, priced against existing IO+VEGF","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.44},{"id":"L7","title":"Plectin cytolinker as the obligate effector of plecstatin anti-invasive activity in mesenchymal HCC","level":"LEAD","status":"RETIRED","confidence":0.08}],"unverifiedCitations":0,"openQuestions":["Do AXIN1-mutant HCC organoids/lines show selective sensitivity to TEAD palmitoylation-site inhibitors (VT3989/IK-930 class) versus CTNNB1ex3-mutant isogenic controls, and is the effect YAP/TAZ-dependent?","Which readout is right for AXIN1 tumours - increased beta-catenin activity by transcriptomic score (PMID:42156413) or weak/absent activation by IHC and organoid reporter (PMID:41804058, PMID:41550750) - and does that decide whether beta-cat","Does CTNNB1ex3/Wnt-high genotype abolish the complete-VETC predictive effect on atezolizumab-bevacizumab outcome, i.e. is VETC an independent biomarker or a proxy for Wnt-wild-type immune-hot biology?","Is there any direct pharmacology (PKA catalytic-site, Aurora, mTOR, or DNAJB1-PRKACA degrader) with preclinical data in fibrolamellar HCC, given the pack yielded only reviews and case reports?","Is TEAD S-palmitoylation among the ABHD17C substrates in HCC, which would unify L1 and L8 into a single lipidation-dependent resistance node?","In the 2025 French genomic initiative, did any HCC patient receiving an ESCAT III/IV matched therapy derive durable benefit, and which alteration classes accounted for it?"],"nextQueries":["(\"hepatocellular carcinoma\" OR \"liver cancer\") AND (TEAD OR \"YAP\" OR \"TAZ\" OR \"VT3989\" OR \"IK-930\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"DNAJB1-PRKACA\" OR \"fibrolamellar\") AND (inhibitor OR degrader OR kinase OR preclinical OR xenograft) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"hepatocellular carcinoma\") AND (\"S-palmitoylation\" OR \"depalmitoylase\" OR ABHD17 OR ZDHHC) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41865801","doi":"10.1016/j.jhep.2026.03.019","year":2026,"isNew":true,"title":"Molecularly guided therapies for advanced primary liver cancers refractory to systemic treatment: Results from the 2025 French genomic medicine initiative"},{"pmid":"41142820","doi":"10.3389/fimmu.2025.1691297","year":2025,"isNew":true,"title":"Role of the Wnt/β-catenin signaling pathway in the development of HCC"},{"pmid":"41550750","doi":"10.1016/j.isci.2025.114501","year":2026,"isNew":true,"title":"Hepatocellular carcinoma-linked &lt;i&gt;AXIN1&lt;/i&gt; mutations drive low Wnt/β-catenin activity enabling niche-independent growth and YAP/TAZ signaling"},{"pmid":"42595050","doi":"10.1016/j.jhepr.2026.101991","year":2026,"isNew":true,"title":"Management of rare primary liver cancers: combined hepato-cholangiocarcinoma and fibrolamellar hepatocellular carcinoma"},{"pmid":"42063471","doi":"10.1016/j.radcr.2026.03.040","year":2026,"isNew":true,"title":"Calcified nest in the liver: Case report of CNSET"},{"pmid":"42281859","doi":"10.5500/wjt.v16.i2.117975","year":2026,"isNew":true,"title":"Bronchobiliary fistula in fibrolamellar hepatocellular carcinoma with anesthetic challenges during living donor liver transplantation: A case report"},{"pmid":"41804058","doi":"10.1097/pas.0000000000002528","year":2026,"isNew":true,"title":"AXIN1 Mutated Hepatocellular Carcinoma"},{"pmid":"42237887","doi":"10.1093/carcin/bgag040","year":2026,"isNew":true,"title":"Wnt/β-catenin signaling in hepatocellular carcinoma: a key player in resistance to targeted and immunotherapies"},{"pmid":"42156413","doi":"10.1038/s41467-026-73212-y","year":2026,"isNew":true,"title":"Integrated genomic analyses identify oncogenic pathway interplay in hepatocarcinogenesis defining specific molecular subtypes"},{"pmid":"42352927","doi":"10.3390/ijms27125201","year":2026,"isNew":true,"title":"Integrative Bioinformatic Characterization of the HDAC6-Driven Cytoskeleton-Wnt Signaling Interface in Hepatocellular Carcinoma: Implications for Immune Modulation and Therapeutic "}],"trialsShown":[{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT06084884","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Phase I/II Study to Evaluate AZD5851 in GPC3+ Advanced/Recurrent Hepatocellular Carcinoma"},{"nct":"NCT06979219","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Streamlining Radioembolization for Small HCC"},{"nct":"NCT06764316","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A First-in-human Study to Learn About the Safety of BAY 3547926 and How Well it Works in Participants With Advanced Liver Cancer"},{"nct":"NCT07727759","phase":"n/a","status":"RECRUITING","isNew":false,"title":"CT Volumetry and Hepatic Vascular Deformation Mapping to Predict Post-Hepatectomy Liver Failure"},{"nct":"NCT07291076","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Evaluate the Safety and Tolerability of Pumitamig Alone or In Combination With Ipilimumab in Participants With First-Line Advance"},{"nct":"NCT07620574","phase":"phase 3","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Long-Term Extension Study for Participants Previously Enrolled in an Exelixis-Sponsored Study"},{"nct":"NCT06944483","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Same-day Radioembolization for Large HCC"}],"usage":{"input":13949,"output":7743},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"fibrolamellar\" OR \"DNAJB1-PRKACA\") AND (PRKACA OR \"protein kinase A\" OR therapy) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"hepatocellular carcinoma\") AND (CTNNB1 OR AXIN1) AND (\"immune exclusion\" OR \"beta-catenin\" OR TEAD OR porcupine) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41865801","PMID:41142820","PMID:41550750","PMID:42595050","PMID:42063471","PMID:42281859","PMID:41804058","PMID:42237887","PMID:42156413","PMID:42352927","NCT07636785","NCT06084884","NCT06979219","NCT06764316","NCT07727759","NCT07291076","NCT07620574","NCT06944483"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787178411572","cycle":144,"visit":14,"ts":"2026-08-19T22:26:51.572Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Retire the TRIM28/SETDB1 and STAT5A persistence-node leads on a third empty targeted pass, and elevate risk-stratified de-escalation on the first agent-specific dose-comparative cohort (dasatinib 50 vs 100 mg: equal molecular depth, pleural effusion 2.2% vs 25.2%), while requiring TDM-guided dosing ","confidence":0.55,"notebook":"Visit 14, control cadence. The desk's convergence on the known mechanism is intact and unchanged: BCR::ABL1 [SOMATIC] fusion as the maintenance driver, ATP-site TKIs plus the allosteric myristoyl-pocket agent asciminib as the answer (L8, DOSSIER 0.8). The live programme is therefore correctly aimed at the residual problems — persistence, dosing window, TFR — not at target discovery.\n\nTwo prespecified kill conditions fired. The GRN query written to test TRIM28/SETDB1 regulon activity in CML single-cell data returned, for the third consecutive pass, nothing on point: a dCas9-APEX2 locus-proteomics method paper in HEK293 (PMID:42025763), an AML CAR-T review (PMID:41800605), a senescence review (PMID:41844438), and a STAT-family multi-omic survey confined to solid tumours whose only CML touchpoint is STAT1 ChIP-seq in K562 (PMID:42195004). L6 (TRIM28/SETDB1) is retired exactly as specified — the chromatin-state model of persistence (PMID:41952641) survives as a framework, but no dataset places TRIM28/SETDB1 in the persistent LSC state, so it should not be re-proposed without primary CML LSC data. L13 (STAT5A) is also retired: PMID:42195004 confirms STAT5 as a conserved master regulator across tumours but supplies no CML replication, no primary-cell data and no isoform-selective chemistry, leaving the original single-line K562 report unreplicated across four visits.\n\nThe dosing arm gained real, if imperfect, evidence. A 50 mg versus 100 mg frontline dasatinib observational cohort found equivalent 12-month CCyR/MMR/MR4/MR4.5 and 2-year EFS with pleural effusion at 2.2% versus 25.2%, and among 37 patients reduced from 100→50 mg, 35/37 maintained or deepened response with 13 MMR patients reaching DMR (PMID:41668074). This is the strongest de-escalation dataset the desk holds for a specific ATP-site agent, and it corroborates L7 on a fifth evidence-bearing visit; but it is non-randomised with unequal follow-up (30.3 vs 56.1 months) and 94.6% versus 61.3% sustained first-line therapy, so immortal-time and selection bias are unexcluded and MR4.5 is numerically lower at 50 mg. L7 rises modestly; the missing prospective randomised trial remains the tier-limiting gap. A QoL review adds the endpoint argument — fatigue dominates residual morbidity and dose reduction is where PRO gains are plausible (PMID:41976356).\n\nConsequence for L9: a flat halving achieved equivalent MMR without any TDM, so concentration-guided dosing must now beat a fixed sub-label dose, not just label dose. Weakened. L15 (CD26) untested this visit — no CD26-directed query ran; one final targeted pass before the clock expires.","leadChanges":[{"id":"L6","title":"TIF1beta/TRIM28-SETDB1 chromatin node as a BCR-ABL1-kinase-independent LSC-state dependency","level":"LEAD","status":"RETIRED","confidence":0.08},{"id":"L13","title":"STAT5A as a druggable transcriptional node of BCR-ABL1-kinase-independent TKI resistance","level":"LEAD","status":"RETIRED","confidence":0.1},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"DOSSIER","status":"STRENGTHENED","confidence":0.76},{"id":"L9","title":"Concentration-floor (TDM-anchored) de-escalation: reduce exposure to a measured pharmacokinetic threshold, not to a fraction of label dose","level":"CANDIDATE","status":"WEAKENED","confidence":0.55},{"id":"L15","title":"CD26 (DPP4) as a CML-restricted surface antigen for antibody- or cell-mediated eradication of the persistent BCR::ABL1+ LSC","level":"LEAD","status":"WEAKENED","confidence":0.18}],"unverifiedCitations":0,"openQuestions":["Does any prospective randomised CML trial (or a matched-exposure re-analysis of PMID:41668074) test dose de-escalation with MR4.0/MR4.5, TFR and PRO co-primary endpoints, and does the MR4.5 gap at 50 mg dasatinib persist after adjustment fo","Does TDM-guided dosing outperform a flat halved dose for DMR attainment in any agent, once adherence/relative dose intensity is deconfounded and Cmax_2h is compared with trough?","Has any CD26/DPP4-directed depleting construct been tested against primary CML LSCs, with measured surface density versus activated normal T cells and same-donor CD34+ HSPCs?","What is the mutation-resolved kinase-domain spectrum at asciminib failure beyond A337V/P465S in the Japanese postmarketing cohort, and which ATP-site agent rescues each?","Which transcription factors or chromatin regulators are actually nominated by published CML single-cell GRN inference in the persistent chronic-phase LSC state (agnostic search, no prior candidate), and is any of them accompanied by primary","Has the IL-6/MCP-1 plus CD8dim/NK clonality discontinuation decision tree been replicated in any independent DMR cohort adjusted for TKI duration and prior interferon?"],"nextQueries":["(\"chronic myeloid leukemia\" OR CML) AND (CD26 OR DPP4) AND (CAR OR \"chimeric antigen\" OR antibody OR immunotoxin OR \"antibody-drug conjugate\") AND (\"leukemic stem cell\" OR CD34) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"chronic myeloid leukemia\") AND (\"dose reduction\" OR de-escalation OR \"half dose\" OR \"low dose\") AND (randomized OR randomised OR \"phase 3\" OR \"phase III\" OR prospective) AND (\"treatment-free remission\" OR MR4 OR \"quali","(\"chronic myeloid leukemia\") AND (asciminib) AND (\"kinase domain\" OR mutation OR resistance) AND (sequencing OR NGS OR spectrum) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"42025763","doi":"10.1016/j.mcpro.2026.101570","year":2026,"isNew":true,"title":"In Depth Characterization of the Promoter Proximal Proteome of Single Copy Locus FOXP2"},{"pmid":"41800605","doi":"10.1080/07853890.2026.2640457","year":2026,"isNew":true,"title":"Preclinical advances and mechanistic insights of CAR-T therapy for acute myeloid leukemia: from target iteration to microenvironment regulation"},{"pmid":"42195004","doi":"10.3390/genes17050547","year":2026,"isNew":true,"title":"Integrated Evolutionary and Multi-Omic Analysis of STAT Family Activation Across Solid Tumors"},{"pmid":"41844438","doi":"10.1016/j.tranon.2026.102729","year":2026,"isNew":true,"title":"Exploiting cellular senescence in hematologic malignancies"},{"pmid":"41668074","doi":"10.1186/s12885-026-15719-7","year":2026,"isNew":true,"title":"Efficacy and safety of 50 mg versus 100 mg daily frontline dasatinib therapy in chronic-phase chronic myeloid leukemia: a non-controlled, observational dose-comparative cohort stud"},{"pmid":null,"doi":null,"year":2026,"isNew":true,"title":"Four Decades of Molecular Innovation in Chronic Myeloid Leukemia: From Antisense Targeting to Treatment-Free Remission"},{"pmid":"41976356","doi":"10.3390/cancers18071133","year":2026,"isNew":true,"title":"A Current Overview of Quality-of-Life Research in Chronic Myeloid Leukemia (CML)"},{"pmid":"40647447","doi":"10.3390/cancers17132148","year":2025,"isNew":false,"title":"Real-World Evidence of Treatment-Free Remission Strategies and Outcomes in Chronic Myeloid Leukemia"},{"pmid":"42312095","doi":"10.1016/j.coemr.2026.100615","year":2026,"isNew":false,"title":"Remodeling the marrow fat niche: BMAT in cancer bone metastases and hematological malignancies"},{"pmid":"41952641","doi":"10.3324/haematol.2025.287767","year":2026,"isNew":false,"title":"Understanding drug resistance in chronic myeloid leukemia through the lens of leukemic stem cell states: insights from single-cell analyses"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":17462,"output":7310},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"chronic myeloid leukemia\" OR CML) AND (\"single-cell\" OR scRNA-seq OR multiome OR \"regulatory network\" OR SCENIC) AND (TRIM28 OR KAP1 OR SETDB1 OR STAT5A OR \"leukemic stem cell\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"chronic myeloid leukemia\") AND (\"dose reduction\" OR de-escalation OR \"low dose\" OR \"optimal biologic dose\") AND (prospective OR randomized OR trial) AND (\"molecular response\" OR MR4 OR \"treatment-free remission\") AND S"],"evidenceIds":["PMID:42025763","PMID:41800605","PMID:42195004","PMID:41844438","PMID:41668074","untracked","PMID:41976356","PMID:40647447","PMID:42312095","PMID:41952641","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787178192844","cycle":143,"visit":3,"ts":"2026-08-19T22:23:12.844Z","cancer":{"key":"gastric cancer","name":"gastric cancer","mondo":{"id":"MONDO:0001056","name":"gastric cancer"}},"control":false,"modelLabel":"SCIENCE","summary":"Promote the gastric lipid-metabolism/immune-escape lead to CANDIDATE on a second independent gastric review (PMID:41158287), retire the G3BP1–14-3-3zeta–Bax lead for lack of gastric perturbation data, and test ITGA5/FAK as an alternative RPRD-family effector in RPRD1B-high gastric models.","confidence":0.42,"notebook":"Visit 3 evidence is almost entirely review-grade, with one informative primary paper that is not gastric.\n\nThe targeted RPRD1B/CREPT/TOPBP1 gastric query again returned no primary gastric corroboration — third consecutive miss. What it did return is RPRD1A in HCC (PMID:42171939): RPRD1A competes with RPAP2 for RNA Pol II, derepressing ITGA5 via c-JUN and driving lenvatinib resistance, reversible with volociximab or defactinib. That validates the *class* logic behind L1 (RPRD-family proteins set drug resistance through Pol II-associated transcriptional derepression) but not the gastric RPRD1B→TOPBP1→ATR chain specifically, and it names a different effector. L1 therefore stays weakened (0.45→0.40) while gaining a cheap orthogonal test: assay ITGA5/FAK in RPRD1B-high gastric lines and PDX, since a FAK-inhibitor partner would be a faster repurposing route than ATRi if the effector is shared [INFERRED].\n\nThe lipid axis moved. P7 (PMID:41158287) is a second, independent gastric-specific review of lipid metabolic reprogramming driving immune escape and chemoresistance, backed by TME (PMID:41630007) and FAO/TME syntheses (PMID:41640669, PMID:42164655). That is enough new independent literature to move L6 (lipid-metabolic reprogramming of the gastric TIME) to CANDIDATE, with the explicit caveat that no gastric perturbation experiment — CD36 blockade or CPT1A inhibition plus PD-1 in an MSS model — exists anywhere in this pack; the promotion reflects convergent review consensus, not efficacy data. Conversely, answering my own open question 4: the SNHG15–miR-451a–CAV1 chain remains unreplicated after two visits, so L2 is formally restructured to a CPT1A/FAO-dependency claim with CAV1 demoted to correlate (0.42→0.40).\n\nL3 (G3BP1–14-3-3ζ–Bax) is retired as pre-committed: two visits, no gastric primary perturbation data, ubiquitous stress-adaptor targets, no assay-ready window. The desk should not re-propose it without co-IP/PLA data from gastric material.\n\nOne new lead: gastric-specific m6A review (PMID:41832397) links H. pylori and transcription factors to m6A-regulator dysregulation, chemo/radio/ICB resistance and immune evasion — a plausible METTL3-inhibitor (STM2457-class [KNOWN]) stratum, entered low and explicitly connected to L4's H. pylori cascade.\n\nNext visit must prioritise primary data, not reviews: gastric CPT1A/CD36 perturbation experiments, METTL3-inhibitor gastric preclinical work, and any RPRD1B gastric functional paper.","leadChanges":[{"id":"L1","title":"RPRD1B(CREPT)-TOPBP1 axis as the druggable node of 5-FU resistance in gastric cancer","level":"LEAD","status":"WEAKENED","confidence":0.4},{"id":"L2","title":"CAV1-driven fatty-acid beta-oxidation as a metabolic vulnerability in oxaliplatin-resistant gastric cancer","level":"LEAD","status":"WEAKENED","confidence":0.4},{"id":"L3","title":"YWHAZ(14-3-3zeta)-G3BP1 stress-granule module sequesters Bax and sets apoptotic resistance in gastric cancer","level":"LEAD","status":"RETIRED","confidence":0.12},{"id":"L6","title":"Lipid-metabolic reprogramming of the gastric immune microenvironment to convert MSS/immune-cold GC to ICB-responsive","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.45},{"id":"L8","title":"m6A regulators (METTL3/FTO/YTHDF axis) as H. pylori-linked drivers of chemo- and immunotherapy resistance in gastric cancer","level":"LEAD","status":"NEW","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["Do RPRD1B-high gastric lines/PDX show ITGA5-FAK activation (pFAK, ITGA5 IHC) and does defactinib sensitise them to fluoropyrimidine, or is the TOPBP1/ATR effector gastric-specific?","Is there ANY primary gastric perturbation experiment (in vivo) of CPT1A, CD36 or FASN inhibition combined with PD-1 blockade, and does the benefit require myeloid rather than tumour-cell FAO?","Which single m6A regulator is rate-limiting in MSS gastric models, and does METTL3 catalytic inhibition (STM2457-class) synergise with platinum/fluoropyrimidine or PD-1 in gastric preclinical data?","In gastric cohorts of NCT04550494 and NCT04644068, do ATM protein-null (IHC) and CDK12-altered tumours respond while MUTYH carriers (pre-registered null) do not?","What is the prevalence and co-mutation structure (PIK3CA, ERBB2, CDH1/CTNNA1) of KRAS G12D in gastric adenocarcinoma, and do G12D gastric PDX exist for ARV-806-class degrader testing (NCT07023731)?","Does SIRT1 loss along the H. pylori cascade intersect the m6A programme (H. pylori-induced METTL3), giving a single chemoprevention node in intestinal metaplasia?"],"nextQueries":["(\"gastric cancer\" OR \"gastric adenocarcinoma\") AND (CPT1A OR CD36 OR etomoxir OR FASN) AND (\"PD-1\" OR \"anti-PD-1\" OR \"immune checkpoint\") AND (mice OR xenograft OR organoid OR knockout) AND SRC:MED AND PUB_YEAR:[2023 TO ","(\"gastric cancer\" OR \"gastric adenocarcinoma\") AND (METTL3 OR STM2457 OR ALKBH5 OR YTHDF1) AND (chemoresistance OR cisplatin OR 5-fluorouracil OR immunotherapy) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"gastric cancer\" OR \"gastric adenocarcinoma\" OR \"hepatocellular\") AND (RPRD1B OR CREPT OR RPRD1A) AND (ITGA5 OR FAK OR defactinib OR TOPBP1) AND SRC:MED"],"papersShown":[{"pmid":"41630007","doi":"10.1186/s12943-026-02572-2","year":2026,"isNew":true,"title":"Tumor microenvironment dynamics in gastric cancer pathogenesis and therapeutic resistance"},{"pmid":"41278473","doi":"10.3389/fcimb.2025.1706040","year":2025,"isNew":true,"title":"Microbial metabolites in tumor metabolic reprogramming and immunotherapy: new insights"},{"pmid":"42171939","doi":"10.1186/s43556-026-00459-8","year":2026,"isNew":true,"title":"RPRD1A drives lenvatinib resistance in hepatocellular carcinoma via the ITGA5-FAK signaling axis"},{"pmid":"41832397","doi":"10.1007/s10565-026-10141-y","year":2026,"isNew":true,"title":"RNA m&lt;sup&gt;6&lt;/sup&gt;A modification is a driver and therapeutic target in gastric cancer"},{"pmid":"42245480","doi":"10.3389/fcell.2026.1809222","year":2026,"isNew":true,"title":"Ubiquitination mediated by RING-type E3 ligases in the progression of digestive system tumors: mechanistic insights and potential therapeutic strategies"},{"pmid":"42211570","doi":"10.3389/fcell.2026.1811421","year":2026,"isNew":true,"title":"p300: expanding beyond acetylation to mastermind lactylation-dependent tumorigenesis"},{"pmid":"41158287","doi":"10.1515/mr-2025-0035","year":2025,"isNew":true,"title":"Recent advances in understanding the relationship between lipid metabolism and immune escape in the tumor microenvironment of gastric cancer"},{"pmid":"42164655","doi":"10.1002/mco2.70749","year":2026,"isNew":true,"title":"Fatty Acid Metabolism in Health and Cancer: From Fundamental Mechanisms to Therapeutic Application"},{"pmid":"41640669","doi":"10.1016/j.gendis.2025.101772","year":2026,"isNew":true,"title":"Fatty acid metabolic reprogramming in the tumor microenvironment: Unraveling mechanisms and therapeutic prospects"},{"pmid":"41098086","doi":"10.3724/abbs.2025166","year":2025,"isNew":true,"title":"The role of lipid metabolic interactions in reshaping the tumor microenvironment"}],"trialsShown":[{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT07646574","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Non-surgical Management After NIT for dMMR/MSI-H GC"},{"nct":"NCT06203600","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"Adding Nivolumab to Usual Treatment for People With Advanced Stomach or Esophageal Cancer, PARAMUNE Trial"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04550494","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations"},{"nct":"NCT07001748","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"Testing the Addition of Paclitaxel Administered Into the Abdominal Cavity Combined With Chemotherapy for Patients With Gastric Cancer Spread"},{"nct":"NCT04644068","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies"},{"nct":"NCT05203627","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Telehealth for the Self-Management of Dietary Quality of Life in Patients After Stomach Cancer Surgery"}],"usage":{"input":12633,"output":7307},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"gastric cancer\" OR \"gastric adenocarcinoma\") AND (RPRD1B OR CREPT OR TOPBP1) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"gastric cancer\" AND (CD36 OR CPT1A OR FASN OR SREBP1) AND (\"PD-1\" OR \"PD-L1\" OR immunotherapy OR \"CD8\") AND SRC:MED"],"evidenceIds":["PMID:41630007","PMID:41278473","PMID:42171939","PMID:41832397","PMID:42245480","PMID:42211570","PMID:41158287","PMID:42164655","PMID:41640669","PMID:41098086","NCT07115043","NCT07646574","NCT06203600","NCT07023731","NCT04550494","NCT07001748","NCT04644068","NCT05203627"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787177973069","cycle":142,"visit":3,"ts":"2026-08-19T22:19:33.069Z","cancer":{"key":"esophageal cancer","name":"esophageal cancer","mondo":{"id":"MONDO:0007576","name":"esophageal cancer"}},"control":false,"modelLabel":"SCIENCE","summary":"In squamous esophageal/upper aerodigestive cancer, ETS1-driven hybrid-EMT defines a STAT1/PD-L1-high immune-cold ICB-resistant stratum distinct from the KLF4-low/MHC-I-low stratum, nominating biomarker-selected HSP90 inhibition plus PD-1 blockade and making ETS1-vs-HLA-ABC co-staining the next decis","confidence":0.47,"notebook":"This visit's pack is review-heavy and returned two informative negatives. The query written explicitly for ESCC + HLA class I/B2M + PD-1 biomarker produced no primary esophageal antigen-presentation biomarker paper, and the esophagus-directed PGE2/PTGS2/cDC1 query produced only cross-disease reviews. Open questions 1, 2 and 3 therefore remain unanswered, and the desk should stop expecting them to resolve passively: L1's KLF4→MHC-I chromatin mechanism is still single-source (PMID:42493491) and no clinical HLA-ABC/B2M stratification data exist. L1 holds at CANDIDATE without promotion; that is the correct read, not a stall.\n\nThe one primary result, PMID:42153907, is the highest-value item and generates a new lead. In upper aerodigestive squamous carcinoma (anatomically inclusive of esophagus, though the abstract does not give the ESCC fraction — ambiguous), single-cell analysis nominates ETS1 as master regulator of a hybrid-EMT intratumoural heterogeneity programme that simultaneously drives metastasis and builds an immune-cold TME by transcriptionally activating STAT1 and CD274/PD-L1, with high ETS1 correlating with ICB resistance across multiple cohorts; drug screening nominates HSP90 inhibition (alvespimycin) acting through HIF-1α-dependent ETS1 transcription. Mechanistically this is *not* the L1 phenotype: ETS1-high tumours carry active STAT1 and high PD-L1, i.e. an IFN-mimicry/adaptive-resistance state, whereas L1/L5 describe antigen-presentation loss. [INFERRED] these are separable immune-cold strata in squamous esophagus, and the co-segregation test (ETS1 vs HLA-ABC/B2M/KLF4 IHC on the same ESCC cores) is now the cheapest discriminating experiment in the programme and would simultaneously answer open question 3.\n\nL5 gains mechanistic specificity but no esophageal anchoring: PMID:40712694 shows dual EP2+EP4 blockade beats single-receptor blockade, EP4 antagonist plus anti-PD-1 raises T-cell infiltration, and nominates PTGES1 inhibition and 15-PGDH augmentation as alternative nodes — all in breast cancer; PMID:41430039 supports DC cross-presentation dysfunction and metabolic reprogramming as targetable. Marginal strengthening only, with explicit cross-disease borrowing flagged. L3 gains only generic support: PMID:41963781 states intratumour microbiota modulate antigen presentation and effector function and thus immunotherapy response, so open question 6 is answered at review level for microbiota generally, not for the L. reuteri D-lactate/STAT3-K631 axis specifically. L4 is weakened: three visits, still no B7-H3/CD276 prevalence or intensity data in esophagus; it stays only as a trial-tracking placeholder and should be retired next visit absent expression data. L2 unchanged.\n\nProgramme-level caution to record: HSP90 inhibitors have a long history of clinical failure and ocular/hepatic toxicity [KNOWN], so L6's translational path is biomarker-selected (ETS1-high) combination, not monotherapy.","leadChanges":[{"id":"L6","title":"ETS1-high hybrid-EMT immune-cold ESCC: HSP90 inhibition as biomarker-selected ICB sensitiser","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L1","title":"KLF4 re-induction to reopen MHC-I chromatin and rescue PD-1 blockade in esophageal cancer","level":"CANDIDATE","status":"WEAKENED","confidence":0.54},{"id":"L5","title":"Dual restoration of direct and cross-presentation: PGE2/VEGF blockade layered onto MHC-I re-induction plus PD-1 in antigen-presentation-low ESCC","level":"LEAD","status":"STRENGTHENED","confidence":0.34},{"id":"L3","title":"Decolonisation-gated ferroptosis sensitisation: intratumour Lactobacillus D-lactate/STAT3-K631 lactylation as a resistance switch","level":"LEAD","status":"STRENGTHENED","confidence":0.42},{"id":"L4","title":"B7-H3-directed ADC plus PD-1 blockade in esophageal cancer","level":"LEAD","status":"WEAKENED","confidence":0.22}],"unverifiedCitations":0,"openQuestions":["What fraction of the PMID:42153907 UASCC cohort is esophageal, and does ETS1-high status independently predict PD-1 failure in ESCC-only cohorts?","Do ETS1-high/STAT1-PD-L1-high and KLF4-low/HLA-ABC-low cold phenotypes co-segregate or define mutually exclusive ESCC strata on the same tissue cores?","Is HSP90i benefit in ETS1-high ESCC ETS1-dependent and CD8-dependent, and can intermittent dosing separate efficacy from known ocular/hepatic toxicity?","Which agent induced KLF4 in PMID:42493491, and is the MHC-I/CD8 rescue abolished in KLF4-null and B2M-null isogenics?","Is there any esophageal-specific PGE2/EP4 or cDC1 primary dataset, and does dual EP2/EP4 antagonism outperform COX-2 inhibition in 4NQO-driven ESCC?","Is there any esophageal-specific SHP2/PTPN11 dependency genotype (ERBB2/EGFR amplification, NF1 loss) with synergy over additivity when combined with anti-ERBB2?"],"nextQueries":["(ETS1 AND (\"esophageal squamous cell carcinoma\" OR \"upper aerodigestive\") AND (\"immune evasion\" OR EMT OR \"HSP90\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","((\"HSP90 inhibitor\" OR alvespimycin OR ganetespib OR onalespib) AND (esophageal OR \"squamous cell carcinoma\") AND (\"PD-1\" OR \"immune checkpoint\" OR xenograft)) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","((\"EP4 antagonist\" OR PTGES1 OR \"15-PGDH\" OR grapiprant) AND (esophageal OR \"squamous cell carcinoma\") AND (immunotherapy OR \"CD8\" OR dendritic)) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"papersShown":[{"pmid":"41430039","doi":"10.1038/s41419-025-08180-0","year":2025,"isNew":true,"title":"The emerging role of dendritic cells in the tumor microenvironment: from antigen presentation to targeted immunotherapy"},{"pmid":"41703602","doi":"10.1186/s12943-026-02583-z","year":2026,"isNew":true,"title":"Targeting inflammatory microenvironments: overcoming therapy resistance and immunosuppression"},{"pmid":"41368628","doi":"10.3389/fimmu.2025.1691661","year":2025,"isNew":true,"title":"Crosstalk between cancer stem cells and myeloid-derived suppressor cells: implications for tumor progression and immunotherapy"},{"pmid":"41431197","doi":"10.1080/07853890.2025.2603755","year":2026,"isNew":true,"title":"Optimizing immunotherapy for head and neck squamous cell carcinoma: recent advances and future directions"},{"pmid":"42153907","doi":"10.1158/0008-5472.can-25-3134","year":2026,"isNew":true,"title":"ETS1 Orchestrates a Hybrid EMT Program Driving Metastasis and Immune Evasion"},{"pmid":"42064043","doi":"10.3389/fimmu.2026.1774615","year":2026,"isNew":true,"title":"Role of innate immunity in the development of cancer immunotherapy immune-mediated adverse events"},{"pmid":"41491612","doi":"10.1002/ctm2.70582","year":2026,"isNew":true,"title":"Targeting neutrophil-driven immunosuppression: A strategy to overcome immune checkpoint inhibitor resistance"},{"pmid":"40712694","doi":"10.1016/j.mce.2025.112617","year":2025,"isNew":true,"title":"Breaking immune evasion in breast cancer by targeting COX-2/PGE2 pathway"},{"pmid":"42207498","doi":"10.1080/19490976.2026.2681842","year":2026,"isNew":true,"title":"The impact of gut microbiota and metabolite-driven immune cell spatiotemporal dynamics on tumors"},{"pmid":"41963781","doi":"10.1080/19490976.2026.2651930","year":2026,"isNew":true,"title":"Microbiota as a modulator of drug response: targeting microbial-drug crosstalk in cancer therapy"}],"trialsShown":[{"nct":"NCT06203600","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"Adding Nivolumab to Usual Treatment for People With Advanced Stomach or Esophageal Cancer, PARAMUNE Trial"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT06748911","phase":"NA","status":"RECRUITING","isNew":false,"title":"Navicam for Detection of Barrett's Esophagus"},{"nct":"NCT00242723","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Evaluation of Cell Changes in Blood and Tissue in Cancers of the Lung, Esophagus and Lung Lining"},{"nct":"NCT07222657","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Liquid Nitrogen Spray Cryotherapy Prior to Neoadjuvant Systemic Therapy in Esophageal Adenocarcinoma"},{"nct":"NCT07182149","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Phase 1 Study of NRM-823 in Participants With Locally Advanced or Metastatic Refractory Solid Tumors"},{"nct":"NCT07217171","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Study Evaluating the Safety, Efficacy, and Pharmacokinetics (PK) of EVOLVE104 in Participants With Advanced Urothelial and Squamous Cell C"},{"nct":"NCT06780111","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Substudy 06E: Umbrella Study of Combination Therapies in Esophageal Cancer (MK-3475-06E/KEYMAKER-U06)"}],"usage":{"input":12356,"output":7051},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"esophageal squamous cell carcinoma\" AND (\"HLA class I\" OR B2M OR \"antigen presentation\") AND (\"PD-1\" OR pembrolizumab OR nivolumab) AND biomarker) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"esophageal\" AND (PGE2 OR PTGS2 OR EP4 OR \"cDC1\" OR \"cross-presentation\") AND (immunotherapy OR \"immune checkpoint\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41430039","PMID:41703602","PMID:41368628","PMID:41431197","PMID:42153907","PMID:42064043","PMID:41491612","PMID:40712694","PMID:42207498","PMID:41963781","NCT06203600","NCT07023731","NCT06748911","NCT00242723","NCT07222657","NCT07182149","NCT07217171","NCT06780111"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787177763715","cycle":141,"visit":4,"ts":"2026-08-19T22:16:03.715Z","cancer":{"key":"small cell lung cancer","name":"small cell lung cancer","mondo":{"id":"MONDO:0008433","name":"small cell lung carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Visit 4 returned no SCLC-specific evidence: retire the epigenetic plasticity-blockade lead (L5) on its pre-registered condition, open a low-confidence SLFN11-stratified PARP-dual/degrader lead (L7) as the only citable handle on RB1/TP53-null synthetic lethality, and re-run narrowed single-anchor que","confidence":0.42,"notebook":"A low-yield visit, and the pack's composition is itself the finding. The two targeted queries — one aimed squarely at open question 1 (RB1/TP53-null synthetic lethality: WEE1/CHK1/ATR/PARP/SLFN11), one at post-engager antigen coverage — returned seven papers of which none is an SCLC experiment: tramadol/HIF-1α in breast lines (PMID:41526224), ovarian nanomedicine (PMID:41423932), gynaecological ferroptosis (PMID:42318797), PROTAC degraders of PARP/GPX4/epigenetic regulators (PMID:41885448), a curcumin null result in A549/H460 (PMID:41858052), PARP dual-inhibitor medicinal chemistry (PMID:41395847), PIWI/piRNA (PMID:42253754), plus the already-seen cisplatin-resistance review (PMID:41869709). Trials are similarly off-axis (EGFR NSCLC, lazertinib neuropathy prophylaxis, HCC); NCT07203053 and NCT07472517 recur with no read-out; NCT07115043 introduces AZD6750 with rilvegostomig but the pack discloses no target, so I will not build on it.\n\nConsequences. First, open question 1 is now three visits unanswered with a query that was well-formed, so I treat this as a retrieval-strategy failure rather than evidence of absence, and I narrow the next queries to single anchors (SLFN11; ATR/berzosertib; talazoparib+temozolomide) instead of long OR-chains that let generic PARP chemistry reviews dominate. Mechanistically the only usable content is negative-framing: PMID:41395847 states plainly that PARP-inhibitor benefit remains tethered to HR-deficiency phenotypes with haematological toxicity as the ceiling — in RB1/TP53-null SCLC, which is not HR-deficient, that argues any PARP re-entry must be stratified (SLFN11 [SOMATIC]) and/or dual-target/degrader-based to escape the HR dependency and marrow overlap with platinum/etoposide. I log that as a new, deliberately low-confidence pharmacology-only lead (L7) with an explicit kill date, so the desk stops re-proposing naked PARPi in SCLC.\n\nSecond, L5 dies. I pre-registered its retirement condition at visit 3: no SCLC experiment showing pharmacological prevention or reversal of subtype switching. Nothing in this pack does so; PMID:41869709 again only lists subtype transition and epigenetic reprogramming among seven cisplatin-resistance mechanisms. Retired, with the notebook constraint recorded that LSD1/EZH2-mediated plasticity blockade in SCLC remains an assertion, not a result; it reopens only on a citable persister-emergence experiment.\n\nL1, L3, L4, L6 are untouched — no new citation, so no promotion and no artificial movement; L1 in particular still lacks patient-level antigen-kinetics data and stays a CANDIDATE below the 10–20% durable-response bar. L2 unchanged (NCT06406465 recurs without SCLC content). Next visit must recover the two questions that actually gate L3 and L6: spatial coexistence of DLL3+ versus B7-H3+/YAP1+ compartments, and internalization kinetics in persisters.","leadChanges":[{"id":"L5","title":"Epigenetic blockade of subtype plasticity to prevent, not chase, antigen loss","level":"LEAD","status":"RETIRED","confidence":0.1},{"id":"L7","title":"SLFN11-stratified, HR-independent PARP re-entry in RB1/TP53-null SCLC via dual-target inhibitors or PARP1-selective degraders","level":"LEAD","status":"NEW","confidence":0.18}],"unverifiedCitations":0,"openQuestions":["Is there any citable SCLC-specific synthetic-lethal dataset - SLFN11-stratified PARP/temozolomide, ATR (berzosertib), CHK1, WEE1 or Aurora - in RB1/TP53-null disease? (fourth attempt, now with single-anchor queries)","In relapsed SCLC lesions, do DLL3+ and YAP1+/B7-H3+ compartments coexist spatially (mandating concurrent engager + B7-H3 ADC or a bystander payload) or replace each other temporally (permitting sequencing)?","What are DLL3, SEZ6 and B7-H3 internalization kinetics in NE versus YAP1+ persister states - is impaired endocytosis a real SCLC persister feature favouring extracellular-release ADC design?","What is the CD58 expression status of SCLC and of the YAP1-emergent state, and is CD58 loss an independent DLL3-engager resistance route?","Are there ifinatamab deruxtecan or SEZ6-ADC efficacy data in DLL3-engager-pretreated patients, and is antigen profiling used for selection?","Does the NCT07203053 PS 2 read-out separate toxicity-driven discontinuation from efficacy loss - is the engager ceiling in unfit patients T-cell-fitness-limited or tumour-biology-limited?"],"nextQueries":["SLFN11 AND (\"small cell lung\" OR SCLC) AND (talazoparib OR temozolomide OR olaparib OR berzosertib OR ATR) AND SRC:MED","(tarlatamab OR \"DLL3 bispecific\" OR obrixtamig) AND (biopsy OR ctDNA OR \"antigen loss\" OR relapse OR resistance) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","(ifinatamab OR \"B7-H3\" OR SEZ6) AND \"small cell lung\" AND (heterogeneity OR internalization OR bystander OR multiplex) AND SRC:MED"],"papersShown":[{"pmid":"41526224","doi":"10.1080/13510002.2025.2588866","year":2026,"isNew":true,"title":"Tramadol induced hypoxia signaling and paraptosis-like cell death in breast cancer cells via HIF-1α and ATF4 dependent pathways"},{"pmid":"41423932","doi":"10.1080/10717544.2025.2605387","year":2026,"isNew":true,"title":"Nanotherapeutics for enhanced treatments for ovarian cancer: a comprehensive minireview"},{"pmid":"42318797","doi":"10.1080/07853890.2026.2688328","year":2026,"isNew":true,"title":"Research progress of ferroptosis in gynecological diseases"},{"pmid":"41885448","doi":"10.1080/14756366.2026.2636394","year":2026,"isNew":true,"title":"PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators"},{"pmid":"41858052","doi":"10.1080/13880209.2026.2640678","year":2026,"isNew":true,"title":"Low, plasma level‑informed native curcumin concentrations fail to induce cell death in human lung and colorectal cancer cells"},{"pmid":"41395847","doi":"10.1080/14756366.2025.2598478","year":2026,"isNew":true,"title":"Antitumor activity and structure-activity relationship of poly (ADP-ribose) polymerase (PARP)-based dual inhibitors"},{"pmid":"42253754","doi":"10.1016/j.gendis.2025.101854","year":2026,"isNew":true,"title":"Unraveling the role of PIWI/piRNAs in stem cell therapy: Epigenetic mechanisms and therapeutic potentials"},{"pmid":"41869709","doi":"10.1080/07853890.2025.2601401","year":2026,"isNew":false,"title":"Application and mechanistic research of novel therapeutic strategies in cisplatin-resistant small cell lung cancer"}],"trialsShown":[{"nct":"NCT07774520","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Randomized Study to Evaluate the Efficacy of a Reduced Starting Dose of Lazertinib (Leclaza) and Preemtive Magnesium Supplementation to Pr"},{"nct":"NCT07203053","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Trial of Tarlatamab in Patients With Pretreated Extensive-stage Small Cell Lung Cancer (ES-SCLC) and ECOG PS 2"},{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT04181060","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Osimertinib With or Without Bevacizumab as Initial Treatment for Patients With EGFR-Mutant Lung Cancer"},{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT07472517","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"DAREON ® -Lung-1: A Study in People With Advanced Small Cell Lung Cancer to Compare Obrixtamig Plus Atezolizumab, Carboplatin, and Etoposide"},{"nct":"NCT06194448","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"To Evaluate the Efficacy/Safety of Osimertinib Prior to CRT and Maintenance of it With Stage III, Unresectable NSCLC With EGFR Mutations"},{"nct":"NCT06406465","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A UGT1A1 Genotype-Directed Study of Belinostat Pharmacokinetics and Toxicity"}],"usage":{"input":11513,"output":5535},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"small cell lung\" OR SCLC) AND (WEE1 OR CHK1 OR \"Aurora\" OR ATR OR PARP OR SLFN11 OR \"synthetic lethal\") AND (RB1 OR TP53 OR \"replication stress\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"small cell lung\" OR SCLC) AND (\"ifinatamab\" OR \"B7-H3\" OR CD276 OR SEZ6 OR \"antigen heterogeneity\" OR \"bystander effect\") AND (\"tarlatamab\" OR \"prior DLL3\" OR relapsed OR resistance) AND SRC:MED AND PUB_YEAR:[2024 TO 2"],"evidenceIds":["PMID:41526224","PMID:41423932","PMID:42318797","PMID:41885448","PMID:41858052","PMID:41395847","PMID:42253754","PMID:41869709","NCT07774520","NCT07203053","NCT07115043","NCT04181060","NCT07636785","NCT07472517","NCT06194448","NCT06406465"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787177566433","cycle":140,"visit":4,"ts":"2026-08-19T22:12:46.433Z","cancer":{"key":"cholangiocarcinoma","name":"cholangiocarcinoma","mondo":{"id":"MONDO:0019087","name":"cholangiocarcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"MTAP IHC loss is present in ~19-35% of hepatobiliary carcinomas and is scorable on bile duct biopsies (PMID:42242395), making MTAP-null CCA a standalone, prospectively selectable PRMT5-inhibitor population rather than merely a rescue strategy for CDKN2A-null FGFR2-fusion tumours.","confidence":0.62,"notebook":"MTAP is the story of this visit. P8 (PMID:42242395) supplies exactly the assay-level data open question 2 demanded: MTAP IHC loss in 21% of small-duct iCCA, 35% of large-duct iCCA, 19% of extrahepatic CCA, 21% of cHCC-CCA, 7% of IPNB (all invasive) and 0% of bile duct adenoma, concordant with p16 loss, and scorable on bile duct biopsy material (52 biopsies). So an FFPE-deployable, biopsy-compatible selector for an MTAP-null population of roughly one in five hepatobiliary carcinomas now exists — larger than the 12.8% seen by NGS in the 1254-patient cohort (PMID:42360806), consistent with IHC capturing epigenetic/hemizygous silencing beyond deep deletion [INFERRED]. P7 (PMID:42352533) independently lists MTAP loss alongside IDH1, FGFR2 and KRAS as defining a distinct immunologic phenotype in CCA. L8 therefore moves to CANDIDATE.\n\nBut the same data partly dissolve the L1↔L8 bridge I built last visit. MTAP loss is highest in large-duct iCCA, whereas FGFR2 fusions are enriched in small-duct iCCA [KNOWN]; if that anti-correlation holds, most PRMT5i-eligible tumours sit *outside* the FGFRi-refractory fusion population, and L8 stands on its own footing rather than as a rescue for CDKN2A-null fusions. Direct co-testing of MTAP IHC with fusion status in one cohort is now the decisive experiment.\n\nP10 (PMID:41682001) restates FGFR2 fusion prevalence (10–16% iCCA), kinase-domain plus bypass resistance, next-generation inhibitors and ctDNA monitoring. It is a review, adds no independent data, and does not adjudicate CDKN2A versus TP53/RAS as the adverse co-alteration, so L1 stays CANDIDATE — I decline to promote on narrative synthesis, and question 3 remains open.\n\nP6 (PMID:41887529) gives ABC-01/-02/-03 individual-level benchmark survival for 117 eCCA and 112 GBC on CisGem — the natural-history comparator any single-arm eCCA/GBC KRAS G12D degrader expansion will need, given the PFS-without-OS problem. That is trial-design support for L4, not target validation; confidence barely moves.\n\nBoth targeted queries for ROS1 fusions and PTPN3 in biliary cancer returned nothing on-topic, and P2's iCCA pathway review names FGFR/IDH/HER2 and lesser-known receptors without them. Two failed searches plus absence from the large genomic cohorts: I am retiring the KG anchors ROS1 and PTPN3 as small-series artefacts and will not re-propose them. BRCA1/2 remain live only through L2, still [GERMLINE]/[SOMATIC] unresolved in the BilT-02 subgroup. P1, P3, P5, P9 (metabolism/splicing/PTM/RNA-modification reviews) and P4 (orbital metastasis case) are off-programme; logged as non-informative.","leadChanges":[{"id":"L8","title":"PRMT5 inhibition in MTAP-deleted biliary tract cancer, enriched in the CDKN2A-null FGFRi-refractory subset","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.6},{"id":"L1","title":"Covalent pan-FGFR inhibition (futibatinib) and combination FGFR/VEGF/PD-L1 blockade in FGFR2-fusion cholangiocarcinoma","level":"CANDIDATE","status":"WEAKENED","confidence":0.75},{"id":"L4","title":"KRAS G12D degradation (ARV-806) in the KRAS-mutant, predominantly extrahepatic/gallbladder cholangiocarcinoma subset","level":"LEAD","status":"STRENGTHENED","confidence":0.46}],"unverifiedCitations":0,"openQuestions":["What is the actual co-occurrence of MTAP IHC loss with FGFR2 fusion status in one CCA cohort — does the large-duct skew of MTAP loss mean PRMT5i eligibility is depleted, not enriched, among FGFRi-refractory fusion tumours?","Does non-deletional MTAP protein loss (IHC-negative, 9p21-intact by NGS) confer the same MTA accumulation and PRMT5i sensitivity as homozygous deletion?","Does TP53/RAS-pathway co-alteration outperform CDKN2A as the predictive marker of FGFR inhibitor failure when both are tested in the same cohort?","Is the DNMTi+PARPi effect in CCA HR-dependent (RAD51-foci loss) or senescence/SASP- and immune-dependent, and does priming-then-PARPi beat concurrent dosing?","Is MTAP-null CCA immunologically cold, and does PRMT5 inhibition restore antigen presentation or T-cell infiltration in immunocompetent MTAP-null models?","With CDKN2A-null FGFR2-fusion tumours now lacking an MTAP-based rescue, is there any published FGFRi + CDK4/6i biliary data or preclinical support at all?"],"nextQueries":["(cholangiocarcinoma OR \"biliary tract cancer\" OR \"intrahepatic cholangiocarcinoma\") AND (MTAP AND (FGFR2 OR \"large duct\" OR \"small duct\")) AND SRC:MED","(cholangiocarcinoma OR \"biliary tract cancer\") AND (\"CDK4/6\" OR palbociclib OR abemaciclib OR ribociclib) AND (FGFR OR CDKN2A) AND SRC:MED","(cholangiocarcinoma OR \"biliary tract cancer\") AND (azacitidine OR decitabine OR \"hypomethylating\") AND (PARP OR olaparib OR niraparib OR senescence) AND SRC:MED"],"papersShown":[{"pmid":"40975127","doi":"10.1016/j.jare.2025.09.025","year":2026,"isNew":true,"title":"Dynamic remodeling of amino acid metabolism in tumor-associated macrophages: Fueling immunosuppression, reshaping tumor niches, and unlocking metabolic checkpoints"},{"pmid":"41465387","doi":"10.3390/ijms262411961","year":2025,"isNew":true,"title":"Molecular Alterations and Pathways in Intrahepatic Cholangiocarcinoma: Available Evidence and New Perspectives"},{"pmid":"42346144","doi":"10.3390/cells15121117","year":2026,"isNew":true,"title":"The Interplay of Splicing and Metabolism in Cancer"},{"pmid":"40685225","doi":"10.1136/bcr-2025-265765","year":2025,"isNew":true,"title":"Orbital metastasis in advanced gallbladder and biliary tract malignancy"},{"pmid":"42345006","doi":"10.1002/mco2.70816","year":2026,"isNew":true,"title":"RNA Modifications in Tumor Microenvironment: A New Dimension for Cancer Treatment"},{"pmid":"41887529","doi":"10.1016/j.jhepr.2026.101833","year":2026,"isNew":true,"title":"Advanced extrahepatic cholangiocarcinoma and gallbladder cancer: Post-hoc analysis of the ABC-01, -02 and -03 clinical trials"},{"pmid":"42352533","doi":"10.3390/cancers18122001","year":2026,"isNew":true,"title":"The Evolving Landscape of Immune Regulation and Immunotherapy in Cholangiocarcinoma and Biliary Tract Cancer"},{"pmid":"42242395","doi":"10.1016/j.humpath.2026.106194","year":2026,"isNew":true,"title":"Clinicopathological significance of methylthioadenosine phosphorylase (MTAP) expression loss in hepatobiliary tumors"},{"pmid":"42221857","doi":"10.1093/pcmedi/pbag014","year":2026,"isNew":true,"title":"Protein modification systems as cancer biomarkers and therapeutic targets"},{"pmid":"41682001","doi":"10.3390/cancers18030531","year":2026,"isNew":true,"title":"FGFR2-Rearranged Biliary Tract Cancer: Biology, Resistance Mechanisms, and Emerging Therapeutic Strategies"}],"trialsShown":[{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04645160","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Evaluating Efficacy of Tivozanib (AV-951) in Biliary Tract Cancers"},{"nct":"NCT01915225","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Obtaining Solid Tumor Tissue From People Having Biopsy or Surgery for Certain Types of Cancer"},{"nct":"NCT03212274","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations"},{"nct":"NCT07043387","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Streamlining Radioembolization for CCC and Metastatic Liver Cancer"},{"nct":"NCT06048133","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of Gemcitabine, Cisplatin, AB680 and AB122 During First Line Treatment of Advanced Biliary Tract Cancers (QUIC)"},{"nct":"NCT04891289","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Gemcitabine and Oxaliplatin Chemotherapy With or Without a Floxuridine and Dexamethasone Pump in People With Cholangiocarcinoma That Cannot "},{"nct":"NCT06439485","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Phase I/II Trial of Pemigatinib in Combination With Atezolizumab and Bevacizumab for Treatment of Advanced Cholangiocarcinoma With FGFR2 Fus"}],"usage":{"input":14261,"output":6796},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(cholangiocarcinoma OR \"biliary tract cancer\") AND (MTAP OR PRMT5 OR MAT2A OR \"methylthioadenosine\") AND SRC:MED","(cholangiocarcinoma OR \"biliary tract cancer\") AND (\"ROS1\" OR PTPN3) AND (fusion OR rearrangement OR prevalence) AND SRC:MED"],"evidenceIds":["PMID:40975127","PMID:41465387","PMID:42346144","PMID:40685225","PMID:42345006","PMID:41887529","PMID:42352533","PMID:42242395","PMID:42221857","PMID:41682001","NCT07023731","NCT04645160","NCT01915225","NCT03212274","NCT07043387","NCT06048133","NCT04891289","NCT06439485"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787177359355","cycle":139,"visit":4,"ts":"2026-08-19T22:09:19.355Z","cancer":{"key":"pancreatic cancer","name":"pancreatic cancer","mondo":{"id":"MONDO:0009831","name":"malignant pancreatic neoplasm"}},"control":false,"modelLabel":"SCIENCE","summary":"Human resection data show PDAC is largely low-bacterial-biomass, demoting the cdd/gemcitabine-inactivation lead to hypothesis status, while pan-RAS(ON) inhibition is promoted to DOSSIER and its dominant non-genetic escape route is now mechanistically specified as an IFN-TRIM22-NF-kB-EMT switch with ","confidence":0.62,"notebook":"Visit 4 changes the microbiome lead's direction of travel and hands the resistance programme a druggable escape antigen.\n\nThe decisive negative is P1 (PMID:39795998): the first human PDAC resection series to test the gammaproteobacteria–gemcitabine hypothesis directly found bacterial DNA in frozen tumour and adjacent normal at levels comparable to negative controls, and in FFPE indistinguishable from paraffin blanks, across nine long-term and nine short-term survivors after neoadjuvant gemcitabine. That is exactly the prevalence datum L1 has been waiting three visits for, and it argues the intratumoral compartment is low-biomass and contamination-dominated in most resections. 16S amplicon cannot exclude a functionally relevant minority carriage, and it does not test cdd copy number or deaminase activity, so the lead is not dead — but the mechanistic literature that keeps arriving (PMID:41422344, PMID:42125497, PMID:41630692) is all review-level, so L1 loses its CANDIDATE standing and drops to LEAD at 0.35. Any further investment must be quantitative and contamination-controlled: total-cdd qPCR with blanks, culture, and intratumoral LC-MS gemcitabine:dFdU — no more 16S.\n\nL6 is promoted to DOSSIER. PMID:41801133 shows adaptive RAS-MAPK reactivation after mutant-selective KRAS^G12D blockade is lineage-partitioned — EGFR/ERBB3 in epithelial-differentiated PDAC, FGFR1 in mesenchymal — corroborated in TCGA expression correlations, and reports a RAS(ON) multi-selective agent in that comparison; with PMID:42279426 framing WT-RAS/RTK compensation as the generic failure mode of allele-selective inhibitors, the wild-type-bypass-proof argument now has independent mechanistic support on top of RASolute-302 survival. This same paper squeezes L2: a G12D degrader still faces two RTK bypasses whose identity depends on differentiation state, so the GAB1/PI3K co-target from visit 3 is necessary but insufficient — FGFR co-inhibition is required in mesenchymal models. L2 weakened to 0.45; its remaining justification is window, not efficacy.\n\nL8 becomes a CANDIDATE on PMID:42008116: sustained KRAS-MAPK inhibition relieves ERK-mediated repression of IRF1/IRF9, induces TRIM22, which degrades IκBα, giving sustained NF-κB, EMT and basal-like state with marked TROP2 (TACSTD2) upregulation — and sacituzumab govitecan plus KRAS or ERK inhibition suppressed xenograft growth. Non-RAS cell-state escape now has a named transcription-factor axis and an approved ADC. [INFERRED] daraxonrasib should induce the same axis; TROP2 IHC on progression biopsies is the immediate test.\n\nNew lead L9: KRAS G12R (15–20% of PDAC) sterically excludes switch-II pocket binders and depends on amplified autophagy with attenuated PI3Kα/MEK coupling (PMID:42226005), while autophagy also degrades MHC-I to enforce immune exclusion (PMID:42226008) — one intervention, two payoffs.","leadChanges":[{"id":"L1","title":"cdd_L+ intratumoral Enterobacter as an antibiotic-reversible driver of gemcitabine inactivation","level":"LEAD","status":"WEAKENED","confidence":0.35},{"id":"L6","title":"Pan-RAS(ON) tri-complex inhibition as the wild-type-bypass-proof alternative to allele-selective G12D therapy","level":"DOSSIER","status":"STRENGTHENED","confidence":0.8},{"id":"L8","title":"Post-daraxonrasib resistance: sequencing RAS degraders, RAS-cleaving biologics and prenylation-bypass co-inhibition after pan-RAS failure","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55},{"id":"L2","title":"KRAS G12D targeted degradation (ARV-806) in PDAC","level":"CANDIDATE","status":"WEAKENED","confidence":0.45},{"id":"L9","title":"Autophagy blockade as dual-purpose therapy for KRAS G12R PDAC and for KRAS-enforced MHC-I loss","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["Does TROP2 protein rise on treatment in paired pre/progression biopsies from daraxonrasib- or KRAS-G12D-inhibitor-treated PDAC patients, and does TRIM22/IRF1 expression mark the patients who escape by cell-state rather than by RAS mutation?","In a contamination-controlled quantitative assay (total-cdd qPCR with blanks, culture, intratumoral LC-MS gemcitabine:dFdU), does any subset of human PDAC resections carry functionally deaminating bacteria at all, given the negative 16S bio","Is adaptive RTK bypass of pan-RAS(ON) genuinely absent, or merely attenuated, in mesenchymal FGFR1-high versus epithelial EGFR/ERBB3-high PDAC, and does differentiation state predict daraxonrasib depth of response?","Does autophagy inhibition plus RAS-pathway blockade produce differential benefit in KRAS G12R versus G12D PDAC models, and does restored surface MHC-I translate into anti-PD-1 sensitivity?","Can the residual case for allele-selective G12D degradation be settled by a head-to-head window comparison (crypt proliferation, skin/GI toxicity, chemo- and ADC-combinability) against pan-RAS at equivalent pERK suppression?"],"nextQueries":["(\"pancreatic ductal adenocarcinoma\" AND (TROP2 OR TACSTD2 OR \"sacituzumab govitecan\" OR datopotamab) AND (KRAS OR \"RAS inhibitor\" OR resistance)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"pancreatic\" AND (\"KRAS G12R\" OR autophagy OR hydroxychloroquine OR PPT1 OR ULK1) AND (\"MHC-I\" OR \"antigen presentation\" OR immunotherapy OR trial)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(pancrea* AND (daraxonrasib OR \"RMC-6236\" OR \"pan-RAS\") AND (FGFR OR EGFR OR mesenchymal OR \"cell state\" OR ctDNA OR \"acquired resistance\")) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]"],"papersShown":[{"pmid":"39795998","doi":"10.3390/ijms26010140","year":2024,"isNew":true,"title":"Low Bacterial Biomass in Human Pancreatic Cancer and Adjacent Normal Tissue"},{"pmid":"42008116","doi":"10.1158/0008-5472.can-25-4114","year":2026,"isNew":true,"title":"Prolonged KRAS-MAPK Inhibition Induces Interferon Signaling That Promotes Cell State Transition and Confers Therapeutic Vulnerabilities"},{"pmid":"42279434","doi":"10.3390/cancers18111852","year":2026,"isNew":true,"title":"Targeting Circulating Tumor Cells in Pancreatic Ductal Adenocarcinoma: Rationale, Current Evidence, and a CEACAM6 CAR-T Strategy"},{"pmid":"42279426","doi":"10.3390/cancers18111844","year":2026,"isNew":true,"title":"Pan-RAS Inhibitors: Expanding Therapeutic Potential and Evading Resistance"},{"pmid":"42226008","doi":"10.1093/oncolo/oyag160","year":2026,"isNew":true,"title":"KRAS-driven immune exclusion in pancreatic ductal adenocarcinoma: mechanisms and therapeutic reversal"},{"pmid":"42226005","doi":"10.1093/oncolo/oyag155","year":2026,"isNew":true,"title":"KRAS G12R in pancreatic cancer: why this mutation resists current inhibitor strategies"},{"pmid":"41801133","doi":"10.1158/1078-0432.ccr-25-1788","year":2026,"isNew":true,"title":"Overcoming Adaptive Resistance to KRASG12D Blockade in Pancreatic Cancer through Vertical Pathway Inhibition"},{"pmid":"41422344","doi":"10.1038/s41416-025-03324-7","year":2026,"isNew":true,"title":"Intratumoral microbiome and pancreatic cancer: an enabling hallmark and path to novel treatments?"},{"pmid":"42125497","doi":"10.3389/fcimb.2026.1817579","year":2026,"isNew":true,"title":"The association between periodontal disease and pancreatic cancer: epidemiology, mechanisms, and implications for clinical management"},{"pmid":"41630692","doi":"10.1097/cm9.0000000000003986","year":2026,"isNew":true,"title":"Microbiota in pancreatic ductal adenocarcinoma progression and therapy: The hidden players"}],"trialsShown":[{"nct":"NCT04999969","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic "},{"nct":"NCT05692323","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Supervised Prehabilitation Program for Patients With Pancreatic Cancer"},{"nct":"NCT07226154","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Prediction of Neoadjuvant Chemotherapy Response in Pancreatic Cancer"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04550494","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations"},{"nct":"NCT04644068","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies"},{"nct":"NCT03454035","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Ulixertinib/Palbociclib in Patients With Advanced Pancreatic and Other Solid Tumors"},{"nct":"NCT01174121","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer"}],"usage":{"input":14956,"output":9289},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"pancreatic ductal adenocarcinoma\" AND (daraxonrasib OR \"RMC-6236\" OR \"RASolute\") AND (\"acquired resistance\" OR ctDNA OR biopsy OR \"ternary complex\")) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","(pancrea* AND (\"cytidine deaminase\" OR \"CDD\" OR Gammaproteobacteria OR Aggregatibacter) AND (resection OR cohort OR prevalence OR \"tumor microbiome\") AND gemcitabine) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:39795998","PMID:42008116","PMID:42279434","PMID:42279426","PMID:42226008","PMID:42226005","PMID:41801133","PMID:41422344","PMID:42125497","PMID:41630692","NCT04999969","NCT05692323","NCT07226154","NCT07023731","NCT04550494","NCT04644068","NCT03454035","NCT01174121"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787177124430","cycle":138,"visit":4,"ts":"2026-08-19T22:05:24.430Z","cancer":{"key":"glioblastoma","name":"glioblastoma","mondo":{"id":"MONDO:0018177","name":"glioblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Reframe the mitochondrial-proteostasis programme around ClpP agonism (promoted to CANDIDATE on new non-midline H3K27M clinical activity, PMID:38386699) while holding LonP1 inhibition back for absent brain-exposure data, and pre-specify KEAP1/NRF2 status and host sex as determinants of whether ROS-ba","confidence":0.46,"notebook":"This visit's two targeted queries were aimed at the delivery gap in L1 and the directionality question in L7. The first failed cleanly: nothing in the pack reports BT317, CC4 or CDDO-class plasma:brain ratios, unbound brain fraction, or P-gp/BCRP substrate status. Open Question 1 is now unanswered after a dedicated query, so L1 is **weakened** — it retains best-in-programme target genetics but has no citable CNS pharmacokinetics and still no orthotopic efficacy. Two class liabilities now surface: reviews of the related triterpenoid electrophiles celastrol and cucurbitacin B document severe narrow-window toxicity and promiscuous off-target signalling (RAF1-MEK-ERK activation for cucurbitacin B) (PMID:42193972, PMID:42278536), which [INFERRED] is the expected hazard profile for an α,β-unsaturated-carbonyl warhead like CDDO/BT317.\n\nThe second query paid off. ONC201/dordaviprone produced investigator-reported one complete and one partial response in five patients with recurrent **non-midline** H3K27M-mutant cerebral gliomas, though blinded central review downgraded two of these (one non-measurable, one stable) (PMID:38386699). Mechanistically this decouples ClpP-agonist activity from midline anatomy while leaving the H3K27M dependency intact — so the L7 question is now sharply reframed: is response mutation-driven or protease-driven? Two independent reviews position ClpP agonism as the leading mitochondrial-directed modality in high-grade glioma and note the mitochondrial-metabolism/epigenetics link that could explain H3K27M selectivity (PMID:41008904, PMID:41155556); the latter also stresses that both activators and inhibitors of ClpP are antitumour, echoing the LonP1 inhibit-versus-hyperactivate ambiguity. L7 is **promoted to CANDIDATE** (new, independent literature; ORR caveat recorded so the desk does not overread n=5).\n\nA genuinely new confounder emerges for every ROS-based arm in this programme: CDDO-class compounds are canonical NRF2 activators [KNOWN], and NRF2 output is sex-dependent, with androgen-mediated suppression in males and CYP3A/body-composition pharmacokinetic differences (PMID:41921312), against a background where moderate ROS is pro-tumorigenic and only supra-threshold ROS kills (PMID:41881983). [INFERRED] KEAP1/NRF2 status and host sex may determine whether LonP1/proteasome dual inhibition crosses the lethal ROS threshold — a falsification test for L1 and a new lead (L9).\n\nNext I need: (i) any primary PK of CDDO-class agents in brain, including approved omaveloxolone as a CNS-exposed comparator; (ii) whether ClpP agonism has been tested in H3-wildtype GSCs; (iii) whether NRF2/KEAP1 status stratifies mitochondrial-proteostasis drug response.","leadChanges":[{"id":"L1","title":"LonP1 inhibition to resensitise glioblastoma to temozolomide (MGMT-independent)","level":"CANDIDATE","status":"WEAKENED","confidence":0.48},{"id":"L7","title":"ClpP hyperactivation (dordaviprone/ONC201) versus LonP1 inhibition — opposing mitochondrial protease modalities in H3-wildtype GBM","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.42},{"id":"L9","title":"KEAP1/NRF2 antioxidant capacity and host sex as the response determinant for ROS-generating mitochondrial therapy in GBM","level":"LEAD","status":"NEW","confidence":0.24}],"unverifiedCitations":0,"openQuestions":["Does any primary study report brain/tumour exposure of a CDDO-class or CC4-derived LonP1 inhibitor — and if a third targeted query fails, should L1 be reclassified as delivery-blocked pending a new chemotype rather than a therapeutic lead?","Is ONC201/ClpP-agonist cytotoxicity H3K27M-dependent or protease-expression-dependent in H3-wildtype GBM stem-like cells, and does CLPP/LONP1 expression stratify it?","Do KEAP1/NRF2 pathway status and GSH reserve determine whether LonP1/proteasome dual inhibition crosses the lethal ROS threshold in patient-derived GBM, and is the effect sex-dependent?","Are ClpP agonism and LonP1 inhibition synergistic or mutually buffering when applied together to the same GSC line?","Does any primary in vivo glioma experiment show MCT1/MCT4 or LDHA blockade improving bevacizumab, RT or anti-PD-1 efficacy (L2/L6, unanswered for three visits)?","Can the newly listed Optune+TMZ+pembrolizumab phase 3 (NCT06556563) serve as the myeloid-biomarker context for L3 alongside NCT06816927?"],"nextQueries":["(omaveloxolone OR bardoxolone OR CDDO OR \"triterpenoid\") AND (\"brain penetration\" OR \"plasma:brain\" OR \"P-glycoprotein\" OR pharmacokinetics) AND (glioma OR brain OR CNS) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(ONC201 OR dordaviprone OR ClpP) AND (\"H3 wildtype\" OR \"IDH-wildtype\" OR \"glioma stem\" OR glioblastoma) AND (sensitivity OR resistance OR expression OR biomarker) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(NFE2L2 OR NRF2 OR KEAP1) AND (glioblastoma OR \"glioma stem\") AND (temozolomide OR radioresistance OR \"reactive oxygen\" OR ferroptosis) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"41881983","doi":"10.1038/s41392-026-02583-x","year":2026,"isNew":true,"title":"Reactive oxygen species (ROS) in cancer: from mechanism to therapeutic implications"},{"pmid":"38386699","doi":"10.1093/neuonc/noae021","year":2024,"isNew":true,"title":"Selective DRD2 antagonist and ClpP agonist ONC201 in a recurrent non-midline H3 K27M-mutant glioma cohort"},{"pmid":"41008904","doi":"10.3390/cancers17183062","year":2025,"isNew":true,"title":"Targeting the Mitochondria in High-Grade Gliomas"},{"pmid":"40075726","doi":"10.3390/cancers17050879","year":2025,"isNew":true,"title":"The Complexity of Malignant Glioma Treatment"},{"pmid":"41155556","doi":"10.3390/ph18101443","year":2025,"isNew":true,"title":"Mitochondrial Protease ClpP: Cancer Marker and Drug Target"},{"pmid":"41952187","doi":"10.1186/s40164-026-00773-5","year":2026,"isNew":true,"title":"Decoding the spatiotemporal characteristics of ferroptosis: reshaping tumour therapeutic strategies"},{"pmid":"41921312","doi":"10.1016/j.redox.2026.104128","year":2026,"isNew":true,"title":"Sex-based differences in the NRF2 oxidative stress response: Implications for precision therapeutics"},{"pmid":"41894093","doi":"10.1007/s12035-026-05802-2","year":2026,"isNew":true,"title":"Kynurenine Pathway, Nrf2 and NF-κB Cross-Regulation in the CNS: An Overview"},{"pmid":"42278536","doi":"10.3390/ijms27115011","year":2026,"isNew":true,"title":"Cucurbitacin B Promotes Tumor Necrosis Factor Receptor 1 Ectodomain Shedding by Selectively Activating the Extracellular Signal-Regulated Kinase Signaling Pathway"},{"pmid":"42193972","doi":"10.3390/biom16050620","year":2026,"isNew":true,"title":"The Antitumor Potential of Celastrol: Research Progress on Antitumor Mechanisms and Strategies for Toxicity Reduction with Efficacy Enhancement"}],"trialsShown":[{"nct":"NCT06108206","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Adaptive Radiotherapy and MRIs Based on Patients With Newly Diagnosed High-Grade Glioma"},{"nct":"NCT06816927","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Trial of Glioblastoma Immunotherapy Advancement With Nivolumab and Relatlimab"},{"nct":"NCT06860594","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Testing the Addition of an Anti-Cancer Drug, Triapine, to the Usual Radiation Therapy for Recurrent Glioblastoma or Astrocytoma"},{"nct":"NCT02977780","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"INdividualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT)"},{"nct":"NCT06556563","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"EF-41/KEYNOTE D58: Phase 3 Study of Optune Concomitant With Temozolomide Plus Pembrolizumab in Newly Diagnosed Glioblastoma"},{"nct":"NCT04047264","phase":"NA","status":"RECRUITING","isNew":false,"title":"Feasibility of Intra- and Post-operative Microdialysis During Neurosurgery for Central Nervous System Lesions"},{"nct":"NCT03212274","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations"},{"nct":"NCT06319027","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Identifying Findings on Brain Scans That Could Help Make Better Predictions About Brain Cancer Progression, The GABLE Trial"}],"usage":{"input":15024,"output":6907},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(BT317 OR CDDO OR \"coumarinic compound 4\") AND (LONP1 OR \"Lon protease\" OR proteasome) AND (glioma OR glioblastoma OR pharmacokinetics OR \"brain penetration\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(ONC201 OR dordaviprone OR \"ClpP agonist\") AND (glioblastoma OR \"H3 wildtype\" OR \"glioma stem\") AND (mitochondrial OR OXPHOS OR proteostasis) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41881983","PMID:38386699","PMID:41008904","PMID:40075726","PMID:41155556","PMID:41952187","PMID:41921312","PMID:41894093","PMID:42278536","PMID:42193972","NCT06108206","NCT06816927","NCT06860594","NCT02977780","NCT06556563","NCT04047264","NCT03212274","NCT06319027"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787176912053","cycle":137,"visit":1,"ts":"2026-08-19T22:01:52.053Z","cancer":{"key":"endometrial cancer","name":"endometrial cancer","mondo":{"id":"MONDO:0011962","name":"endometrial cancer"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise HER2-directed therapy in serous/carcinosarcoma endometrial cancer (phase 3 NCT05256225 plus T-DXd data) as the lead axis, with metformin-driven AMPK-FOXO1-CALB2 reversal of progestin resistance as the strongest new mechanistic lead.","confidence":0.44,"notebook":"Visit 1 opens the programme. The pack is mostly off-target (P3 hysteroscopy analgesia, P5 nursing self-efficacy, P6 PDAC glycolysis, P7 TFPI2, P8 prostate lncRNA) — logged as non-actionable so the desk does not re-mine them. P4 (ferroptosis in gynaecological disease) is a narrative review with no EC-specific target or agent; parked, not a lead.\n\nAnchor hygiene first. MSH3 [GERMLINE] and CDH1 [GERMLINE] are predisposition alleles; MLH3/MSH6 [SOMATIC/germline-overlap] read out as the MMRd axis. Critically, JAZF1, SUZ12, YWHAE, NUTM2A and NUTM2B are [KNOWN] the recurrent fusion partners of endometrial stromal sarcoma (JAZF1–SUZ12 in low-grade; YWHAE–NUTM2A/B in high-grade) — uterine mesenchymal, not endometrioid carcinoma. Monarch has collapsed two diseases into one MONDO term; I will keep the sarcoma biology as a separate, explicitly labelled lead rather than let it contaminate carcinoma hypotheses.\n\nFour leads open. (1) HER2: T1 (NCT05256225) is a phase 3 NCI trial adding Herceptin Hylecta/Phesgo to carboplatin-paclitaxel specifically in HER2+ serous carcinoma/carcinosarcoma, and P10 reports T-DXd activity in HER2+ EC — this is the most mature, repurposing-first axis. Normal-tissue window: HER2 in cardiac myocytes and GI epithelium; expect cardiotoxicity monitoring (T1 includes echocardiography) and, for T-DXd, interstitial lung disease [KNOWN]. Resistance: HER2 heterogeneity/loss, PIK3CA-mutant bypass [INFERRED]. (2) Progesterone-resistance reversal: P9 gives a concrete mechanism — metformin drives FOXO1 nuclear localisation, FOXO1 represses CALB2, loss of CALB2 buffering causes mitochondrial Ca²⁺ overload and apoptosis, with rescue by FOXO1 knockdown or CALB2 re-expression, active in MPA-resistant lines. P2 is observational (n=53) but the lifestyle arm outperformed semaglutide and sleeve gastrectomy on complete remission (85% vs 73.9% vs 60%), which argues weight loss per se is not the effector and keeps the mechanistic weight on AMPK–FOXO1 rather than GLP-1 agonism. (3) IO-refractory MMRp disease: P1 confirms dostarlimab+carbo/paclitaxel as accepted first line (economic model only — no efficacy data added), so the unmet need is MMRp/pMMR progression; T8 (cabozantinib+nivolumab) and T6 (TIL+pembrolizumab) are the live shots on goal. (4) PRC2: T5 (tulmimetostat, EZH2i) in advanced solid tumours is the only clinical handle on SUZ12-fusion biology.\n\nNext I need EC-specific efficacy data, not economics: HER2 IHC/ISH prevalence and T-DXd response by histotype, whether AZD5305-type PARP1-selective agents have any EC-specific rationale (CCNE1/HRD), and CALB2 expression in human progestin-refractory specimens.","leadChanges":[{"id":"L1","title":"HER2-directed antibody and ADC therapy in serous/carcinosarcoma endometrial cancer","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"Metformin + progestin to reverse progesterone resistance via AMPK-FOXO1-CALB2 and mitochondrial Ca2+ overload","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"Salvage strategies for MMR-proficient, checkpoint-refractory endometrial cancer","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L4","title":"PRC2/EZH2 inhibition in SUZ12- and YWHAE-fusion uterine mesenchymal tumours (lineage-separated from endometrial carcinoma)","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["What is the prevalence of HER2 3+/ISH-amplified and HER2-low status by EC histotype and TCGA molecular class, and does T-DXd activity extend to HER2-low serous/carcinosarcoma?","Is CALB2 (calretinin) actually overexpressed in human progestin-refractory endometrial lesions versus responders, and does nuclear FOXO1 track response to metformin+progestin in trial specimens?","For pMMR/IO-refractory EC, what are the reported ORR and biomarker correlates of cabozantinib+nivolumab (NCT03367741) versus lenvatinib+pembrolizumab, and are there head-to-head or sequencing data?","Does endometrial cancer have a defensible PARP rationale (HRD scores, CCNE1 amplification, ARID1A/ATM loss) that would justify PARP1-selective AZD5305 plus ADC combinations (NCT04644068)?","Do JAZF1-SUZ12 or YWHAE-NUTM2A/B fusion uterine sarcomas show PRC2 dependency and EZH2-inhibitor sensitivity in any preclinical model?","Is there any EC-specific ferroptosis vulnerability (GPX4, SLC7A11, ACSL4 status) with an agent-level handle, or should the ferroptosis thread be closed?"],"nextQueries":["(\"endometrial\" AND (\"HER2\" OR \"trastuzumab deruxtecan\") AND (\"serous\" OR \"carcinosarcoma\" OR \"HER2-low\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"endometrial\" AND (\"progestin resistance\" OR \"progesterone resistance\") AND (\"FOXO1\" OR \"CALB2\" OR \"metformin\")) AND SRC:MED","((\"endometrial stromal sarcoma\" AND (\"JAZF1\" OR \"SUZ12\" OR \"YWHAE\" OR \"NUTM2\")) OR (\"endometrial cancer\" AND \"pMMR\" AND (\"resistance to immunotherapy\" OR \"lenvatinib\" OR \"cabozantinib\"))) AND SRC:MED AND PUB_YEAR:[2023 T"],"papersShown":[{"pmid":"42535775","doi":"10.1080/13696998.2026.2706988","year":2026,"isNew":true,"title":"Estimating the budget impact of introducing dostarlimab as first line in treating endometrial cancer in Saudi Arabia"},{"pmid":"42495930","doi":"10.1080/01443615.2026.2701996","year":2026,"isNew":true,"title":"Comparison of lifestyle, surgery, and semaglutide for weight management in endometrial cancer: a prospective observational study"},{"pmid":"42339852","doi":"10.1080/07853890.2026.2688466","year":2026,"isNew":true,"title":"Paracervical block in office hysteroscopy with vaginoscopic approach to reduce patients' pain perception: a propensity score matching analysis"},{"pmid":"42318797","doi":"10.1080/07853890.2026.2688328","year":2026,"isNew":true,"title":"Research progress of ferroptosis in gynecological diseases"},{"pmid":"42281656","doi":"10.1016/j.apjon.2026.100971","year":2026,"isNew":true,"title":"Self-efficacy as a mediator between digital health literacy and self-care behaviors in older adults with cancer undergoing chemotherapy"},{"pmid":"42262932","doi":"10.1080/07853890.2026.2672785","year":2026,"isNew":true,"title":"The regulatory roles of non-coding RNAs in aerobic glycolysis and therapeutic potential in pancreatic ductal adenocarcinoma"},{"pmid":"42216563","doi":"10.1080/15384047.2026.2678642","year":2026,"isNew":true,"title":"TFPI2 in tumor metastasis: a double-edged sword with clinical implications"},{"pmid":"42187002","doi":"10.1080/15384047.2026.2678636","year":2026,"isNew":true,"title":"Diagnostic and prognostic value of lncSPATA8-AS1 in prostate cancer and its regulatory effect on tumor progression"},{"pmid":"42163698","doi":"10.2174/0109298673492535260512101635","year":2026,"isNew":true,"title":"Metformin Reverses Progesterone Resistance in Endometrial Cancer by Targeting the AMPK-FOXO1-CALB2 Pathway"},{"pmid":"42125712","doi":"10.3389/fonc.2026.1706826","year":2026,"isNew":true,"title":"Research progress of antibody-drug conjugates in the treatment of endometrial cancer"}],"trialsShown":[{"nct":"NCT05256225","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Testing the Addition of Herceptin Hylecta or Phesgo to the Usual Chemotherapy for HER2 Positive Endometrial Serous Carcinoma or Carcinosarco"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04567771","phase":"NA","status":"RECRUITING","isNew":true,"title":"Comparison of Proton or Intensity Modulated Radiation Therapy After Surgery for Endometrial or Cervical Cancer"},{"nct":"NCT04644068","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies"},{"nct":"NCT04104776","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas"},{"nct":"NCT01174121","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer"},{"nct":"NCT05564377","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Targeted Therapy Directed by Genetic Testing in Treating Patients With Locally Advanced or Advanced Solid Tumors, The ComboMATCH Screening T"},{"nct":"NCT03367741","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Cabozantinib S-malate and Nivolumab in Treating Patients With Advanced, Recurrent, or Metastatic Endometrial Cancer"}],"usage":{"input":8966,"output":5794},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"endometrial cancer\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"endometrial cancer\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42535775","PMID:42495930","PMID:42339852","PMID:42318797","PMID:42281656","PMID:42262932","PMID:42216563","PMID:42187002","PMID:42163698","PMID:42125712","NCT05256225","NCT07023731","NCT04567771","NCT04644068","NCT04104776","NCT01174121","NCT05564377","NCT03367741"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787176712219","cycle":136,"visit":1,"ts":"2026-08-19T21:58:32.219Z","cancer":{"key":"colorectal cancer","name":"colorectal cancer","mondo":{"id":"MONDO:0005575","name":"colorectal cancer"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise LIG1 inhibition (gambogenic acid class) plus oxaliplatin/FOLFOX as a ZBP1-dependent PANoptosis strategy to convert MSS colorectal cancer into an anti-PD-1-responsive setting, and track KRAS G12D degradation (ARV-806) as the parallel direct-driver arm.","confidence":0.42,"notebook":"Visit 1 opens the programme; nothing to retire yet. The pack is review-heavy, so I am weighting the two mechanistic items and the trial landscape and refusing to build leads on the survivorship/Delphi and single-gene prognostic-signature material (P4, P2 — CRY2 knockdown in one xenograft with a TIDE-based immune claim is hypothesis-grade at best, no chemical matter, not a lead).\n\nHighest-value new mechanism: LIG1 as a chemosensitisation node (PMID:42442130). LIG1 (nick ligation in BER and Okazaki-fragment maturation, [KNOWN] essential in proliferating normal crypt and marrow) is overexpressed in CRC; the natural-product binder gambogenic acid potentiates oxaliplatin across cells, drug-tolerant persisters, organoids and in vivo, and — the part that matters strategically — converts the response to ZBP1-dependent PANoptosis with immunogenic cell death, improving anti-PD-1 responsiveness on a FOLFOX backbone. [INFERRED] This is a route into MSS/pMMR CRC, the immunotherapy-refractory majority, via DNA-damage-driven innate sensing rather than TMB. Caveats from abstract only: GNA selectivity/polypharmacology unverified, no PD marker, therapeutic window versus crypt/marrow LIG1 dependence unaddressed. [SPECULATIVE] LIG1 blockade should be tested for synthetic lethality with PARP1-selective inhibition (AZD5305, NCT04644068) and in MUTYH-mutant [GERMLINE] BER-compromised backgrounds, since both converge on unligated BER intermediates.\n\nSecond: KRAS G12D is now directly drug-hunted in CRC via targeted protein degradation (ARV-806, NCT07023731) — catalytic, sub-stoichiometric knockdown, plausibly deeper pathway suppression than occupancy inhibitors. Expected resistance: RTK/ERK rebound (EGFR, FGFR), KRAS amplification or secondary allele switching, loss of the recruited E3 machinery, MAPK reactivation via BRAF/MEK — argues for upfront vertical combination. Normal-tissue window: G12D is neoantigenic-absent from normal tissue, wild-type RAS spared.\n\nThird: immune sensitisation of RAS-mutant MSS CRC by oncolytic reovirus (pelareorep) on FOLFIRI/bevacizumab (NCT07446322) — same conceptual bet as the PANoptosis axis (make a cold tumour visible), independent modality, worth tracking as a comparator arm rather than a separate hypothesis.\n\nFourth, weaker: the SFN/14-3-3σ–YY1 module sustaining the unfolded protein response and chemotolerance in CRC (PMID:42507757) — an evidence-graded review claim, no chemical matter; kept as a LEAD only because it names a testable perturbation (disrupt the phospho-client complex, not total 14-3-3) and connects to persister biology from P10. PI4K2B amplification in COAD (PMID:42445966) is filed as a note, not a lead: retrospective, family-wide heterogeneity, no inhibitor.\n\nNext I need: primary LIG1 target-engagement/selectivity data and whether ZBP1 expression stratifies responders; ARV-806 CRC-specific cohort readouts; whether PARP1-selective agents have any CRC signal.","leadChanges":[{"id":"L1","title":"LIG1 inhibition to break oxaliplatin resistance via ZBP1-dependent PANoptosis and immunogenic cell death","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L2","title":"KRAS G12D targeted degradation with upfront vertical MAPK/RTK blockade in CRC","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"Innate-immune sensitisation of RAS-mutant MSS CRC by oncolytic reovirus on chemo-antiangiogenic backbone","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L4","title":"Disrupt the 14-3-3sigma (SFN)-YY1 module to collapse UPR-dependent chemotolerance","level":"LEAD","status":"NEW","confidence":0.22}],"unverifiedCitations":0,"openQuestions":["Is gambogenic acid's chemosensitisation genuinely LIG1-dependent (knockout/rescue, selectivity panel), and does any tool compound exist with a usable therapeutic index against crypt and marrow LIG1?","Does ZBP1 expression (or RIPK3/caspase-8 integrity) predict PANoptosis conversion and anti-PD-1 benefit in MSS CRC, and can it be scored in clinical specimens?","Do PARP1-selective inhibitors (AZD5305) have any CRC signal, and is BER-ligation blockade synthetically lethal with PARP1 loss or MUTYH-mutant [GERMLINE] background?","What CRC-specific response depth and resistance genotypes emerge from KRAS G12D degradation (ARV-806), and is upfront EGFR/MEK co-blockade required?","Are any microbiome interventions (SynComs, exercise-driven modulation) supported by controlled outcome data in CRC rather than review-level mechanism, i.e. worth opening a lead at all?","Is PI4K2B amplification in COAD reproducible in independent cohorts and does any PI4K inhibitor show CRC-selective dependency?"],"nextQueries":["(LIG1 OR \"DNA ligase 1\") AND (inhibitor OR \"synthetic lethal\" OR PANoptosis) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"colorectal cancer\" AND (ZBP1 OR PANoptosis OR \"immunogenic cell death\") AND (\"microsatellite stable\" OR \"PD-1\") AND SRC:MED","(\"KRAS G12D\" AND (degrader OR PROTAC OR \"colorectal\")) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"42603146","doi":"10.1080/19490976.2026.2719056","year":2026,"isNew":true,"title":"Synthetic microbial communities: emerging live biotherapeutics for targeted gut microbiome modulation"},{"pmid":"42550740","doi":"10.1080/07853890.2026.2712007","year":2026,"isNew":true,"title":"Prognostic risk modeling based on integrated multi-omics analysis identifies CRY2 as a key regulator in tumor immunity and patient survival in colorectal cancer"},{"pmid":"42546541","doi":"10.1016/j.jpba.2026.117676","year":2026,"isNew":true,"title":"In depth study on the mechanism of Xiao-Chai-Hu-Tang in ameliorating irinotecan-induced intestinal toxicity and enhancing antitumor immunity via intestinal microbiota and fecal met"},{"pmid":"42540402","doi":"10.1016/j.apjon.2026.101003","year":2026,"isNew":true,"title":"Development of a physical activity promotion intervention for colorectal cancer survivors who are physically inactive: A Delphi study integrating the analytic hierarchy process"},{"pmid":"42507757","doi":"10.1080/15384047.2026.2710413","year":2026,"isNew":true,"title":"Stress-specific 14-3-3-client modules in digestive cancers: an evidence-graded review of adaptive survival and therapy resistance"},{"pmid":"42502958","doi":"10.1080/15384047.2026.2683096","year":2026,"isNew":true,"title":"Targeting molecular and genetic pathways driving tumorigenesis for precision therapy in colorectal cancer"},{"pmid":"42445966","doi":"10.1080/15384047.2026.2692173","year":2026,"isNew":true,"title":"xinguangA preliminary characterization of PI4K/PIPK alterations across solid tumors: an exploratory framework for prognostic and therapeutic stratification"},{"pmid":"42433082","doi":"10.1080/21505594.2026.2696642","year":2026,"isNew":true,"title":"Colorectal cancer landscape from gut microbiota: Insights into mutations, epigenetic dysregulation, and immune microenvironment alterations"},{"pmid":"42539807","doi":"10.3389/fphar.2026.1782130","year":2026,"isNew":true,"title":"Research progress of small molecule protein kinase inhibitors (SMKIs) in the treatment of colorectal cancer: mechanism, application, and future prospects"},{"pmid":"42442130","doi":"10.1016/j.drup.2026.101445","year":2026,"isNew":true,"title":"Targeting LIG1 to overcome oxaliplatin resistance by inducing PANoptosis in colorectal cancer"}],"trialsShown":[{"nct":"NCT07446322","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"FOLFIRI and Bevacizumab With or Without Pelareorep for Second-Line Treatment of Metastatic RAS-Mutated, Microsatellite-Stable Colorectal Can"},{"nct":"NCT06202183","phase":"NA","status":"RECRUITING","isNew":true,"title":"Exercise for Gut Microbiome in Patients With Young-Onset Colorectal Cancer Undergoing Chemotherapy: The COURAGE Trial"},{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT07328516","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Natural History Study of Early Life Exposures in Agriculture (ELEA)"},{"nct":"NCT06995924","phase":"NA","status":"RECRUITING","isNew":true,"title":"Improving Uptake of Surveillance in Colorectal Cancer Survivors Through Navigation and Web Education"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04644068","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies"},{"nct":"NCT01174121","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer"}],"usage":{"input":8825,"output":4917},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"colorectal cancer\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"colorectal cancer\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42603146","PMID:42550740","PMID:42546541","PMID:42540402","PMID:42507757","PMID:42502958","PMID:42445966","PMID:42433082","PMID:42539807","PMID:42442130","NCT07446322","NCT06202183","NCT07636785","NCT07328516","NCT06995924","NCT07023731","NCT04644068","NCT01174121"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787176522884","cycle":135,"visit":1,"ts":"2026-08-19T21:55:22.884Z","cancer":{"key":"prostate cancer","name":"prostate cancer","mondo":{"id":"MONDO:0008315","name":"prostate cancer"}},"control":false,"modelLabel":"SCIENCE","summary":"PTEN-deficient prostate cancer now has a validated AKT-inhibition axis (capivasertib + abiraterone/ADT, CAPItello-281), and SLC3A1-mediated ferroptosis evasion plus PI3K-AKT activation in enzalutamide-resistant models nominates a cystine/AKT co-targeting combination as the priority preclinical test.","confidence":0.55,"notebook":"Visit 1 opens the programme; four leads instantiated, three items explicitly parked.\n\nThe highest-value item is P8 (PMID:42359636), which reports CAPItello-281 (NCT04493853): capivasertib + abiraterone + ADT improved rPFS in PTEN-deficient mCSPC, with FDA approval. This converts the KG's top causal anchor, PTEN [GERMLINE anchor but overwhelmingly SOMATIC/epigenetic loss in tumours — the anchor label misleads here], from \"undruggable suppressor\" into a functioning synthetic-lethal-adjacent axis: PTEN loss → unopposed PIP3 → AKT1-3 activation, plus reciprocal AR/PI3K crosstalk that explains why ARPI monotherapy underperforms in this subgroup [KNOWN]. Open issues from the abstract alone: PTEN assay (IHC vs genomic loss, intratumoural heterogeneity), whether benefit extends to mCRPC, no OS reported, and hyperglycaemia/diarrhoea/rash as the window-defining toxicities (AKT2 in insulin signalling; therapeutic window is subgroup-restricted, not broad).\n\nP10 (PMID:42606826) creates an independent but converging lead: SLC3A1 (rBAT, the heavy subunit chaperoning SLC7A9/xCT-family cystine transport) is upregulated in enzalutamide-resistant models, suppresses ferroptosis, and activates PI3K-AKT; knockdown reduced pAKT. [INFERRED] this puts cystine/GSH-dependent ferroptosis evasion downstream of the same AKT node capivasertib hits, suggesting an AKT-inhibitor + cyst(e)ine-deprivation/GPX4-axis combination in ARPI-resistant disease. Normal-tissue caveat: rBAT is renal proximal tubule/intestinal; germline loss causes cystinuria [KNOWN], so systemic blockade risks nephrolithiasis. Evidence is bioinformatics + LNCaP/xenograft only — one paper, no independent confirmation.\n\nPSMA remains the delivery axis: T5 (NCT04506567, fractionated/multi-dose 225Ac-J591) and T6 (NCT06085664, REGN5678 anti-PSMA×CD28 presurgical) probe alpha-emitter and costimulatory-bispecific modalities; P3 (PMID:42565339) is a cost-consequence model, not new efficacy — it reiterates TheraP's PSA/rPFS advantage for Lu-PSMA with OS non-significant (16.4 vs 19.4 mo), which I record as a discipline note against overclaiming radioligand survival benefit.\n\nDDR lead is deliberately modest: NCT04550494 (talazoparib in DNA-repair-variant advanced cancers) plus the KG BRCA2/ATM/CHEK2/NBN anchors, and P2 (PMID:42576962) supplies a real-world constraint — PARPi/tacrolimus interaction and nephrotoxicity in transplant recipients.\n\nParked, do not re-propose without stronger data: Aurora-A peptide P1 (MST/MTT only, no in vivo, peptide developability; alisertib history in prostate is discouraging [KNOWN]); curcumin hydrogel P4 and the TPM/PCD review P9 (no target discipline); ZIF-8 Zn²⁺/STING platform P5 (interesting zinc-loss biology [KNOWN] but efficacy rests on OVA-antigen models — immunogenicity artefact). P6/P7/T8/T2/T4 are staging, economics, survivorship, screening — out of scope for target work.","leadChanges":[{"id":"L1","title":"AKT inhibition in PTEN-deficient prostate cancer, biomarker-refined","level":"LEAD","status":"NEW","confidence":0.7},{"id":"L2","title":"SLC3A1-dependent cystine uptake and ferroptosis evasion as an enzalutamide-resistance target","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L3","title":"PSMA as delivery axis: alpha-emitter and CD28-costimulatory bispecific","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L4","title":"PARP inhibition beyond BRCA: ATM/CHEK2/NBN-mutant prostate cancer","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":1,"openQuestions":["Which PTEN-loss assay (IHC vs biallelic genomic loss vs transcriptional signature) actually predicted capivasertib benefit in CAPItello-281, and does benefit extend to mCRPC or PIK3CA/AKT1-mutant PTEN-intact tumours?","Is SLC3A1 upregulation reproducible in independent enzalutamide-resistant models and patient tissue, and does cystine deprivation or GPX4 inhibition resensitise in vivo?","Does AKT inhibition and ferroptosis induction synergise, i.e. is the SLC3A1-AKT link causal or correlative?","What are the reported salivary/renal toxicity and PSMA-loss/neuroendocrine escape rates with 225Ac-J591 and other alpha-emitters, and any signal for radioligand+PARPi combinations?","Per-gene PARPi response in ATM/CHEK2/NBN-altered prostate cancer with zygosity annotation, and whether ATR/WEE1 inhibition outperforms PARPi in ATM-null disease?","Does any credible clinical evidence support cGAS-STING agonism or zinc restoration in prostate cancer outside OVA-model artefacts?"],"nextQueries":["(\"prostate cancer\") AND (capivasertib OR ipatasertib OR \"AKT inhibitor\") AND (PTEN) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"prostate cancer\") AND (ferroptosis OR GPX4 OR SLC7A11 OR cystine) AND (enzalutamide OR \"androgen receptor\" OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"prostate cancer\") AND (\"225Ac\" OR \"actinium-225\" OR \"alpha therapy\" OR \"PSMA x CD28\" OR bispecific) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"42578512","doi":"10.1080/14756366.2026.2700842","year":2026,"isNew":true,"title":"Structure-based screening and identification of a novel Aurora-A-targeting peptide with antiproliferative activity against prostate cancer cells"},{"pmid":"42576962","doi":"10.1016/j.curtheres.2026.100841","year":2026,"isNew":true,"title":"Prostate cancer initially misdiagnosed as prostatic abscess in a 36-year-old kidney transplant recipient"},{"pmid":"42565339","doi":"10.1080/13696998.2026.2709297","year":2026,"isNew":true,"title":"Clinical and economic outcomes of cabazitaxel versus Lu-PSMA in mCRPC: a US perspective"},{"pmid":"42519119","doi":"10.1016/j.ijpx.2026.100609","year":2026,"isNew":true,"title":"Curcumin-releasing oxidized konjac/GelMA hydrogel for ROS-mediated suppression of postoperative prostate cancer recurrence and metastasis"},{"pmid":"42519115","doi":"10.1016/j.ijpx.2026.100603","year":2026,"isNew":true,"title":"ZIF-8 nanoplatform coordinating Zn&lt;sup&gt;2+&lt;/sup&gt; overload and STING activation for enhanced prostate cancer immunotherapy"},{"pmid":"42464573","doi":"10.1080/13696998.2026.2699645","year":2026,"isNew":true,"title":"Cost-effectiveness of ferumoxtran-enhanced macrophage-specific-MRI and PSMA-PET/CT versus ePLND for nodal staging in primary prostate cancer: a decision analysis based on updated p"},{"pmid":"42434846","doi":"10.1080/02813432.2026.2701788","year":2026,"isNew":true,"title":"Barriers to satisfactory primary care contacts for Swedish cancer survivors: a cross-sectional survey"},{"pmid":"42359636","doi":"10.1080/15384047.2026.2694128","year":2026,"isNew":true,"title":"Targeting the PI3K/AKT pathway in prostate cancer: the role of PTEN deficiency and biomarker-guided therapy"},{"pmid":"42523794","doi":"10.3389/fimmu.2026.1833601","year":2026,"isNew":true,"title":"Programmed cell death mechanisms of traditional plant medicine in prostate cancer therapy"},{"pmid":"42606826","doi":"10.1002/jbt.71080","year":2026,"isNew":true,"title":"SLC3A1 Mitigates Ferroptosis and Promotes Enzalutamide Resistance in Prostate Cancer."}],"trialsShown":[{"nct":"NCT03866382","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare G"},{"nct":"NCT05424783","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"MRI And GPS Informing Choices for Prostate Cancer Treatment (MAGIC)"},{"nct":"NCT04423211","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Treating Prostate Cancer That Has Come Back After Surgery With Apalutamide and Targeted Radiation Based on PET Imaging"},{"nct":"NCT07328516","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Natural History Study of Early Life Exposures in Agriculture (ELEA)"},{"nct":"NCT04506567","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Fractionated and Multiple Dose 225Ac-J591 for Progressive mCRPC"},{"nct":"NCT06085664","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Pilot Presurgical Trial of REGN5678 (Anti-PSMA x CD28) in Patients With High-risk, Localized Prostate Cancer Followed by Radical Prostatec"},{"nct":"NCT04550494","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations"},{"nct":"NCT07109427","phase":"NA","status":"RECRUITING","isNew":true,"title":"Impact of an Electronic Health Record Maintenance Alert on PSA Screening Rates in a 10-Hospital Integrated Health System"}],"usage":{"input":8957,"output":5460},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"prostate cancer\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"prostate cancer\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42578512","PMID:42576962","PMID:42565339","PMID:42519119","PMID:42519115","PMID:42464573","PMID:42434846","PMID:42359636","PMID:42523794","PMID:42606826","NCT03866382","NCT05424783","NCT04423211","NCT07328516","NCT04506567","NCT06085664","NCT04550494","NCT07109427"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787176327028","cycle":134,"visit":1,"ts":"2026-08-19T21:52:07.028Z","cancer":{"key":"ovarian cancer","name":"ovarian cancer","mondo":{"id":"MONDO:0008170","name":"ovarian cancer"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise PARP1-selective (AZD5305) chemo/ADC combinations with [18F]-FTT as a target-engagement biomarker in HGSOC, and pursue dual EZH1/2 inhibition in SMARCA4/ARID1A-deficient ovarian subtypes; ferroptosis/cuproptosis and KIF18A remain unvalidated in ovarian primary data.","confidence":0.42,"notebook":"Programme opens with a thin, largely off-target pack: six of ten papers concern osteosarcoma, DLBCL, head-and-neck, NSCLC, brown adipose tissue or nursing outcomes and generate no ovarian lead. Signal concentrates in three reviews (PMID:42582447, PMID:42343901, PMID:42318797) and four trials.\n\nStrongest actionable axis is next-generation PARP pharmacology rather than new biology. NCT04644068 tests the PARP1-selective inhibitor AZD5305 with carboplatin/paclitaxel and with T-DXd/Dato-DXd; the mechanistic argument is a therapeutic window one — PARP2 trapping in haematopoietic progenitors drives the anaemia/thrombocytopenia that caps first-generation PARPi combination dosing, so PARP1-selectivity should permit chemotherapy- and ADC-combination intensities olaparib/niraparib cannot reach [KNOWN]. NCT04550494 (talazoparib in non-BRCA DNA-repair variants) probes the HRD boundary beyond BRCA1/2 [SOMATIC], and NCT03604315 supplies an orthogonal readout: [18F]-fluorthanatrace is a PARP-1 binding tracer, i.e. a candidate pharmacodynamic/target-abundance biomarker for exactly these combinations [INFERRED]. Expected resistance: BRCA reversion, 53BP1/Shieldin loss, ABCB1 upregulation, and for ADC arms, TOP1 mutation or HER2/TROP2 antigen loss [KNOWN].\n\nSecond lead comes from the KG anchor plus one trial. SMARCA4 [SOMATIC] is listed as correlated; SMARCA4-deficient SCCOHT and ARID1A-mutant clear-cell ovarian cancer are the canonical SWI/SNF-loss synthetic lethality with PRC2 [KNOWN]. NCT04104776 puts the dual EZH1/EZH2 inhibitor tulmimetostat into advanced solid tumours, giving a live vehicle for that hypothesis; dual EZH1/2 blockade may evade the PRC2 residual-activity escape that limits selective EZH2 inhibition [SPECULATIVE]. Window caveat: EZH2 is required for germinal-centre B-cell and HSC function [KNOWN].\n\nThird, and weaker: the three redox/cell-death reviews converge on platinum resistance as a redox-homeostasis state — GSH/GPX4 buffering, mitochondrial Cu/Fe handling, cuproptosis and ferroptosis as orthogonal death routes in cisplatin-resistant cells (PMID:42343901, PMID:42582447, PMID:42275298). These are reviews, not primary data; I record this as a low-confidence lead demanding a repurposing test (sulfasalazine/xCT, auranofin/TXNRD1, elesclomol or disulfiram-Cu) in isogenic platinum-resistant HGSOC lines. GPX4 is essential in normal tissue — the window is the main risk, and FSP1–CoQ10 upregulation is the predicted escape [KNOWN].\n\nFourth, provisional: PMID:42328720 shows KIF18A dependency is created by whole-genome doubling and is SAC-dependent, with AM-1882 active and non-toxic in xenografts. HGSOC is the archetypal WGD/CIN-high tumour [KNOWN], so extrapolation is reasonable but untested here; SAC attenuation is the built-in resistance route.\n\nNext visit must test each of these against primary ovarian data, not reviews.","leadChanges":[{"id":"L1","title":"PARP1-selective inhibition (AZD5305) as the combination backbone in HRD/HGSOC","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L2","title":"Dual EZH1/EZH2 inhibition in SMARCA4-deficient SCCOHT and ARID1A-mutant clear-cell ovarian cancer","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"Redox/metal-ion vulnerability of platinum-resistant ovarian cancer (ferroptosis and cuproptosis induction)","level":"LEAD","status":"NEW","confidence":0.28},{"id":"L4","title":"KIF18A inhibition as a CIN/whole-genome-doubling-selective vulnerability in HGSOC","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does NCT04644068 report ovarian-specific efficacy and, critically, lower grade 3/4 anaemia than first-generation PARPi + platinum combinations?","Which non-BRCA HR/DNA-repair genotypes (RAD51C/D, PALB2, BRIP1, CDK12) confer talazoparib or AZD5305 sensitivity, and can [18F]-FTT uptake predict it independently of genotype?","Is there SMARCA4- or ARID1A-stratified ovarian data for tulmimetostat or any dual EZH1/2 inhibitor, and does dual inhibition outperform tazemetostat in SCCOHT models?","Is there any primary (non-review) ovarian evidence that GPX4, SLC7A11 or FDX1/cuproptosis dependency is enriched in platinum-resistant versus naive tumours?","Are clinical-stage KIF18A inhibitors being tested in HGSOC, and does WGD status stratify response in ovarian models?","What is AZD6750 (NCT07115043) mechanistically, and does the rilvegostomig combination carry an ovarian rationale worth a lead?"],"nextQueries":["(\"ovarian\" AND (SMARCA4 OR ARID1A) AND (EZH2 OR PRC2 OR tazemetostat OR tulmimetostat)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"ovarian\" AND (AZD5305 OR \"PARP1-selective\" OR saruparib OR \"fluorthanatrace\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"ovarian cancer\" AND (\"platinum-resistant\" OR \"cisplatin-resistant\") AND (GPX4 OR SLC7A11 OR FSP1 OR FDX1 OR cuproptosis) AND (xenograft OR PDX OR \"cell line\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42328720","doi":"10.1080/15384047.2026.2689181","year":2026,"isNew":true,"title":"KIF18A inhibitor prevents chromosomally unstable osteosarcoma growth by activating spindle assembly checkpoint"},{"pmid":"42318797","doi":"10.1080/07853890.2026.2688328","year":2026,"isNew":true,"title":"Research progress of ferroptosis in gynecological diseases"},{"pmid":"42308349","doi":"10.1080/15384047.2026.2680347","year":2026,"isNew":true,"title":"ULK1's role in cancer progression and its emerging therapeutic potential"},{"pmid":"42295078","doi":"10.1080/14756366.2026.2674446","year":2026,"isNew":true,"title":"Shikonin suppresses diffuse large B-cell lymphoma progression by inducing ferritinophagy and ferroptosis &lt;i&gt;via&lt;/i&gt; lncRNA ADPGK-AS1 downregulation"},{"pmid":"42294496","doi":"10.1016/j.jdsr.2026.05.003","year":2026,"isNew":true,"title":"Metadherin: A pivotal oncogene and therapeutic target in head and neck cancer - a systematic review"},{"pmid":"42281656","doi":"10.1016/j.apjon.2026.100971","year":2026,"isNew":true,"title":"Self-efficacy as a mediator between digital health literacy and self-care behaviors in older adults with cancer undergoing chemotherapy"},{"pmid":"42275298","doi":"10.1080/13510002.2026.2687238","year":2026,"isNew":true,"title":"Significance of GSH and H&lt;sub&gt;2&lt;/sub&gt;S regulation for cancer: an intricate interplay between diet, microbiota, metabolic reprogramming, and immune health"},{"pmid":"42265935","doi":"10.1080/2162402x.2026.2684116","year":2026,"isNew":true,"title":"CXCL13-expressing CD4&lt;sup&gt;+&lt;/sup&gt; T cells coordinate the lymphocytes triad to promote the anti-tumor immunity in NSCLC"},{"pmid":"42582447","doi":"10.3389/or.2026.1850292","year":2026,"isNew":true,"title":"Advancing the frontiers of ovarian cancer therapy: a comprehensive synthesis of emerging cell death paradigms"},{"pmid":"42343901","doi":"10.3389/fcell.2026.1852307","year":2026,"isNew":true,"title":"Cisplatin resistance in ovarian cancer: exploration and insights from metal ion homeostasis imbalance"}],"trialsShown":[{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT03049462","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta3-Adrenergic Receptor Agonists"},{"nct":"NCT04550494","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations"},{"nct":"NCT04644068","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies"},{"nct":"NCT04104776","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas"},{"nct":"NCT03604315","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Serial Imaging of the Novel Radiotracer [^18F] FLuorthanatrace ([^18F] FTT) by PET/CTF"},{"nct":"NCT01174121","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer"}],"usage":{"input":8745,"output":5540},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"ovarian cancer\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"ovarian cancer\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42328720","PMID:42318797","PMID:42308349","PMID:42295078","PMID:42294496","PMID:42281656","PMID:42275298","PMID:42265935","PMID:42582447","PMID:42343901","NCT07115043","NCT07023731","NCT03049462","NCT04550494","NCT04644068","NCT04104776","NCT03604315","NCT01174121"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787176134093","cycle":133,"visit":1,"ts":"2026-08-19T21:48:54.093Z","cancer":{"key":"breast cancer","name":"breast cancer","mondo":{"id":"MONDO:0007254","name":"breast cancer"}},"control":false,"modelLabel":"SCIENCE","summary":"In PIK3CA-mutant breast cancer, PI3K-pathway inhibition induces FOXO1/FOXO3-driven IRS2 upregulation that sustains PI3K signalling, nominating IRS2/IGF1R as a rational co-target with alpelisib, inavolisib or capivasertib — but only if the insulin-signalling therapeutic window can be spared.","confidence":0.5,"notebook":"Visit 1 opens the programme. The pack is mostly noise for therapeutic purposes: P1 (shoulder arthroplasty/TRT), P2/P3 (diagnostic-delay protocols), P5 (circRNA correlative bioinformatics, 24 patients, no functional target), P6 (DOX-induced ALT-like telomere repair in MDA-MB-231 — mechanistically interesting but no tractable node yet), P7 (graphene photothermal xenograft meta-analysis, 46 vs 46 animals, no toxicity/clearance data), P8 (canine HCC transporters; \"breast cancer resistance protein\" is a keyword artefact). T4/T5/T6/T8 are behavioural/biomarker-collection studies. None of these seed a lead; recording them so the desk does not re-mine this seam.\n\nThree signal-bearing items.\n\nFirst and strongest: P10 (PMID:42575435) defines a FOXO1/FOXO3-dependent feedback loop in which PI3K-pathway inhibition raises IRS2 protein/mRNA, and IRS2 sustains PI3K output specifically in PIK3CA-mutant (not WT) cells, with IRS2 abundance correlating with inhibitor resistance across mutant lines. This maps directly onto the KG anchors PIK3CA and AKT1 [SOMATIC in the tumour-maintenance sense; the Monarch \"causal\" call is germline-flavoured — do not conflate]. IRS1 is unaffected, which argues for adaptor-selective, not generic, feedback. [INFERRED] the actionable node is the receptor input feeding IRS2 — INSR/IGF1R — or IRS2 itself via degrader chemistry, layered on alpelisib/inavolisib/capivasertib. The therapeutic-window argument is the hard part: IRS2 is the principal hepatic/β-cell insulin adaptor [KNOWN], and PI3Kα inhibitors already cause hyperglycaemia, so INSR-directed blockade is likely metabolically prohibitive; selective IGF1R or tumour-restricted IRS2 degradation is the honest path. Opens as LEAD.\n\nSecond: T3 (NCT05919108) — neoadjuvant neratinib in HER2-mutated stage I-III lobular breast cancer. Lobular histology is the CDH1-loss context in the anchor set [GERMLINE for predisposition, somatic biallelic loss in tumours], and HER2 kinase-domain mutations are an activating-oncogene target amenable to covalent pan-HER inhibition. Opens as LEAD; expected resistance is secondary HER2 mutation, PIK3CA co-mutation, HER3/NRG1 bypass.\n\nThird: a ferroptosis axis. P9 (PMID:42524322) shows PVT1 silencing depletes GSH and raises ROS/LPO, resensitising doxorubicin-resistant BC in vivo; P4 (PMID:42540475) independently converges on GSH depletion/GPX4 inactivation via Fe-cycling plus artesunate. Two independent routes to the same node in one pack is worth a LEAD, but the nanoplatform is not a near-term asset and PVT1 is not directly druggable — the tractable read-out is whether anthracycline-resistant tumours are GPX4/SLC7A11-dependent.\n\nNext visit: test whether IRS2 has clinical-tissue support, and whether ferroptosis dependence is subtype-restricted.","leadChanges":[{"id":"L1","title":"IRS2 adaptor feedback as the resistance node for PI3Kalpha/AKT inhibition in PIK3CA-mutant breast cancer","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L2","title":"HER2 kinase-domain mutations as a direct oncogene target in CDH1-deficient lobular breast cancer","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"Ferroptosis sensitisation to reverse anthracycline resistance (PVT1-GSH-GPX4 axis)","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["Does IRS2 protein/RNA abundance in archival tumour tissue predict progression on alpelisib, inavolisib or capivasertib, and is the rise detectable on-treatment biopsy?","Can IGF1R-selective blockade (sparing INSR) suppress the IRS2 feedback arm without compounding PI3Ki hyperglycaemia, or is tumour-restricted IRS2 degradation the only viable route?","What are the response rates and resistance mechanisms for pan-HER inhibition in HER2-mutant, CDH1-null lobular carcinoma, and does PIK3CA co-mutation abolish benefit?","Is ferroptosis dependency in anthracycline-resistant breast cancer subtype-restricted (mesenchymal/TNBC vs HR+), and does FSP1 status gate it?","What is the current evidence base for HER2-ultralow ADC benefit (T-DXd, NCT05945732) and does membrane HER2 quantity or payload trafficking set the threshold?"],"nextQueries":["(IRS2 OR \"insulin receptor substrate 2\" OR IGF1R) AND (alpelisib OR inavolisib OR capivasertib OR \"PI3K inhibitor\") AND \"breast cancer\" AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"lobular\" AND \"breast cancer\") AND (CDH1 OR \"HER2 mutation\" OR ERBB2) AND (neratinib OR \"pan-HER\" OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"breast cancer\" AND (GPX4 OR SLC7A11 OR FSP1 OR ferroptosis) AND (resistance OR doxorubicin OR anthracycline) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42602516","doi":"10.1016/j.jsea.2026.100063","year":2026,"isNew":true,"title":"Pre-operative injectable testosterone therapy is associated with increased five-year revision risk after total shoulder arthroplasty: a TriNetX database analysis"},{"pmid":"42564769","doi":"10.1016/j.mex.2026.104057","year":2026,"isNew":true,"title":"Time to diagnosis and treatment and breast cancer outcomes in young women: a systematic review protocol"},{"pmid":"42555458","doi":"10.1016/j.mex.2026.104035","year":2026,"isNew":true,"title":"Assessing health beliefs and patient delay among breast cancer patients in West Sumatra, Indonesia"},{"pmid":"42540475","doi":"10.1016/j.ijpx.2026.100607","year":2026,"isNew":true,"title":"Artesunate-loaded bovine serum albumin nanoplatform with metal-polyphenol network coating for ferroptosis-driven breast cancer therapy"},{"pmid":"42524694","doi":"10.1002/ansa.70098","year":2026,"isNew":true,"title":"Identification of a Circular RNA as a Potential Diagnostic and Prognostic Biomarker in Breast Cancer Through Integrated Bioinformatic and Experimental Analyses"},{"pmid":"42489337","doi":"10.1080/19491034.2026.2688655","year":2026,"isNew":true,"title":"Repair and misrepair of telomeric DNA in dynamic interactions with PML nuclear bodies and lamin B1 in doxorubicin-treated cancer cells"},{"pmid":"42449201","doi":"10.1080/02656736.2026.2699379","year":2026,"isNew":true,"title":"Efficacy of doxorubicin-loaded graphene nanoplatform chemo-photothermal therapy versus photothermal therapy alone for breast cancer xenograft tumors: a meta-analysis"},{"pmid":"42441046","doi":"10.1002/vro2.70038","year":2026,"isNew":true,"title":"OATP1A2 mRNA downregulation in canine hepatocellular carcinoma"},{"pmid":"42524322","doi":"10.2147/bctt.s583235","year":2026,"isNew":true,"title":"Long Non-Coding RNA PVT1 Promotes Doxorubicin Resistance by Inhibiting Ferroptosis in Breast Cancer"},{"pmid":"42575435","doi":"10.1016/j.jbc.2026.113426","year":2026,"isNew":true,"title":"Insulin receptor substrate 2 (IRS2) confers resistance to PI3K pathway inhibition in PIK3CA mutant breast cancer"}],"trialsShown":[{"nct":"NCT06860529","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Serplulimab Combined With Chemotherapy for Early-stage HR+/HER2- Breast Cancer"},{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT05919108","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Neoadjuvant Neratinib in Stage I-III HER2-Mutated Lobular Breast Cancers"},{"nct":"NCT06112613","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Mobile Health for Adherence in Breast Cancer Patients"},{"nct":"NCT02732171","phase":"NA","status":"RECRUITING","isNew":true,"title":"PENN-Surveillance Markers of Utility for Recurrence After (Neo)Adjuvant Therapy for Breast Cancer"},{"nct":"NCT07635147","phase":"NA","status":"RECRUITING","isNew":true,"title":"Decision Support Tool for Patients With Advanced Breast Cancer"},{"nct":"NCT05945732","phase":"n/a","status":"RECRUITING","isNew":true,"title":"DESTINY Breast Respond HER2-(Ultra)Low Europe"},{"nct":"NCT06275126","phase":"NA","status":"RECRUITING","isNew":true,"title":"Optimizing Surgical Decisions in Young Adults With Breast Cancer"}],"usage":{"input":8947,"output":4873},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"breast cancer\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"breast cancer\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42602516","PMID:42564769","PMID:42555458","PMID:42540475","PMID:42524694","PMID:42489337","PMID:42449201","PMID:42441046","PMID:42524322","PMID:42575435","NCT06860529","NCT07115043","NCT05919108","NCT06112613","NCT02732171","NCT07635147","NCT05945732","NCT06275126"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787175946004","cycle":132,"visit":13,"ts":"2026-08-19T21:45:46.004Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Guideline-level confirmation that optimal biologic dose is safer and equally effective, with dose reduction preferred over TKI switching, promotes risk-stratified de-escalation (L7) to DOSSIER and strengthens the TDM concentration-floor lead (L9), while a sitagliptin allo-HSCT paper shows enzymatic ","confidence":0.5,"notebook":"This visit's pack was near-empty for the programme: two targeted queries (CD26/DPP4-directed depletion in CML; asciminib failure mutation spectrum) returned almost nothing on-topic — CAR-macrophage, GIST dormancy, splenic remodelling, gallic acid, CRISPRi and MASLD reviews are off-target and not citable to any lead. Two items matter.\n\nFirst, PMID:42209462 (Blood Cancer Journal treatment-algorithm review) states explicitly that post-approval studies show an optimal biologic dose is safer than and as effective as the approved dose, and that for TKI toxicity dose reduction — not switching — is the preferred manoeuvre unless toxicity is prohibitive. This is guideline-level, independent endorsement of the two exposure leads. It converges with the desk's primary data: asciminib flat MMR across exposure quartiles 2–4 with a low-quartile penalty (PMID:40848059), nilotinib TDM efficacy floor with a ~1290 ng/mL hyperbilirubinaemia ceiling (PMID:40978483), equivalent TFR across abrupt/taper/reduced arms (PMID:40647447), and real-world label-dose asciminib reproducing trial depth (PMID:41917309). L7 accordingly moves to DOSSIER: three-plus evidence-bearing visits, ten citations, and it has survived my own kill attempts (ELTS AUROC 0.53; CD26+ counts disqualified as an on-treatment surrogate, PMID:40116978). The residual gap is unchanged and load-bearing — no prospective randomised de-escalation trial with molecular-depth endpoints. L9 strengthens modestly; the review supports floor-plus-plateau but adds no PK.\n\nSecond, PMID:42053786: low-dose sitagliptin added to allo-HSCT prophylaxis reduced liver aGVHD and accelerated neutrophil engraftment. Mechanistically this is the wrong direction for L15 — enzymatic DPP4 inhibition is stem-cell-supportive (CXCL12/SDF-1 preservation [KNOWN]), so it cannot be read as CD26-directed LSC depletion, and it raises the [SPECULATIVE] concern that DPP4 blockade could favour leukaemic homing. Combined with a second consecutive empty query for any anti-CD26 antibody/ADC/CAR tested against primary CML LSCs and no published density differential versus activated T cells, L15 weakens to 0.2 with a prespecified retirement condition next visit.\n\nL1 weakens again (0.30): a query written to surface asciminib+ponatinib/olverembatinib exposure and compound-mutant data returned only the title-only blast-phase case already held (PMID:41376545); NCT03906292 is silent for a twelfth visit. L6 is untouched because no atlas-mining query ran — its retirement clock resumes next visit. Review-only mention of ELVN-001/olverembatinib is noted but not lead-worthy.\n\nNothing here dislodges the solved core: BCR::ABL1 [SOMATIC] fusion, ATP-site and myristoyl-pocket inhibition; the open frontier remains dose/exposure optimisation and kinase-independent persistence.","leadChanges":[{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"DOSSIER","status":"STRENGTHENED","confidence":0.72},{"id":"L9","title":"Concentration-floor (TDM-anchored) de-escalation: reduce exposure to a measured pharmacokinetic threshold, not to a fraction of label dose","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.6},{"id":"L15","title":"CD26 (DPP4) as a CML-restricted surface antigen for antibody- or cell-mediated eradication of the persistent BCR::ABL1+ LSC","level":"LEAD","status":"WEAKENED","confidence":0.2},{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"WEAKENED","confidence":0.3}],"unverifiedCitations":1,"openQuestions":["Does GRN inference on published CML single-cell/multiomic atlases show TRIM28/SETDB1 (or STAT5A) regulon enrichment in the persistent CD26+CD35- LSC state? Prespecified retirement of L6/L13 if the next pass is again empty.","Has any CD26/DPP4-directed depleting agent (antibody, ADC, CAR-T, CAR-M) been tested against primary CML LSCs, and what is the measured CD26 surface density differential versus activated normal T cells and same-donor CD34+ HSPCs?","What is the published kinase-domain mutation spectrum at asciminib failure beyond A337V/P465S, and which ATP-site agent rescues each (mutation-resolved response in the Japanese postmarketing cohort)?","Is there any prospective or randomised CML trial testing dose de-escalation or an optimal-biologic-dose rule with MR4.0/MR4.5 and TFR endpoints, rather than retrospective/consensus support?","Can a DMR-specific asciminib Cmin floor be derived once adherence/relative dose intensity is deconfounded, and does Cmax_2h outperform trough?","Does the diagnosis-time CD26+CD35- primitive-fraction gate predict 12-month molecular failure independently, head-to-head against the Morphoclinical cytomorphology model?"],"nextQueries":["(\"chronic myeloid leukemia\" OR CML) AND (\"single-cell\" OR scRNA-seq OR multiome OR \"regulatory network\" OR SCENIC) AND (TRIM28 OR KAP1 OR SETDB1 OR STAT5A OR \"leukemic stem cell\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"chronic myeloid leukemia\") AND (\"dose reduction\" OR de-escalation OR \"low dose\" OR \"optimal biologic dose\") AND (prospective OR randomized OR trial) AND (\"molecular response\" OR MR4 OR \"treatment-free remission\") AND S","(\"chronic myeloid leukemia\") AND (asciminib OR olverembatinib OR ELVN-001) AND (\"kinase domain mutation\" OR \"compound mutation\" OR \"next-generation sequencing\") AND SRC:MED AND PUB_YEAR:[2025 TO 2026]"],"papersShown":[{"pmid":"41964040","doi":"10.1186/s13045-026-01792-9","year":2026,"isNew":true,"title":"Optimizing next-generation CAR-macrophages against solid tumors: challenges and potential strategies"},{"pmid":"41955967","doi":"10.1016/j.neo.2026.101306","year":2026,"isNew":true,"title":"Targeting tumor dormancy: the next frontier in gastrointestinal stromal tumor therapy"},{"pmid":"41861100","doi":"10.1002/advs.202600027","year":2026,"isNew":true,"title":"Tumor-Induced Splenic Remodeling: Mechanisms of Systemic Immunosuppression and Emerging Therapeutic Opportunities"},{"pmid":"42101165","doi":"10.1002/mnfr.70491","year":2026,"isNew":true,"title":"The Evolving Therapeutic Landscape of Gallic Acid: A Review of Mechanistic Insights and Clinical Potential"},{"pmid":"42074203","doi":"10.3390/ijms27083564","year":2026,"isNew":true,"title":"CRISPR Interference to Inhibit Oncogenes for Cancer Therapy"},{"pmid":"42073640","doi":"10.3390/cancers18081316","year":2026,"isNew":true,"title":"Beyond Insulin Resistance: Exploring the Centrality of the Gut-Liver Axis in Mediating Immunometabolic Dysregulation Driving Hepatocellular Carcinoma in MASLD and Diabetes"},{"pmid":"42053786","doi":"10.1007/s00277-026-07036-7","year":2026,"isNew":true,"title":"Low dose of sitagliptin: effectively prevent liver aGVHD and accelerate neutrophil engraftment"},{"pmid":"42209462","doi":"10.1038/s41408-026-01527-6","year":2026,"isNew":true,"title":"Chronic myeloid leukemia: incorporation of recent advances into current treatment algorithms"},{"pmid":"42327472","doi":"10.1002/hsr2.72579","year":2026,"isNew":false,"title":"Genetic Variants of BMI1 (rs1042059 and rs11591377) and Their Potential Role in Leukemia Susceptibility: A Narrative Review"},{"pmid":"41376545","doi":"10.3324/haematol.2025.289085","year":2026,"isNew":false,"title":"Combined asciminib and olverembatinib in blast-phase chronic myeloid leukemia"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":17621,"output":7387},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"chronic myeloid leukemia\" OR \"CML\") AND (CD26 OR DPP4 OR dipeptidyl-peptidase) AND (\"leukemic stem cell\" OR antibody OR CAR OR depletion) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"chronic myeloid leukemia\") AND (asciminib) AND (\"kinase domain\" OR mutation OR compound OR ponatinib OR olverembatinib) AND (failure OR resistance OR sequencing) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]"],"evidenceIds":["PMID:41964040","PMID:41955967","PMID:41861100","PMID:42101165","PMID:42074203","PMID:42073640","PMID:42053786","PMID:42209462","PMID:42327472","PMID:41376545","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787175732523","cycle":131,"visit":1,"ts":"2026-08-19T21:42:12.523Z","cancer":{"key":"dyskeratosis congenita","name":"dyskeratosis congenita","mondo":{"id":"MONDO:0015780","name":"dyskeratosis congenita"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise restorative telomerase-flux strategies in dyskeratosis congenita — PAPD5/TENT4B inhibition to stabilise TERC and TERC-promoter-calibrated DKC1 gene therapy — while scoring reduced-toxicity HSCT as marrow-only given severe TBD-associated childhood ILD.","confidence":0.55,"notebook":"Visit 1 opens the programme. The anchor set is dominated by germline telomere-maintenance genes (DKC1, TERC, TERT, RTEL1, TINF2, WRAP53, NOP10, NHP2, ACD, DCLRE1B [GERMLINE]); PARN, CTC1, USB1 are listed \"correlated\" but are in fact germline TBD/poikiloderma genes [KNOWN] — I will not treat them as somatic drivers. NPM1 and TYMS are the only entries that plausibly reflect somatic/secondary biology (NPM1 = AML clonal evolution in a cancer-predisposition marrow [KNOWN]); TYMS is mechanistically interesting because it puts dNTP supply on the map.\n\nMechanistic frame this visit: the disease is a dosage/flux problem at the telomerase RNP, not an activated oncogene, so every credible therapeutic is restorative (raise functional telomerase/TERC/dyskerin, or reduce replicative demand on stem cells), and each carries an intrinsic oncogenic-window argument because the same axis is what tumours exploit [KNOWN]. P1 (PMID:40234053) gives the structural scaffold — holoenzyme assembly and transient accessory factors — i.e. multiple non-catalytic nodes are in principle drug-addressable. P8 (PMID:42337823) is the highest-value mechanistic paper: it consolidates PARN/telomerase as coupled 3'-tail modifiers and flags p53 crosstalk. That supports [KNOWN] PAPD5/TENT4B inhibition (dihydroquinolizinones from HBV programmes) as the cleanest restorative node — block TERC hyperadenylation, rescue TERC steady state in PARN- and DKC1-mutant cells — so I open it as a lead despite no DC-specific trial. P5 (PMID:42564579) is the strongest translational datum: in DKC1-edited cord-blood CD34+ cells, PGK-driven dyskerin rescued proliferation only, whereas TERC-promoter-driven dyskerin also restored telomere maintenance and rRNA maturation — a dosage/stoichiometry lesson that generalises to any DKC1 gene-therapy or mRNA strategy. P7 (PMID:42497987) reframes phenotype: human-range telomeres are permissive at steady state but fail under 5-FU or transplant stress, so conditioning intensity and G-CSF-type proliferative demand are themselves disease-modifying variables — mechanistic support for the radiation/alkylator-free HSCT programmes (NCT01659606, NCT03579875, NCT01962415, and the cord-augmented MUD data in PMID:41840938). P10 (PMID:42316340) is the sobering counterweight: paediatric TBD-ILD with severe course in 7/10 — marrow-directed cures do not touch lung, so any HSCT lead must be scored as partial. P2/P3 are context, not evidence. P6 (XCI reactivation) I decline to make a lead: female DKC1 carriers are typically protected by skewing, so reactivation is more likely harmful [INFERRED].\n\nTwo active phase 1s define the near-term readout landscape: nucleoside therapy (NCT06817590) and quercetin (NCT07628972); I record quercetin as low-confidence pending any stated telomere-relevant mechanism. Androgens/danazol remain the pharmacologic baseline [KNOWN] but are unsupported by anything in this pack.","leadChanges":[{"id":"L1","title":"PAPD5/TENT4B inhibition to restore TERC steady-state levels in PARN- and DKC1-mutant TBD","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"Dosage-calibrated DKC1 gene therapy for X-linked DC HSPCs using TERC-promoter-driven dyskerin","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L3","title":"Deoxynucleoside (dC/dT) supplementation to relieve dNTP-limited telomere maintenance","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L4","title":"Radiation- and alkylator-free reduced-toxicity conditioning as marrow-only, stress-minimising HSCT for DC","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L5","title":"Senotherapeutic quercetin as symptom/attrition modifier in DC/TBD — low prior, mechanism unspecified","level":"LEAD","status":"NEW","confidence":0.22}],"unverifiedCitations":0,"openQuestions":["Is there any direct evidence that PAPD5/TENT4B inhibition raises TERC and elongates telomeres in DKC1-, PARN- or TERC-mutant human HSPCs, and what is the hepatic/erythroid toxicity of dihydroquinolizinone PAPD5/7 inhibitors?","What is the permissive dyskerin expression window in pTERC-DKC1-corrected HSPCs (vector copy number vs telomere and rRNA correction), and does correction persist through serial in vivo proliferative stress?","Does deoxycytidine/deoxythymidine supplementation act telomerase-dependently, and are there interim telomere-length or hematologic readouts from NCT06817590?","Which interventions, if any, address TBD pulmonary fibrosis/chILD rather than marrow failure — is there evidence for antifibrotics (nintedanib/pirfenidone) or lung-directed telomerase restoration in TBD-specific cohorts?","How should somatic clonal evolution (NPM1, and reported somatic TERT-promoter/POT1 rescue events) be monitored or exploited after any restorative therapy in this cancer-predisposition background?","Does the quercetin phase 1 (NCT07628972) declare a senescence-biomarker mechanism, and is senolysis safe in a hypocellular TBD marrow?"],"nextQueries":["(PAPD5 OR TENT4B OR PAPD7 OR \"poly(A) polymerase\") AND (TERC OR telomerase OR \"telomere\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"telomere biology disorder\" OR \"dyskeratosis congenita\" OR \"short telomere syndrome\") AND (\"pulmonary fibrosis\") AND (nintedanib OR pirfenidone OR danazol OR androgen OR treatment) AND SRC:MED AND PUB_YEAR:[2022 TO 2026","(\"dyskeratosis congenita\" OR \"telomere biology disorder\") AND (\"somatic\" AND (\"clonal hematopoiesis\" OR \"TERT promoter\" OR POT1 OR NPM1 OR \"myelodysplastic\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"40234053","doi":"10.1101/cshperspect.a041697","year":2026,"isNew":true,"title":"Structural Biology of Telomerase and Associated Factors"},{"pmid":"41859097","doi":"10.3389/fimmu.2026.1773574","year":2026,"isNew":true,"title":"Established and emerging non-cellular therapies in inherited bone marrow failure syndromes"},{"pmid":"42151033","doi":"10.1053/j.seminhematol.2026.04.002","year":2025,"isNew":true,"title":"Telomere biology disorders as an example of rare disease advocacy"},{"pmid":"41840938","doi":"10.1080/07853890.2026.2635832","year":2026,"isNew":true,"title":"Cord blood transfusion added matched unrelated donor transplantation as a preferable choice for aplastic anaemia: a comparative study from a single centre"},{"pmid":"42564579","doi":"10.1016/j.omta.2026.201811","year":2026,"isNew":true,"title":"The potential of gene therapy to rescue telomeric and extratelomeric defects in X-linked dyskeratosis congenita"},{"pmid":"42180998","doi":"10.1016/j.gendis.2025.101964","year":2026,"isNew":true,"title":"From inactivation to intervention: X chromosome silencing in disease pathogenesis and emerging therapeutic strategies"},{"pmid":"42497987","doi":"10.1016/j.jbc.2026.113364","year":2026,"isNew":true,"title":"Human length telomeres restrict the regenerative potential of hematopoietic stem cells in mice"},{"pmid":"42337823","doi":"10.1002/wrna.70049","year":2026,"isNew":true,"title":"Molecular Interplay of PARN and Telomerase: Tail Modifiers and Disease Implications"},{"pmid":"42333174","doi":"10.1007/s12288-025-02178-6","year":2026,"isNew":true,"title":"Beyond Hemoglobinopathies: Non-Hemoglobinopathy Causes of Transfusion-Dependent Anemia in Children"},{"pmid":"42316340","doi":"10.3345/cep.2026.00290","year":2026,"isNew":true,"title":"Telomere biology disorders associated with childhood interstitial lung disease"}],"trialsShown":[{"nct":"NCT00027274","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Cancer in Inherited Bone Marrow Failure Syndromes"},{"nct":"NCT06817590","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Nucleoside Therapy in Patients With Telomere Biology Disorders"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT02720679","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Investigation of the Genetics of Hematologic Diseases"},{"nct":"NCT07628972","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Quercetin Dyskeratosis Congenita (DC)/Telomere Biology Disorders (TBD)"},{"nct":"NCT01659606","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita"},{"nct":"NCT03579875","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders"},{"nct":"NCT01962415","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT"}],"usage":{"input":8426,"output":6795},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"dyskeratosis congenita\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"dyskeratosis congenita\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:40234053","PMID:41859097","PMID:42151033","PMID:41840938","PMID:42564579","PMID:42180998","PMID:42497987","PMID:42337823","PMID:42333174","PMID:42316340","NCT00027274","NCT06817590","NCT03050268","NCT02720679","NCT07628972","NCT01659606","NCT03579875","NCT01962415"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787175514720","cycle":130,"visit":1,"ts":"2026-08-19T21:38:34.720Z","cancer":{"key":"nijmegen breakage syndrome","name":"Nijmegen breakage syndrome","mondo":{"id":"MONDO:0009623","name":"Nijmegen breakage syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise radiation/alkylator-sparing HSCT conditioning (low-dose treosulfan+PTCy, NCT06198842) as the near-term intervention in Nijmegen breakage syndrome, and test whether residual p70-NBS1/MRN assembly is R2TP/HSP90-dependent before any chaperone-inhibitor exposure in these patients.","confidence":0.42,"notebook":"**Visit 1 — programme opened.** The pack is mostly off-target (m5C, lactylation, gastric lactylation reviews, cardiac fibrosis) and contains no NBS-specific therapeutic trial data beyond one registration. Four usable threads.\n\nThe only clinically actionable item is T1 (NCT06198842): phase 2, low-dose treosulfan conditioning plus post-transplant cyclophosphamide for HSCT in NBS. This matters because NBS cells are hypersensitive to ionising radiation and radiomimetics [KNOWN — hypomorphic *NBN* 657del5 truncation, MRN-dependent DSB signalling], so TBI/busulfan-heavy myeloablation carries excess regimen-related mortality. P4 (PMID:42244353), though written about A-T, states explicitly that FA/NBS experience supports radiation-sparing, fludarabine-based conditioning and documents VOD/GvHD/hepatic failure with myeloablation in a sister MRN/ATM disorder — independent corroboration of the *principle*, not of treosulfan specifically. Opening as LEAD-1. The key unresolved point: HSCT restores haematopoiesis and immunity but does **not** correct the germline *NBN* defect in non-haematopoietic tissue, so solid-tumour and neurologic risk should persist post-transplant [INFERRED]; long-term second-malignancy data are the decisive endpoint I need.\n\nP5 (PMID:42248294) supplies a genuinely new mechanistic handle: the R2TP (RUVBL1–RUVBL2–RPAP3–PIH1D1)/HSP90 chaperone assembles both PIKKs (ATM/ATR/DNA-PK) and the MRE11–RAD50–NBS1 complex. If assembly of the residual p70-NBS1/MRN pool in hypomorphs is chaperone-dependent [SPECULATIVE], HSP90 and RUVBL1/2 inhibitors would be predicted to be disproportionately toxic in NBS patients — a contraindication worth testing in patient LCLs — while conversely offering a vulnerability in tumours that have lost the residual allele. Opened as LEAD-2, low confidence, explicitly a testable pharmacology experiment rather than a therapy.\n\nP3 (PMID:42567300) shows alloimperatorin collapses a c-MYC→NBS1 axis and synergises with gemcitabine via sustained DSBs; P8 (PMID:42059277) frames c-MYC as a DDR/resistance node. Since NBS-associated lymphomas are frequently MYC-translocated B-NHL/DLBCL [KNOWN], MYC-driven NBS1 upregulation may be what rescues repair in the tumour despite the germline hypomorph — making NBS1-axis collapse plus replication-stress agents attractive but with an inverted therapeutic window (normal tissue is *also* NBN-deficient). LEAD-3, flagged window-limited.\n\nP9 (PMID:41798197) is a cautionary datapoint: near-6-year unplanned rhGH exposure in a *RAD50*-mutant NBS-like child before genetic diagnosis. GH/IGF-1 axis stimulation in an MRN-deficient, cancer-predisposed background is a pharmacovigilance question, not a therapy. Recorded as LEAD-4 (safety).\n\nRetired pre-emptively so the desk never re-proposes it: undifferentiated PARP-inhibitor monotherapy for NBS-associated tumours on germline-HR-defect logic alone — without evidence of a somatic second hit, the normal-tissue window is absent.","leadChanges":[{"id":"L1","title":"Reduced-toxicity, radiation-sparing conditioning for allogeneic HSCT in NBS (low-dose treosulfan + PTCy)","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"R2TP/HSP90 chaperone dependency of residual NBS1-p70/MRN assembly — contraindication test and tumour vulnerability","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L3","title":"c-MYC/NBS1 axis collapse plus replication-stress chemotherapy in MYC-driven NBS-associated lymphoma","level":"LEAD","status":"NEW","confidence":0.28},{"id":"L4","title":"Growth-hormone/IGF-1 axis exposure as a modifiable risk hazard in MRN-deficiency syndromes (safety lead)","level":"LEAD","status":"NEW","confidence":0.18}],"unverifiedCitations":0,"openQuestions":["Do NBS-associated lymphomas/solid tumours carry a somatic second hit at NBN (LOH or loss of the residual hypomorphic allele), which is the only condition under which HR-directed synthetic lethality (PARP/ATR/POLQ) has a therapeutic window?","What are the long-term post-HSCT second-malignancy and neurologic outcomes in NBS, given that transplant does not correct the germline NBN defect outside the haematopoietic compartment?","How does low-dose treosulfan+PTCy (NCT06198842) compare with fludarabine/melphalan or FA-adapted regimens in NBS for engraftment, VOD, GvHD and immune reconstitution?","Is residual p70-NBS1/MRN assembly R2TP/HSP90-dependent, and are NBN-hypomorph cells hypersensitive to HSP90 or RUVBL1/2 inhibitors?","Do reported NBS1/RAD51/XLF lactylation events modulate residual MRN function, making LDHA or glycolytic inhibition a modifier of chemosensitivity in NBN-hypomorph tumours?","Is there any registry signal linking rhGH/IGF-1 axis exposure to malignancy incidence in NBS or RAD50-deficient patients?"],"nextQueries":["(\"Nijmegen breakage syndrome\" OR \"NBN\" OR \"NBS1\") AND (transplantation OR conditioning OR treosulfan OR fludarabine) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"NBN\" OR \"NBS1\") AND (lymphoma OR \"loss of heterozygosity\" OR \"somatic\" OR \"PARP inhibitor\" OR \"ATR inhibitor\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"MRE11-RAD50-NBS1\" OR MRN) AND (RUVBL1 OR RUVBL2 OR R2TP OR HSP90) AND SRC:MED"],"papersShown":[{"pmid":"41778387","doi":"10.1080/15592294.2026.2629068","year":2026,"isNew":true,"title":"Emerging roles of RNA N5-methylcytosine modification in reproductive physiology and gynecological diseases"},{"pmid":"42169652","doi":"10.3892/or.2026.9138","year":2026,"isNew":true,"title":"Dual roles of lactylation modification in gastric cancer: Crosstalk between metabolic reprogramming and epigenetic regulation (Review)"},{"pmid":"42567300","doi":"10.1016/j.ejphar.2026.179215","year":2026,"isNew":true,"title":"Alloimperatorin enhances chemosensitivity by modulating the c-MYC/NBS1 axis to induce sustained DNA damage"},{"pmid":"42244353","doi":"10.1002/1545-5017.70414","year":2026,"isNew":true,"title":"The Role of Hematopoietic Cell Transplantation in Ataxia-Telangiectasia"},{"pmid":"42248294","doi":"10.1016/j.cstres.2026.100192","year":2026,"isNew":true,"title":"Insights into the function and structure of the R2TP (RUVBL1-RUVBL2-RPAP3-PIH1D1) chaperone complex"},{"pmid":"42070390","doi":"10.1016/j.redox.2026.104193","year":2026,"isNew":true,"title":"Oxidative stress-driven m&lt;sup&gt;5&lt;/sup&gt;C methylation by NSUN5 confers cisplatin resistance in lung adenocarcinoma through promoting glycolysis"},{"pmid":"42346100","doi":"10.3390/cells15121073","year":2026,"isNew":true,"title":"Metabolic Reprogramming-Driven Lactylation: Emerging Mechanisms Linking DNA Damage Repair and Chemoresistance in Cancer"},{"pmid":"42059277","doi":"10.3892/mmr.2026.13892","year":2026,"isNew":true,"title":"Oncogene c‑Myc: From molecular mechanism to targeted therapy (Review)"},{"pmid":"41798197","doi":"10.3389/fendo.2026.1755251","year":2026,"isNew":true,"title":"Novel &lt;i&gt;RAD50&lt;/i&gt; variants lead to Nijmegen Breakage Syndrome-like disorder and unplanned recombinant human growth hormone treatment response"},{"pmid":"42535577","doi":"10.1161/jaha.126.049049","year":2026,"isNew":true,"title":"Cellular Retinoic Acid-Binding Protein 2 Promotes Ischemia-Induced Cardiac Fibroblast Activation and Fibrosis Through Suppression of MRE11-RAD50-NBS1-Mediated DNA Repair"}],"trialsShown":[{"nct":"NCT06198842","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Low Dose Treosulfan Based Conditioning Regimen and PTCy in HSCT for Nijmegen Breakage Syndrome"}],"usage":{"input":7613,"output":6304},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Nijmegen breakage syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Nijmegen breakage syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41778387","PMID:42169652","PMID:42567300","PMID:42244353","PMID:42248294","PMID:42070390","PMID:42346100","PMID:42059277","PMID:41798197","PMID:42535577","NCT06198842"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787175307389","cycle":129,"visit":1,"ts":"2026-08-19T21:35:07.389Z","cancer":{"key":"rothmund-thomson syndrome","name":"Rothmund-Thomson syndrome","mondo":{"id":"MONDO:0010002","name":"Rothmund-Thomson syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"RECQL4's essential replication function is helicase-independent and satisfied by trace levels of an N-terminal 480-aa fragment, so the desk should pursue (a) C-degron/CRL2-mediated stabilisation of human RTS truncation products and (b) a minimal mini-RECQL4 transgene in the hematopoietic compartment","confidence":0.42,"notebook":"Programme opens. Four causal genes are anchored but the pack speaks almost exclusively to RECQL4; ANAPC1, CRIPT and DNA2 [GERMLINE] are mechanistically untouched here and stay as open questions, not leads.\n\nThe highest-information item is P8 (PMID:41807760). A forward genetic screen in patient-like Recql4 mice found loss of KLHDC3 — the CRL2 substrate receptor — as the top rescue allele, acting by stabilising trace amounts of an N-terminal 480-aa RECQL4 fragment lacking the ATPase domain. Two consequences. First, RECQL4's essential replication function is helicase-independent and dose-permissive: femtomolar-scale protein suffices. That reframes therapy from \"restore helicase activity\" to \"restore a small amount of scaffold.\" Second, the authors state the neo-degron is Cre-derived and does not apply to human alleles — so I will not claim degron rescue for patients. But RTS-2 alleles are predominantly truncating/frameshift [KNOWN], and truncation generates novel C-termini that are exactly the substrate class of C-degron E3s (KLHDC2/KLHDC3, FEM1A-C) [INFERRED]. The actionable question is empirical: do human RTS truncations carry recognisable C-degrons, and does CRL2 blockade (or NEDD8/pevonedistat-class inhibition [SPECULATIVE, poor specificity]) raise their steady-state level above the low threshold P8 defines? Corollary lead: a ~480-aa mini-RECQL4 becomes a small, AAV/lentivirus-tractable transgene, and P5 (PMID:41798738) shows the RECQL4 T-cell defect is hematopoietic-intrinsic and correctable by unmanipulated marrow infusion without conditioning — i.e. a compartment where minimal-cargo gene therapy has a defined readout and an unconditioned engraftment route around the radiosensitivity constraint.\n\nP1 and P2 supply the tumour-side hypothesis: RECQL4 loss is a G4/replication-stress lesion, predicting dependence on residual G4-resolution and checkpoint machinery (WRN, BLM, FANCJ, ATR) [INFERRED]. P3 keeps osteosarcoma as the clinical target. The therapeutic-window argument is the weak point and I record it now: in RTS-2 the germline biallelic defect is shared by normal tissue, and P5's explicit radiosensitivity caveat plus known chemo/radiation intolerance [KNOWN] means any replication-stress-amplifying agent (ATR inhibitor, G4 stabiliser, PARP) risks losing selectivity. This lead only survives if tumour-restricted second hits or MYC-driven replication load (P4) create differential dependence — that is the experiment, not an assumption.\n\nNCT03050268 is a predisposition cohort, useful for genotype-stratified natural history rather than intervention. P6, P7, P9, P10 are peripheral; P7's Fe/S theme is noted only because DNA2 is an Fe/S-cluster nuclease-helicase [KNOWN] — parked, not promoted.","leadChanges":[{"id":"L1","title":"C-degron/CRL2 blockade to raise steady-state levels of truncated RECQL4 in RTS-2","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L2","title":"Minimal mini-RECQL4 (N-terminal 480 aa) transgene for the hematopoietic compartment, delivered without genotoxic conditioning","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L3","title":"G4/replication-stress synthetic lethality in RECQL4-deficient osteosarcoma — window-limited","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"Radiation- and alkylator-sparing treatment architecture for RTS malignancy and immunodeficiency","level":"LEAD","status":"NEW","confidence":0.45}],"unverifiedCitations":0,"openQuestions":["Do human RTS-2 RECQL4 truncation products bear functional C-degrons (KLHDC2/3, FEM1 family), or are they eliminated by NMD before protein-level degradation becomes relevant?","Does the helicase-less N-terminal 480-aa RECQL4 fragment also support non-replicative functions (mitochondrial DNA maintenance, telomere and G4 metabolism), or only bulk replication?","Is there any tumour-restricted replication-stress dependence in RTS osteosarcoma (second hits, MYC/CDK4 amplification) that would open a therapeutic window absent in RECQL4-mutant normal tissue?","What are the mechanisms and cancer risks of the non-RECQL4 anchors — ANAPC1 (APC/C), CRIPT, DNA2 [GERMLINE] — and do they converge on replication stress or on distinct pathways?","Which G4-resolving helicase (WRN, BLM, FANCJ, DHX36, PIF1) is the strongest synthetic-lethal partner of RECQL4 loss in an isogenic setting?","What is the documented chemotherapy/radiotherapy toxicity profile of RTS patients treated for osteosarcoma, by genotype?"],"nextQueries":["(\"RECQL4\" OR \"RTS\") AND (\"synthetic lethal\" OR \"CRISPR screen\" OR \"dependency\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"C-degron\" OR \"KLHDC2\" OR \"KLHDC3\" OR \"CRL2\") AND (truncating OR \"nonsense\" OR \"frameshift\") AND (stabilization OR degradation) AND SRC:MED","(\"ANAPC1\" OR \"CRIPT\" OR \"DNA2\") AND (\"Rothmund-Thomson\" OR poikiloderma OR \"cancer predisposition\") AND SRC:MED"],"papersShown":[{"pmid":"41975004","doi":"10.1038/s42003-026-09966-4","year":2026,"isNew":true,"title":"Rare genetic diseases associated with G-quadruplex-induced replication stress"},{"pmid":"40728512","doi":"10.18632/aging.206291","year":2025,"isNew":true,"title":"An overview of RecQ helicases and related diseases"},{"pmid":"41652616","doi":"10.1186/s13023-026-04243-3","year":2026,"isNew":true,"title":"Unraveling syndrome-driven osteosarcoma: genetic insights and therapeutic frontiers"},{"pmid":"41379383","doi":"10.1007/s12672-025-04256-7","year":2025,"isNew":true,"title":"Decoding osteosarcoma from heterogeneity to precision therapy"},{"pmid":"41798738","doi":"10.70962/jhi.20250169","year":2026,"isNew":true,"title":"Unmanipulated bone marrow infusion without conditioning can rescue &lt;i&gt;RECQL4&lt;/i&gt; &lt;sup&gt;-/-&lt;/sup&gt; severe combined immunodeficiency"},{"pmid":"42074595","doi":"10.3390/genes17040477","year":2026,"isNew":true,"title":"The Epigenetic Landscape and Exposome of Non-Melanoma Skin Cancer: Mechanisms, Biomarkers, and Therapeutic Perspectives"},{"pmid":"41952995","doi":"10.1016/j.isci.2026.115256","year":2026,"isNew":true,"title":"Regulatory networks of iron sulfur cluster biology in cancer mechanisms and therapeutic perspectives"},{"pmid":"41807760","doi":"10.1038/s44319-026-00727-2","year":2026,"isNew":true,"title":"Minute amounts of helicase-deficient truncated RECQL4 are sufficient for DNA replication"},{"pmid":"42075487","doi":"10.3390/medicina62040616","year":2026,"isNew":true,"title":"Mimicry in Cutaneous Malignancy-Rare Forms of Mycosis Fungoides as Diagnostic Pitfalls: A Narrative Review"},{"pmid":"41941604","doi":"10.18632/aging.206366","year":2026,"isNew":true,"title":"A manually curated gene-phenotype catalogue for progeroid syndromes and premature aging"}],"trialsShown":[{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":6769,"output":6160},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Rothmund-Thomson syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Rothmund-Thomson syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41975004","PMID:40728512","PMID:41652616","PMID:41379383","PMID:41798738","PMID:42074595","PMID:41952995","PMID:41807760","PMID:42075487","PMID:41941604","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787175100953","cycle":128,"visit":1,"ts":"2026-08-19T21:31:40.953Z","cancer":{"key":"werner syndrome","name":"Werner syndrome","mondo":{"id":"MONDO:0010196","name":"Werner syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"WRN-helicase inhibition is a somatic MSI-H strategy that cannot be repurposed for germline WRN-null Werner syndrome tumours; the actionable near-term work is chemotype-rotation against the newly mapped on-target resistance mutations (L528S/C727R/F730L) and SMARCAL1/MRN-based patient selection, while","confidence":0.62,"notebook":"The pack is overwhelmingly about pharmacological WRN inhibition in MSI-H tumours, i.e. somatic phenocopying of Werner syndrome — not about treating cancers arising in germline WRN-null patients. That distinction organises this programme from the start. In WS proper the tumour spectrum is sarcoma/osteosarcoma, melanoma, thyroid (P2 covers WS-associated osteosarcoma only descriptively; P5 and P9 are clinically informative but therapeutically inert for our purposes; P3/P4 are off-target for WS pathogenesis and I am not building leads on them). Critically, WRN inhibitors — five phase I programmes now (NCT06974110, NCT06898450, NCT07262619, NCT06710847) — are logically inapplicable to WRN-null WS tumours [INFERRED]; the desk should never propose them there. Record that as a closed door.\n\nWhat is new and mechanistically load-bearing: (i) on-target resistance is rapid and clustered in the helicase domain, with L528S/C727R/F730L showing chemotype-selective escape (PMID:41656870), against a backdrop of an emerging covalent series with WC-2 as a low-dose candidate (PMID:42593940) and a medicinal-chemistry landscape review (PMID:41962327) — this argues immediately for scaffold rotation/sequencing and ctDNA WRN-domain surveillance rather than single-agent escalation. (ii) Off-target buffers: SMARCAL1 ATPase activity generates/maintains the cruciform substrate and its loss confers resistance, while MRE11–RAD50–NBS1 (not MUS81 or ERCC1/XPF) executes the lethal cleavage, with ATM contributing modestly (PMID:42484294). This inverts a naive proposal — MRN/ATM inhibitor combinations with WRN inhibitors should be antagonistic, not synergistic [INFERRED] — and nominates SMARCAL1/MRN/ATM loss as pre-existing and acquired resistance biomarkers alongside TA-repeat burden. (iii) WRN dependency extends beyond MSI: eIF4E2 loss relieves miR-130b-3p/301b-3p-mediated translational repression of WRN, raising WRN protein and driving cisplatin resistance in NSCLC, reversed by HRO761 + cisplatin (PMID:42441405). That is the first credible MSS indication for this class.\n\nFor WS itself, the honest position is that germline WRN loss means the therapeutic-window argument for any fork-processing or DDA-sensitising strategy is weak: normal fibroblasts, marrow and vasculature share the defect, and impaired wound healing (PMID:42254035) compounds surgical/cytotoxic risk. The residual hypothesis worth testing is a second-hit synthetic lethality specific to the tumour's somatic genotype, with the WS-tumour dependence on SMARCAL1/MRN inferred from PMID:42484294 as the first place to look.\n\nNext visit I want: WRN-deficient (patient-derived) tumour models and their drug sensitivities; whether SMARCAL1 is druggable; whether ctDNA WRN mutation tracking appears in any trial protocol; and whether the PD-1 combinations (NCT07262619, NCT06710847) have a stated STING/DSB rationale.","leadChanges":[{"id":"L1","title":"Chemotype rotation / next-generation covalent inhibitors against on-target WRN helicase-domain resistance","level":"LEAD","status":"NEW","confidence":0.7},{"id":"L2","title":"SMARCAL1/MRN axis as response biomarker and as a combination anti-pattern for WRN inhibitors","level":"LEAD","status":"NEW","confidence":0.65},{"id":"L3","title":"WRN inhibition to resensitise MSS tumours to DNA-damaging chemotherapy in the eIF4E2-low/WRN-high state","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L4","title":"Germline WRN-null tumours require second-hit synthetic lethality, not fork-stress agents","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Are there WRN-null patient-derived tumour models (WS osteosarcoma, sarcoma, thyroid) with published drug-sensitivity or CRISPR-dependency data, and do any co-dependencies survive a normal-WS-fibroblast toxicity control?","Is SMARCAL1 pharmacologically tractable, and would SMARCAL1 stabilisation/activation rather than inhibition sensitise MSI-H tumours to WRN inhibitors?","Do the PD-1 combination arms (NCT07262619, NCT06710847) rest on a stated cGAS-STING/DSB-neoantigen rationale, and is there preclinical evidence that WRN inhibition raises immunogenicity in MSI-H beyond baseline checkpoint sensitivity?","Do WRN helicase-domain resistance mutations retain enough catalytic and MSI-buffering function to be trackable in ctDNA, and does any trial protocol prespecify such monitoring?","Does WRN loss in the germline WS context alter telomere-maintenance dependence (ALT vs telomerase) in the resulting sarcomas, offering an orthogonal target?","Which repair pathway substitutes for WRN in long-lived WRN-null normal tissue, since that pathway defines the toxicity ceiling for any WS-directed agent?"],"nextQueries":["(\"Werner syndrome\" OR WRN) AND (\"patient-derived\" OR xenograft OR fibroblast) AND (\"drug sensitivity\" OR \"CRISPR screen\" OR dependency) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(WRN OR \"WRN inhibitor\" OR HRO761) AND (\"STING\" OR immunogenic OR \"PD-1\" OR neoantigen) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(SMARCAL1 OR \"MRE11\" OR \"replication fork remodel\") AND (WRN OR \"microsatellite instability\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"41656870","doi":"10.1158/1535-7163.mct-25-0666","year":2026,"isNew":true,"title":"Microsatellite Instable Cancer Cells Acquire On-target Resistance Mutations to WRN Helicase Inhibitors"},{"pmid":"41652616","doi":"10.1186/s13023-026-04243-3","year":2026,"isNew":true,"title":"Unraveling syndrome-driven osteosarcoma: genetic insights and therapeutic frontiers"},{"pmid":"42346079","doi":"10.3390/cells15121051","year":2026,"isNew":true,"title":"The Lamin Proteins in Nuclear Structure, Functions, and Laminopathies"},{"pmid":"41919394","doi":"10.1080/07853890.2026.2627667","year":2026,"isNew":true,"title":"Research progress of mesenchymal stem cells/stromal cells and their derivatives against cell senescence in the treatment of osteoarthritis"},{"pmid":"42327507","doi":"10.1016/j.radcr.2026.05.080","year":2026,"isNew":true,"title":"Squamous dedifferentiation and differentiated high-grade transformation of papillary thyroid carcinoma in metastatic lymph nodes: Two cases and literature review"},{"pmid":"42593940","doi":"10.1021/acs.jmedchem.6c00443","year":2026,"isNew":true,"title":"Discovery and Optimization of a WRN Helicase Inhibitor Series through Structure-Guided Drug Design from a Covalent Fragment Binding Insight"},{"pmid":"42484294","doi":"10.1158/0008-5472.can-26-1023","year":2026,"isNew":true,"title":"CRISPR Screening Identifies SMARCAL1 and MRN as Modulators of WRN Dependency in MSI-H Colorectal Cancer"},{"pmid":"42441405","doi":"10.1016/j.celrep.2026.117686","year":2026,"isNew":true,"title":"eIF4E2 deficiency translationally unleashes WRN to sustain DNA repair-mediated chemoresistance"},{"pmid":"42254035","doi":"10.1016/j.jpra.2026.05.031","year":2026,"isNew":true,"title":"Innervated superficial circumflex iliac artery perforator flap for refractory elbow ulcer with bone exposure in Werner syndrome: A case report"},{"pmid":"41962327","doi":"10.1016/j.ejmech.2026.118842","year":2026,"isNew":true,"title":"Targeting WRN helicase in MSI-H tumors: Synthetic lethality, small molecule discovery, and therapeutic perspectives"}],"trialsShown":[{"nct":"NCT06974110","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Study of Orally Administered MOMA-341 in Participants With Advanced or Metastatic Solid Tumors"},{"nct":"NCT06898450","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study to Assess the Safety, Tolerability, and Efficacy of NDI-219216 in Patients With Advanced Solid Tumors."},{"nct":"NCT07262619","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"EIK1005-002: A Clinical Research Study Evaluating EIK1005, a Werner Helicase Inhibitor, as Monotherapy and in Combination With Pembrolizumab"},{"nct":"NCT06710847","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Investigate the Safety, Pharmacokinetics, and Preliminary Effectiveness of GSK4418959 Alone or in Combination With Other Anti-can"}],"usage":{"input":7721,"output":6711},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Werner syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Werner syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41656870","PMID:41652616","PMID:42346079","PMID:41919394","PMID:42327507","PMID:42593940","PMID:42484294","PMID:42441405","PMID:42254035","PMID:41962327","NCT06974110","NCT06898450","NCT07262619","NCT06710847"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787174886798","cycle":127,"visit":1,"ts":"2026-08-19T21:28:06.798Z","cancer":{"key":"bloom syndrome","name":"Bloom syndrome","mondo":{"id":"MONDO:0008876","name":"Bloom syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Because germline biallelic BLM loss is shared by tumour and normal tissue in Bloom syndrome, the desk pivots from BLM-loss synthetic lethality to (i) genotoxin-sparing/reduced-intensity treatment architecture for BS-associated osteosarcoma and myeloid neoplasms and (ii) checkpoint-rerouting (Chk1/Ch","confidence":0.42,"notebook":"**Visit 1 — programme initialisation.** Bloom syndrome is biallelic germline *BLM* loss (BLM [GERMLINE], RecQ helicase); every cell in the patient is BLM-null. That single fact constrains the whole programme and I am recording it as the desk's founding constraint: any classical synthetic-lethal partner of BLM loss (the BRCA/PARP logic) has **no therapeutic window in a BS patient**, because tumour and normal tissue share the genotype. Tumour-selective vulnerability must therefore come from the *somatic* events layered on top of BLM loss, or from tolerability engineering. This reframes the pack.\n\nWhat the pack gives. P1 (PMID:41064806) frames DDR helicases as a druggable class with emerging synthetic-lethal interactions and confirms BS as a helicase-deficiency disorder. P8 (PMID:42247504) is the operative pharmacological template: WRN inhibition is selectively lethal in ARID1A-mutant cells, and mechanistically it *rewires checkpoint choice* — defective Chk1 signalling forces compensatory Chk2 activation and G1 arrest, potentiated by p21 inhibition. That checkpoint-rerouting logic, not the WRN target itself, is what I want to test against BLM-null backgrounds [INFERRED]; WRN inhibition in a BS patient would remove the last RecQ redundancy in normal tissue and is a predicted toxicity trap [SPECULATIVE]. P10 (PMID:42098304) shows BLM is dose-toxic, not merely protective: SLX4IP restrains BLM-driven replication stress, and SLX4IP/FANCM co-depletion lethality in ALT-positive cells is *fully rescued by BLM loss* — i.e. BLM-null cells are intrinsically resistant to that axis, a negative result for importing ALT-directed FANCM strategies into BS tumours. P4 (PMID:42323025, BLM-high melanoma, FMD-108) and P6 (PMID:42346100, BLM lactylation driving HR in bladder models) define the mirror-image programme — pharmacological BLM suppression in BLM-*over*expressing sporadic cancers — which is not BS therapy but supplies chemical probes to phenocopy BLM loss in isogenic screens. P2 (PMID:41652616) and P3 (PMID:41595160) anchor the clinical reality: BS-associated osteosarcoma and germline-predisposed myeloid neoplasms where germline status dictates conditioning and HSCT strategy — the substrate for a genotoxin-sparing lead.\n\nNoise flagged so the desk never re-parses it: T1 (NCT07209462, MRM-3379 in Fragile X) and T2 (NCT07287332, Mayo dosing feasibility) are acronym collisions on \"BLOOM\"; zero Bloom-syndrome content. P5 (tyrosinaemia HCC) and P7 (E. coli RecBCD/β-clamp) are off-target.\n\nThree leads opened, none promotable this visit (single evidence-bearing visit).","leadChanges":[{"id":"L1","title":"Genotoxin-sparing treatment architecture for BS-associated malignancy (osteosarcoma, MDS/AML)","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"Checkpoint rerouting (Chk1-to-Chk2, p21, ATR) as the tumour-selective axis on a BLM-null background","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L3","title":"Mirror programme: pharmacological BLM suppression in BLM-overexpressing sporadic tumours, and BLM lactylation as the switch","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Do BS-derived tumour lines (osteosarcoma, lymphoid, myeloid) show any dependency NOT shared by BS non-malignant BLM-null cells — i.e. does a real therapeutic window exist at all in this syndrome?","Which somatic co-lesions recur in BS tumours (ARID1A, TP53, MSI, ALT/telomere maintenance mode), and do any of them confer a druggable checkpoint-rerouting vulnerability as in the WRN/ARID1A paradigm?","Is there any published BS-specific evidence on chemotherapy/radiation dose tolerance, alkylator avoidance, or reduced-intensity conditioning outcomes, versus expert opinion only?","Are RecQ paralogues (WRN, RECQL4, RECQL5) upregulated or functionally compensating in BLM-null human cells, and would paralogue inhibition therefore be prohibitively toxic in BS patients?","Does the elevated SCE/genomic-instability phenotype of BLM-null tumours translate into tumour mutational burden or neoantigen load sufficient to justify checkpoint blockade as the genotoxin-sparing modality?","Can FMD-108-class BLM inhibitors serve as validated phenocopy probes (selectivity, on-target proof) or is the melanoma report too preliminary to build on?"],"nextQueries":["(\"Bloom syndrome\" OR \"BLM helicase\") AND (\"synthetic lethal\" OR \"synthetic lethality\" OR \"paralog\" OR WRN OR RECQL4) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"Bloom syndrome\" AND (chemotherapy OR radiotherapy OR \"reduced intensity conditioning\" OR transplantation OR toxicity OR leukemia OR lymphoma) AND SRC:MED","(\"Bloom syndrome\" OR \"BLM-deficient\") AND (\"tumor mutational burden\" OR immunotherapy OR \"checkpoint inhibitor\" OR neoantigen OR \"sister chromatid exchange\") AND SRC:MED"],"papersShown":[{"pmid":"41064806","doi":"10.1093/narcan/zcaf034","year":2025,"isNew":true,"title":"DNA repair helicases: from mechanistic understanding to therapeutic implications"},{"pmid":"41652616","doi":"10.1186/s13023-026-04243-3","year":2026,"isNew":true,"title":"Unraveling syndrome-driven osteosarcoma: genetic insights and therapeutic frontiers"},{"pmid":"41595160","doi":"10.3390/cancers18020240","year":2026,"isNew":true,"title":"Moving Beyond Somatic Alterations: Uncovering the Germline Basis of Myeloid Malignancies"},{"pmid":"42323025","doi":"10.1016/j.bcp.2026.118181","year":2026,"isNew":true,"title":"BLM as a potential therapeutic target in cutaneous malignant melanoma"},{"pmid":"42293468","doi":"10.1016/j.radcr.2026.05.001","year":2026,"isNew":true,"title":"Hepatocellular carcinoma in a child with hereditary tyrosinemia type I despite early NTBC therapy: When should we suspect it?"},{"pmid":"42346100","doi":"10.3390/cells15121073","year":2026,"isNew":true,"title":"Metabolic Reprogramming-Driven Lactylation: Emerging Mechanisms Linking DNA Damage Repair and Chemoresistance in Cancer"},{"pmid":"42273914","doi":"10.1093/nar/gkag570","year":2026,"isNew":true,"title":"The RecBCD complex interacts directly with the DNA sliding clamp in Escherichia coli"},{"pmid":"42247504","doi":"10.1126/sciadv.aeb3726","year":2026,"isNew":true,"title":"Differential DNA damage response to WRN inhibition identifies a targetable vulnerability in &lt;i&gt;ARID1A&lt;/i&gt;-mutated cancers"},{"pmid":"42225652","doi":"10.1038/s41392-026-02662-z","year":2026,"isNew":true,"title":"Insights into the therapeutic strategies for aging and aging-associated diseases"},{"pmid":"42098304","doi":"10.1038/s44318-026-00790-4","year":2026,"isNew":true,"title":"SLX4IP limits replication stress globally and at ALT telomeres"}],"trialsShown":[{"nct":"NCT07209462","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Study of MRM-3379 in Male Participants With Fragile X Syndrome (BLOOM)"},{"nct":"NCT07287332","phase":"NA","status":"RECRUITING","isNew":true,"title":"BLOOM: Pragmatic Feasibility Trial"}],"usage":{"input":7142,"output":6453},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Bloom syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Bloom syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41064806","PMID:41652616","PMID:41595160","PMID:42323025","PMID:42293468","PMID:42346100","PMID:42273914","PMID:42247504","PMID:42225652","PMID:42098304","NCT07209462","NCT07287332"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787174678988","cycle":126,"visit":1,"ts":"2026-08-19T21:24:38.988Z","cancer":{"key":"xeroderma pigmentosum","name":"xeroderma pigmentosum","mondo":{"id":"MONDO:0019600","name":"xeroderma pigmentosum"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise PD-1/PD-L1 blockade for XP-associated cutaneous SCC on the basis of repair-deficiency/UV-synergistic PD-L1 induction, while deprioritising DNA-damaging chemotherapy and germline-defect synthetic lethality in XP because the repair defect is shared by all host tissue.","confidence":0.46,"notebook":"Visit 1 opens the programme with a pack that is unusually informative for a rare genodermatosis: one mechanistic paper that actually nominates a druggable axis, and several that constrain what will not work.\n\nThe anchor finding is P4 (PMID:42173765): in an XPA splice-null child, XP-SCC transcriptomes show coordinate CD274/PDCD1/STAT1 upregulation, XPA-knockdown HaCaT cells show synergistic UV-plus-repair-deficiency PD-L1 induction, and PD-L1 neutralisation reverses the increased Jurkat–keratinocyte engagement. Mechanistically this reads as unrepaired CPD/6-4PP burden → cytosolic DNA/interferon-STAT1 signalling → adaptive immune resistance [INFERRED], layered on the very high UV-signature mutational load expected in NER-null keratinocytes [KNOWN]. That makes checkpoint blockade the lead therapeutic hypothesis for XP-associated cutaneous SCC, with predicted escape via B2M/JAK1-2/IFNGR loss and PD-L1-independent field cancerisation. Caveat: n=1 patient, one cell line, no in vivo or clinical response data.\n\nA programme-level constraint I want on record: in XP the repair defect is germline, so classical synthetic-lethality logic (NER-loss + platinum, PARP, or nucleoside analogues) has no host/tumour differential. P2 (PMID:42607204) shows XPA and pol κ are required to clear chain-terminator-containing template DNA, and P10 (PMID:42092281) shows PARP1–ERCC1/XPF–TDP1 cooperation — both reinforce that XPA/XPF loss sensitises *all* tissues, not just tumour. P8 (PMID:41908666) is consistent: two XPC-truncating internal malignancies (ovarian HG-SCST, renal leiomyosarcoma) were chemo-refractory or relapsed, and P3 (PMID:42528925) reports early AML with complex cytogenetics and poor response. DNA-damaging systemic therapy is therefore deprioritised, and the desk should not re-propose platinum/PARP synthetic lethality here without tumour-restricted delivery.\n\nTwo speculative openings. P7 (PMID:42302177) shows Minnelide kills CIC::DUX4 sarcoma through XPB (ERCC3), degrading RPB1 — a transcription-addiction mechanism, clinically de-risked, worth testing against the chemo-refractory XP sarcomas of P8; but XPB is the TFIIH ATPase, so in ERCC3-hypomorphic XP-B/XP-B-TTD patients the window is unpredictable [SPECULATIVE]. P5 (PMID:42070083) plus T2 (NCT05071222) frame durable correction: AAVrh32.33/IDPΔ reaches dermal fibroblasts and bulge cells for ≥2 years, but XP carcinogenesis is epidermal-keratinocyte, so tropism is mismatched; ex vivo lentiviral correction of epidermal holoclones is the better architecture [KNOWN, EB precedent].\n\nP9 (PMID:41958690) is a single eight-year HDR brachytherapy success questioning the radiotherapy taboo — mechanistically coherent since XP is NER- not DSB-repair-deficient [KNOWN]; low-weight but actionable for unresectable head/neck disease alongside surgery (P6, PMID:42445768). T1 (NCT05484570) is the natural-history platform for endpoints. P1 contributes nothing.","leadChanges":[{"id":"L1","title":"PD-1/PD-L1 blockade for XP-associated cutaneous SCC (repair-deficiency-driven adaptive immune resistance)","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"Ex vivo lentiviral correction of epidermal stem cells for XPC/XPA chemoprevention (not AAV dermal delivery)","level":"LEAD","status":"NEW","confidence":0.32},{"id":"L3","title":"XPB(ERCC3)-directed transcription inhibition (Minnelide) for chemo-refractory XP-associated internal sarcomas","level":"LEAD","status":"NEW","confidence":0.2},{"id":"L4","title":"Radiotherapy is not categorically contraindicated in XP: HDR interstitial brachytherapy for unresectable facial SCC","level":"LEAD","status":"NEW","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["In XP-SCC, is anti-PD-1 benefit dependent on intact IFN-gamma/JAK-STAT and B2M, and how does TMB/UV-signature load compare with sporadic cutaneous SCC?","Can checkpoint blockade act as field chemoprevention (reduction in new primaries) rather than only tumour debulking in XP, and is irAE risk altered by germline NER deficiency?","Which epidermal compartment must be corrected - interfollicular basal keratinocyte versus follicular bulge - for durable XP chemoprevention, and is any published XPC/XPA gene-corrected graft or base-editing data available?","Are XP-associated internal malignancies systematically platinum/anthracycline-refractory, and what somatic driver landscape do XPC-null sarcomas carry?","Is there any direct evidence on radiotherapy tolerance by XP complementation group (XP-A/C/D versus XP-B/TTD) rather than case-level anecdote?","Does the germline nature of NER loss formally exclude PARP-inhibitor or platinum synthetic lethality in XP, or is there a tumour-restricted vulnerability (e.g. pol kappa, TDP1, ERCC1-XPF) with a real window?"],"nextQueries":["(\"xeroderma pigmentosum\" OR \"nucleotide excision repair\") AND (cemiplimab OR pembrolizumab OR nivolumab OR \"PD-1\" OR \"PD-L1\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(XPC OR XPA OR ERCC2 OR ERCC3) AND (\"gene therapy\" OR \"base editing\" OR \"keratinocyte stem cell\" OR \"epidermal graft\" OR lentiviral) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","\"xeroderma pigmentosum\" AND (cisplatin OR carboplatin OR \"PARP inhibitor\" OR radiotherapy OR radiosensitivity) AND SRC:MED AND PUB_YEAR:[2015 TO 2026]"],"papersShown":[{"pmid":"41496737","doi":"10.1111/ijd.70247","year":2026,"isNew":true,"title":"Decoding Genetic Disease Through the Skin: Lessons From the UDN"},{"pmid":"42607204","doi":"10.1073/pnas.2618057123","year":2026,"isNew":true,"title":"Host DNA repair factors empower a mechanism of antiviral nucleoside analog resistance."},{"pmid":"42528925","doi":"10.1002/ccr3.73260","year":2026,"isNew":true,"title":"Acute Myeloid Leukemia in a Patient With Xeroderma Pigmentosum: A Case Report"},{"pmid":"42173765","doi":"10.1016/j.jdermsci.2026.04.008","year":2026,"isNew":true,"title":"Synergistic enhancement of PD-L1 expression from DNA repair dysfunction and UV exposure in xeroderma pigmentosum: Potential therapeutic role of PD-L1 inhibitors"},{"pmid":"42070083","doi":"10.1016/j.ymthe.2026.04.056","year":2026,"isNew":true,"title":"AAVrh32.33 capsid demonstrates unexpected dermal tropism regardless of immunodominant epitope"},{"pmid":"42445768","doi":"10.4103/jwas.jwas_22_25","year":2026,"isNew":true,"title":"Cutaneous Malignancy of the Head and Neck in Patients with Xeroderma Pigmentosum: A Report of Three Cases"},{"pmid":"42302177","doi":"10.1172/jci202218","year":2026,"isNew":true,"title":"Targeting CIC::DUX4 sarcoma with Minnelide in a dual recombinase-initiated genetically engineered mouse model"},{"pmid":"41908666","doi":"10.1016/j.cpt.2026.01.003","year":2026,"isNew":true,"title":"Rare internal malignancies in xeroderma pigmentosum: A report of two cases from Tunisia and analysis of driver mutations"},{"pmid":"41958690","doi":"10.1002/ccr3.72516","year":2026,"isNew":true,"title":"Successful Interstitial HDR Brachytherapy for Nasal Skin SCC in Xeroderma Pigmentosum: An Eight-Year Follow-Up Case Report"},{"pmid":"42092281","doi":"10.1016/j.jhepr.2026.101806","year":2026,"isNew":true,"title":"Nucleotide excision repair and poly(ADP-ribose) polymerase 1 cooperate in HBV cccDNA synthesis: A potential viral therapeutic target"}],"trialsShown":[{"nct":"NCT05484570","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Natural History Study for DNA Repair Disorders"},{"nct":"NCT05071222","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Safety and Efficacy Study of Transplantation of Autologous CD34+ Cells Transduced With the G2ARTE Lentiviral Vector Expressing the DCLRE1C c"},{"nct":"NCT06330324","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Reproductive Options in Inherited Skin Diseases"}],"usage":{"input":7636,"output":7306},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"xeroderma pigmentosum\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"xeroderma pigmentosum\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41496737","PMID:42607204","PMID:42528925","PMID:42173765","PMID:42070083","PMID:42445768","PMID:42302177","PMID:41908666","PMID:41958690","PMID:42092281","NCT05484570","NCT05071222","NCT06330324"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787174460023","cycle":125,"visit":1,"ts":"2026-08-19T21:21:00.023Z","cancer":{"key":"rhabdoid tumor predisposition syndrome","name":"rhabdoid tumor predisposition syndrome","mondo":{"id":"MONDO:0016473","name":"familial rhabdoid tumor"}},"control":false,"modelLabel":"SCIENCE","summary":"Treat RTPS as a carrier-level chemoprevention problem: prioritise an epigenetic maintenance regimen (EZH2 inhibition ± low-dose chemotherapy) for germline SMARCB1/SMARCA4 carriers in remission, tested first in the new porcine RTPS-1 model, with residual-ATPase (SMARCA4/SMARCA2) degradation as the pa","confidence":0.46,"notebook":"**Visit 1 — programme initiation, RTPS (SMARCB1 [GERMLINE, causal]; SMARCA4 [GERMLINE in RTPS2, SOMATIC in sporadic ATRT]).**\n\nThe pack is review- and case-heavy; no interventional trial for RTPS appears in it. Two trials retrieved are ascertainment cohorts, not therapy: NCT03050268 (St. Jude familial predisposition) is usable as a germline-carrier ascertainment channel; NCT01238250 (Simons Searchlight/autism) is retrieval noise and should be excluded from future pulls.\n\nThe one genuinely programme-defining idea in the pack is that RTPS is a *metachronous multi-tumour* disease — intensive therapy induces remission, then synchronous/metachronous tumours appear — so the therapeutic unit is the carrier, not the tumour, and the natural intervention window is maintenance/secondary prevention with low-dose chemotherapy or epigenetic agents (PMID:39434925, PMID:40143702). Mechanistically this is coherent: SMARCB1 loss does not create a mutational burden but an epigenetic imbalance in which residual PRC2/EZH2 activity silences SWI/SNF-dependent enhancers, and EZH2 inhibition is the canonical counter-move [KNOWN]; the pack supplies an adjacent clinical anchor in that SMARCB1-null epithelioid sarcoma is the histology where EZH2 blockade is already established [KNOWN], and PMID:42213312 confirms uniform nuclear SMARCB1 loss with biallelic somatic inactivation in oral ES. That becomes Lead A. Its weakness is that EZH2i single-agent activity in ATRT has historically been modest [KNOWN], and chronic EZH2 inhibition in infants under 3 carries a germinal-centre/haematopoietic and neurodevelopmental window problem — EZH2 and BAF are both required for cortical neurogenesis (PMID:41692879 [SPECULATIVE for toxicity]).\n\nLead B is residual-ATPase dependency: PMID:42293462 states SMARCA2 is upregulated in SMARCA4-deficient cancers and is pharmacologically tractable, with inhibitors, mAbs and a bifunctional agent in trials. The mirror argument — SMARCB1-null rhabdoid tumours retain and depend on residual SMARCA4-containing BAF [KNOWN] — makes SMARCA4/BRG1 degradation a synthetic-lethal proposal for RTPS1 and SMARCA2 degradation for RTPS2. Caveat from PMID:40036664: a novel SMARCA4 missense ATRT with *retained* INI1 and BRG1 by IHC — protein-retaining variants may not generate paralog dependency, so eligibility must be genotype- not IHC-defined.\n\nLead C is enabling: the CRISPR porcine RTPS-1 model (germline SMARCB1 exon 4–5 deletion, the most penetrant allele; protein 100% identical to human) is the first system in which chronic maintenance dosing, CNS penetration and infant-equivalent toxicity of a prevention regimen can be tested (PMID:42352415) — directly serving Lead A. PMID:42347697 supplies age/size/site/stage risk strata to enrich any prevention trial; PMID:41976393 flags MYC-subgroup dominance in spinal ATRT as a stratifier we have not yet costed.","leadChanges":[{"id":"L1","title":"Epigenetic maintenance/secondary prevention in RTPS carriers after first remission","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"Residual SWI/SNF ATPase paralog dependency: SMARCA4 degradation in SMARCB1-null, SMARCA2 in SMARCA4-deficient rhabdoid tumours","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L3","title":"Porcine RTPS-1 (SMARCB1 exon 4-5 deletion) as the preclinical testbed for chronic prevention dosing","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["Does the porcine RTPS-1 line (PMID:42352415) actually develop ATRT/MRT, at what penetrance and latency, and is it usable as a prevention endpoint model?","Is there any published human experience — even case series — of EZH2 inhibition or metronomic maintenance given to RTPS carriers in remission, and what were the second-tumour rates and infant toxicities?","In SMARCB1-null rhabdoid tumours, is dependency on residual SMARCA4/BRG1 supported by degrader-era data (not just knockdown), and what is the CNS/haematopoietic toxicity ceiling?","Do protein-retaining SMARCA4 missense variants (PMID:40036664) generate the SMARCA2 paralog dependency described in PMID:42293462, or must eligibility be restricted to truncating/deleting alleles?","Do the ATRT molecular subgroups (SHH/TYR/MYC) differ in germline RTPS frequency and in sensitivity to epigenetic maintenance, i.e. should prevention be subgroup-stratified?","Can the SEER extracranial-MRT risk model (PMID:42347697) be combined with germline status to define the enrichment cohort for a maintenance trial powered on metachronous tumour-free survival?"],"nextQueries":["(tazemetostat OR \"EZH2 inhibitor\") AND (\"rhabdoid\" OR \"atypical teratoid\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"SMARCA2\" OR \"BRM\" OR \"BRG1\") AND (degrader OR PROTAC OR \"synthetic lethal\") AND (SMARCB1 OR rhabdoid OR \"SMARCA4-deficient\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"atypical teratoid\" OR \"rhabdoid tumor\") AND (\"maintenance therapy\" OR chemoprevention OR surveillance) AND (germline OR predisposition) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"papersShown":[{"pmid":"40143702","doi":"10.3340/jkns.2025.0014","year":2025,"isNew":true,"title":"Rhabdoid Tumor Predisposition Syndrome : A Comprehensive Review of Genetics, Clinical Manifestations, and Management"},{"pmid":"39434925","doi":"10.1093/noajnl/vdae158","year":2024,"isNew":true,"title":"Approaches for prevention of tumors in patients with rhabdoid tumor predisposition syndrome"},{"pmid":"41803273","doi":"10.1007/s00428-026-04459-5","year":2026,"isNew":true,"title":"SMARCA4-deficient carcinoma of the head and neck region: report of 8 new sinonasal and non-sinonasal cases and literature review"},{"pmid":"40036664","doi":"10.1097/mph.0000000000003004","year":2025,"isNew":true,"title":"Novel SMARCA4 Variant in an Infant With Atypical Teratoid Rhabdoid Tumor"},{"pmid":"42347697","doi":"10.1002/cam4.71808","year":2026,"isNew":true,"title":"Proposal of a Risk Stratification Algorithm for Extracranial Malignant Rhabdoid Tumors"},{"pmid":"42352415","doi":"10.3390/cancers18121879","year":2026,"isNew":true,"title":"Development of a Genetically Engineered Porcine Model of Rhabdoid Tumor Predisposition Syndrome Type 1 (RTPS-1)"},{"pmid":"42293462","doi":"10.36401/jipo-25-35","year":2026,"isNew":true,"title":"SMARCA4-Directed Treatment in Oncology Clinical Trials: A Review"},{"pmid":"42213312","doi":"10.1007/s12105-026-01931-1","year":2026,"isNew":true,"title":"Epithelioid Sarcoma of the Oral Cavity: A Multi-institutional Clinicopathologic and Immunophenotypic Characterization of Five Cases and Comprehensive Literature Review"},{"pmid":"41976393","doi":"10.3390/cancers18071171","year":2026,"isNew":true,"title":"Pediatric Spinal Atypical Teratoid Rhabdoid Tumor: Recent Advances in Biology and Management Options"},{"pmid":"41692879","doi":"10.1007/s10571-026-01692-z","year":2026,"isNew":true,"title":"Cooperation of Transcription Factor PAX6 with Chromatin-Remodeling Complex BAF During Embryonic Development in Mammals"}],"trialsShown":[{"nct":"NCT01238250","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":7184,"output":5932},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"rhabdoid tumor predisposition syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"rhabdoid tumor predisposition syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:40143702","PMID:39434925","PMID:41803273","PMID:40036664","PMID:42347697","PMID:42352415","PMID:42293462","PMID:42213312","PMID:41976393","PMID:41692879","NCT01238250","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787174260540","cycle":124,"visit":1,"ts":"2026-08-19T21:17:40.540Z","cancer":{"key":"dicer1 syndrome","name":"DICER1 syndrome","mondo":{"id":"MONDO:0100216","name":"DICER1-related tumor predisposition"}},"control":false,"modelLabel":"SCIENCE","summary":"Open the DICER1 programme on the strand-biased hypomorph model — hotspot RNase IIIb tumours lose 5p/let-7 output while retaining one wild-type allele, making let-7 downstream effectors (IGF1R, IGF2BP1, HMGA2) the first testable tumour-selective nodes — and treat the recruiting DICER1 registries as t","confidence":0.34,"notebook":"Visit 1 opens the programme from zero. The pack is mechanistically thin and clinically noisy: of ten papers, only two (PMID:40940982, PMID:39857323) address DICER1 biology, and both are reviews that explicitly concede the molecular mechanism is unresolved. The remaining eight are off-target capture from the query terms — pediatric thyroid nodule ultrasound risk stratification (PMID:42306160, PMID:41974527, PMID:41784119), non-DICER1 case reports of cystic nephroma in GLIS3 disorder (PMID:42327870), genitourinary/cervical embryonal rhabdomyosarcoma without germline data (PMID:41868466, PMID:42125161), PTC dedifferentiation (PMID:42327507), and a Wilms predisposition cohort in which DICER1 was not among the eight mutated genes reported (PMID:42123644). All four trials are non-interventional natural history or registry protocols (NCT01247597, NCT03382158, NCT03050268, NCT06523582). Notebook entry for the record: as of this visit there is **no interventional targeted-therapy trial in DICER1 syndrome** in the pack, and no fresh drug-mechanism data — do not re-propose \"DICER1 syndrome AND inhibitor\" style queries expecting agents; they return thyroid-imaging noise.\n\nWhat is anchored: biallelic mechanism, germline loss-of-function plus a second somatic RNase IIIb hotspot missense, is confirmed as the canonical two-hit architecture (PMID:40940982), and DICER1 is affirmed as a housekeeping small-RNA processor active across all organ systems (PMID:39857323). The hotspot is a *hypomorph*, not a null — that is the entire therapeutic argument. [INFERRED from PMID:40940982/PMID:39857323] Hotspot tumours retain 3p-strand miRNA production while losing 5p strands, so the dependency is not \"DICER1 loss\" but a specific strand-biased miRNA deficit; [KNOWN] the dominant casualty is the let-7 family, de-repressing HMGA2, IGF2BP1/3, MYC and the IGF axis. The therapeutic window argument is that normal tissue retains one wild-type allele and full 5p output, so downstream-of-let-7 nodes (IGF1R, IGF2BP1) should be tumour-selective. This is Lead 1, opened at LEAD only — both citations are reviews, neither shows drug effect.\n\nLead 2 exploits the KG's somatic anchor: KEAP1 [SOMATIC] co-mutation implies NRF2 hyperactivation as a parallel driver, with a testable glutamine/glutathione dependency. I flag explicitly that neither review abstract mentions KEAP1; this lead rests on the anchor plus [KNOWN] background and is the weakest of the three.\n\nLead 3 is infrastructure, not therapy: the three recruiting registries are the only realistic source of the annotated hotspot-mutant tissue and PDX material needed to test Leads 1–2, and the adult cervical eRMS case (PMID:41868466) argues the enrolment funnel is leaking undiagnosed germline carriers.","leadChanges":[{"id":"L1","title":"let-7 5p-strand deficit as the actionable consequence of RNase IIIb hotspot hypomorphism: target IGF1R/IGF2BP1 downstream","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L2","title":"Somatic KEAP1 loss / NRF2 hyperactivation as a co-driver dependency in DICER1-related tumours","level":"LEAD","status":"NEW","confidence":0.2},{"id":"L3","title":"Registry/natural-history network as the only available tissue and enrolment pipeline for DICER1 target validation","level":"LEAD","status":"NEW","confidence":0.45}],"unverifiedCitations":0,"openQuestions":["Is the 5p/3p strand-bias model of RNase IIIb hotspot function experimentally demonstrated in human DICER1 tumours (small-RNA-seq), or only inferred from in vitro cleavage assays?","Which let-7 target is the dominant dependency in hotspot-mutant tumours — IGF1R/IGF2, HMGA2, IGF2BP1/3, or MYC — and does knockdown kill hotspot but not DICER1-wildtype models?","Does somatic KEAP1/NFE2L2 alteration actually recur in DICER1-related tumours (which histologies, what frequency), and does it track with anaplasia or chemoresistance?","What are the current chemotherapy outcomes and failure patterns in PPB type II/III and DICER1 sarcomas, i.e. what is the standard any targeted proposal must beat?","Are there DICER1 hotspot-mutant preclinical models (PDX, GEMM, organoid) available, and has any targeted agent been tested in them?","Does the germline heterozygous state impose a systemic toxicity constraint on miRNA-pathway or IGF-axis modulation in children?"],"nextQueries":["(\"DICER1\" AND (\"let-7\" OR \"LIN28\" OR \"IGF2BP\" OR \"HMGA2\" OR \"5p strand\" OR \"miRNA arm\")) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"pleuropulmonary blastoma\" OR \"DICER1 sarcoma\" OR \"anaplastic sarcoma of kidney\") AND (chemotherapy OR outcome OR xenograft OR \"patient-derived\" OR \"mouse model\") AND SRC:MED","(\"DICER1\" AND (KEAP1 OR NFE2L2 OR NRF2 OR \"TP53\" OR \"somatic mutation landscape\" OR sequencing)) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"papersShown":[{"pmid":"40940982","doi":"10.3390/cancers17172885","year":2025,"isNew":true,"title":"&lt;i&gt;DICER1&lt;/i&gt; Syndrome: What Do We Know of the Pathogenetic Mechanisms?"},{"pmid":"41784119","doi":"10.1111/cen.70116","year":2026,"isNew":true,"title":"Evaluation and Management of Thyroid Nodules: A Joint Consensus Statement From the British Thyroid Association (BTA), British Association of Endocrine and Thyroid Surgeons (BAETS) "},{"pmid":"39857323","doi":"10.3390/biology14010093","year":2025,"isNew":true,"title":"DICER1: The Argonaute Endonuclease Family Member and Its Role in Pediatric and Youth Pathology"},{"pmid":"42327507","doi":"10.1016/j.radcr.2026.05.080","year":2026,"isNew":true,"title":"Squamous dedifferentiation and differentiated high-grade transformation of papillary thyroid carcinoma in metastatic lymph nodes: Two cases and literature review"},{"pmid":"42327870","doi":"10.14740/jmc5300","year":2026,"isNew":true,"title":"A Novel Renal Manifestation in &lt;i&gt;GLIS3&lt;/i&gt;-Related Disorder in a Pediatric Patient With Cystic Nephroma"},{"pmid":"41868466","doi":"10.1016/j.radcr.2026.02.029","year":2026,"isNew":true,"title":"Cervical embryonal rhabdomyosarcoma beyond childhood: A case report and literature review"},{"pmid":"42306160","doi":"10.3348/jksr.2026.0008","year":2026,"isNew":true,"title":"Imaging Assessment and Management of Pediatric Thyroid Nodules: Emphasis on Application of 2021 K-TIRADS"},{"pmid":"42125161","doi":"10.1002/ccr3.72691","year":2026,"isNew":true,"title":"Clinicopathological Characteristics and Outcomes of Genitourinary Rhabdomyosarcoma in Two Girls"},{"pmid":"42123644","doi":"10.3390/ijms27094066","year":2026,"isNew":true,"title":"Genetic and Epigenetic Drivers of Wilms Tumor Predisposition in Russian Pediatric Patients: A Multicenter Study"},{"pmid":"41974527","doi":"10.3348/kjr.2025.1334","year":2026,"isNew":true,"title":"Ultrasonographic Evaluation of Pediatric Thyroid Nodules: Adult Risk Stratification Systems, 2021 K-TIRADS Revision, and Future Refinements"}],"trialsShown":[{"nct":"NCT01247597","phase":"n/a","status":"RECRUITING","isNew":true,"title":"DICER1-related Pleuropulmonary Blastoma Cancer Predisposition Syndrome: A Natural History Study"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT03382158","phase":"n/a","status":"RECRUITING","isNew":true,"title":"International PPB/DICER1 Registry"},{"nct":"NCT06523582","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients"}],"usage":{"input":7289,"output":5085},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"DICER1 syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"DICER1 syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:40940982","PMID:41784119","PMID:39857323","PMID:42327507","PMID:42327870","PMID:41868466","PMID:42306160","PMID:42125161","PMID:42123644","PMID:41974527","NCT01247597","NCT03050268","NCT03382158","NCT06523582"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787174070192","cycle":123,"visit":1,"ts":"2026-08-19T21:14:30.192Z","cancer":{"key":"neurofibromatosis type 2","name":"neurofibromatosis type 2","mondo":{"id":"MONDO:0007039","name":"NF2-related schwannomatosis"}},"control":false,"modelLabel":"SCIENCE","summary":"In NF2-SWN, bevacizumab is the only systemic agent with reproducible tumour-stabilising and hearing-preserving activity, so the actionable frontier is (a) merlin-loss-proximal YAP/TAZ-TEAD and FAK/adhesion dependencies and (b) mutation-stratified meningioma therapy, while single-agent EGFR/ErbB, MEK","confidence":0.56,"notebook":"Programme opens with NF2 [GERMLINE] biallelic inactivation (germline first hit + somatic LOH/second hit [SOMATIC]) as the sole KG anchor; merlin loss de-represses YAP/TAZ–TEAD, PI3K/AKT/mTOR, MAPK, EGFR/ErbB, PDGFR and VEGF signalling and disrupts cortical actin/adherens-junction contact inhibition (PMID:42142209, PMID:42143176). Merlin is a scaffold, not an enzyme — no direct pharmacology exists, so every lead here is either downstream-node inhibition or synthetic-lethality logic [INFERRED].\n\nWhat the pack actually settles: bevacizumab is the only systemic agent with reproducible activity in NF2-SWN vestibular schwannoma — durable radiographic stabilisation, hearing preservation, tolerable long-term toxicity across 426 pooled patients in 12 studies (PMID:42453176), corroborated by an independent meta-analysis (PMID:42012512) and two independent 2026 reviews (PMID:42142209, PMID:42143176). It becomes the backbone/comparator, not a new lead to chase. Conversely, the pack is a negative record for kinase monotherapy: everolimus, selumetinib, lapatinib, erlotinib, icotinib and brigatinib produce only \"modest activity, primarily disease stabilization\" (PMID:42143176, PMID:42142209). I retire single-agent EGFR/ErbB inhibition and de-prioritise MEK or mTOR monotherapy; the desk should not re-propose them except as bevacizumab-sparing combinations with a hearing endpoint. Note also that the selumetinib/trametinib/mirdametinib trial cluster in the pack (NCT02407405, NCT03962543, NCT06175637, NCT03190915, NCT06541847, NCT04166409) is NF1/RAS-pathway, not NF2 — mechanistically inapplicable, since MEK activation in merlin-deficient Schwann cells is indirect. PMID:42143176's trial audit (21 interventional trials, predominantly early-phase, non-comparative, incomplete reporting) is the structural problem: the field lacks randomised, hearing-endpoint studies.\n\nTwo genuinely new directions. First, mutation-stratified meningioma pharmacology: NCT02523014 runs FAK inhibitor GSK2256098 in the NF2-mutant arm alongside capivasertib and abemaciclib — the FAK arm is a direct test of merlin-loss/adhesion-signalling dependency (PMID:42143176 flags adhesion pathways), and meningiomatosis, not VS, drives much NF2-SWN mortality (PMID:42338700). Second, YAP/TAZ–TEAD is the most proximal consequence of merlin loss and the least clinically tested; TEAD palmitoylation-site inhibitors are the obvious probe [KNOWN, no NF2-specific citation in this pack — flagged as evidence gap].\n\nRadiation tension worth recording: wide dural RT gave 100% 2-year local control over 91 meningiomas in 10 patients (PMID:42338700), yet reviews cite radiation-associated hearing loss and malignant transformation risk (PMID:42142209), and malignant transformation of VS occurs even without NF2 or radiation (PMID:42546347). Cohort is small, follow-up 45.8 months — insufficient for second-malignancy risk.","leadChanges":[{"id":"L1","title":"Bevacizumab (anti-VEGF) as the systemic backbone and comparator arm for NF2-SWN vestibular schwannoma","level":"LEAD","status":"NEW","confidence":0.75},{"id":"L2","title":"YAP/TAZ-TEAD transcriptional dependency as the most merlin-proximal druggable node in NF2-SWN","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"FAK (and AKT/CDK4-6) inhibition against NF2-mutant meningioma via mutation-stratified basket trial","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"Wide dural radiotherapy for NF2-SWN meningiomatosis — efficacy signal versus malignant-transformation liability","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Has any TEAD palmitoylation inhibitor or YAP/TAZ-directed agent been tested in merlin-deficient schwannoma/meningioma models or in NF2-SWN patients, and what is the on-target toxicity profile?","What are the reported response and hearing outcomes specifically in the NF2-mutant arm of NCT02523014 (GSK2256098 FAK inhibition), and is FAK dependency validated in primary merlin-null schwannoma cells?","What defines bevacizumab non-response and acquired resistance in NF2-SWN (angiogenic switch markers, tumour volume vs oedema, rebound after discontinuation), and can biomarker-guided intermittent dosing preserve hearing benefit?","What is the long-term (>=10 year) incidence of malignant peripheral nerve sheath tumour and secondary malignancy after wide-field dural or fractionated radiotherapy in germline-NF2 carriers, stratified by variant class?","Does germline NF2 variant type (truncating vs missense vs mosaic) predict tumour burden, meningiomatosis risk, or response to any systemic agent?","Are there merlin-loss-specific synthetic-lethal vulnerabilities beyond the Hippo axis (e.g. CDK4/6, AXL, mTORC1/2 dual, arginine or glutamine metabolism) with published NF2-null screen support?"],"nextQueries":["(\"NF2\" OR \"merlin\") AND (\"TEAD\" OR \"YAP\" OR \"TAZ\" OR \"Hippo\") AND (inhibitor OR palmitoylation OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"NF2-related schwannomatosis\" OR \"vestibular schwannoma\" OR meningioma) AND (bevacizumab) AND (resistance OR \"hearing outcome\" OR discontinuation OR rebound) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"NF2\" OR \"merlin-deficient\") AND (\"focal adhesion kinase\" OR GSK2256098 OR \"CRISPR screen\" OR \"synthetic lethality\") AND SRC:MED AND PUB_YEAR:[2019 TO 2026]"],"papersShown":[{"pmid":"42338700","doi":"10.1016/j.ctro.2026.101188","year":2026,"isNew":true,"title":"Wide dural radiation therapy for NF2-SWN associated meningiomatosis"},{"pmid":"42546347","doi":"10.3171/case251003","year":2026,"isNew":true,"title":"Sporadic sarcoma arising from a previously resected benign vestibular schwannoma without neurofibromatosis or radiosurgery: illustrative case"},{"pmid":"42453176","doi":"10.1093/nop/npag017","year":2026,"isNew":true,"title":"The effectiveness of targeted therapy in the treatment of patients with neurofibromatosis type 2-related schwannomatosis and vestibular schwannomas: A systematic review"},{"pmid":"42012512","doi":"10.1007/s00405-026-10174-3","year":2026,"isNew":true,"title":"Efficacy and safety of bevacizumab for vestibular schwannomas in neurofibromatosis type-2: a systematic review and meta-analysis"},{"pmid":"41731704","doi":"10.1177/10668969251407312","year":2026,"isNew":true,"title":"&lt;i&gt;BRCA2&lt;/i&gt; and &lt;i&gt;NF2&lt;/i&gt;-Mutated High-Grade Renal Cell Carcinoma: A Case Report and Literature Review"},{"pmid":"42264666","doi":"10.1016/j.nec.2026.02.006","year":2026,"isNew":true,"title":"Intramedullary Spinal Cord Tumors Associated with the Neurofibromatoses"},{"pmid":"42177837","doi":"10.1016/j.redox.2026.104223","year":2026,"isNew":true,"title":"Nitration in cancer signaling"},{"pmid":"41981748","doi":"10.1097/mao.0000000000004917","year":2026,"isNew":true,"title":"Cochlear Implantation and Vestibular Schwannoma Removal: The Gruppo Otologico Experience in 73 Consecutive Cases"},{"pmid":"42142209","doi":"10.1007/s11060-026-05599-z","year":2026,"isNew":true,"title":"A review of targeted therapies for NF2-related vestibular schwannoma: molecular pathogenesis, emerging therapeutics, and future clinical horizons"},{"pmid":"42143176","doi":"10.1007/s11060-026-05621-4","year":2026,"isNew":true,"title":"Vestibular schwannoma: genetic and epigenetic mechanisms, hearing loss, and emerging therapies"}],"trialsShown":[{"nct":"NCT04166409","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma"},{"nct":"NCT02407405","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibroma"},{"nct":"NCT06175637","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Observational Study to Evaluate the Effect and Safety of Selumetinib in Pediatric Patients With NF1-PNs"},{"nct":"NCT00598351","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Natural History Study of Patients With Neurofibromatosis Type 2"},{"nct":"NCT02523014","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Vismodegib, FAK Inhibitor GSK2256098, Capivasertib, and Abemaciclib in Treating Patients With Progressive Meningiomas"},{"nct":"NCT06541847","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Phase 2, Open-Label Study to Evaluate the Safety and Effects of HLX-1502 in Patients With Neurofibromatosis Type 1"},{"nct":"NCT03190915","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia"},{"nct":"NCT03962543","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas"}],"usage":{"input":8219,"output":6470},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"neurofibromatosis type 2\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"neurofibromatosis type 2\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42338700","PMID:42546347","PMID:42453176","PMID:42012512","PMID:41731704","PMID:42264666","PMID:42177837","PMID:41981748","PMID:42142209","PMID:42143176","NCT04166409","NCT02407405","NCT06175637","NCT00598351","NCT02523014","NCT06541847","NCT03190915","NCT03962543"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787173859562","cycle":122,"visit":1,"ts":"2026-08-19T21:10:59.562Z","cancer":{"key":"neurofibromatosis type 1","name":"neurofibromatosis type 1","mondo":{"id":"MONDO:0018975","name":"neurofibromatosis type 1"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise FAK (PTK2) inhibitor + RAF/MEK inhibitor combination testing in chromosome-8-gain NF1-associated MPNST, with chr8 copy number as the prospective selection biomarker.","confidence":0.55,"notebook":"Programme opens with a pack that is ~half noise: P1 (hsa_circ_0077658/miR-15a-5p/NF1 in paediatric pneumonia, PMID:42343224) and P2 (sepsis senescence genes, PMID:42219284) are off-target hits on the string \"NF1\"/gene symbol collision and carry no oncology signal — logged so the desk never re-queries them. P4, P8, P9 are single case reports (DAVF embolisation, periampullary GIST, 60-kg PN resection) — surgical, no mechanism.\n\nThe one genuinely new therapeutic hypothesis is FAK. A CRISPR knockout screen of chromosome 8 in MPNST nominated PTK2/FAK among 58 chr8-essential genes; FAKi alone reduced proliferation and xenograft growth, and FAKi + RAF/MEKi suppressed p-FAK, p-STAT3 and p-AKT while inducing cleaved caspase-3/PARP-1, with the largest PDX benefit in chr8-gain tumours (PMID:42579369). Mechanistically this is coherent: [KNOWN] NF1-null MPNST shows ERK hyperactivation with rapid adaptive PI3K/AKT and STAT3 rebound on MEKi alone; FAK sits upstream of both via integrin/adhesion signalling, so co-targeting closes the bypass. Chr8 gain is a copy-number-defined selection biomarker — testable retrospectively in existing MPNST cohorts. [KNOWN] defactinib and GSK2256098 are clinic-ready; FAK's normal role in adhesion/endothelial and cardiac function sets the window, and combination toxicity with MEKi (rash, ocular, cardiac EF) is the realistic limiter. Expected resistance: CRAF/ERK reactivation, YAP/TAZ-driven FAK independence, RTK (PDGFRA, EGFR) reactivation.\n\nSecond lead: abemaciclib in NF1 atypical neurofibromatous neoplasms of uncertain biologic potential (NCT04750928) — [KNOWN] ANNUBP is defined by CDKN2A/B biallelic loss, making CDK4/6 dependence a near-textbook consequence of tumour-suppressor loss rather than a druggable oncogene; this is the pre-malignant window where you can plausibly prevent MPNST rather than treat it.\n\nThird, MEK inhibition is now the backbone, not a hypothesis: pooled patient-reported pain fell −1.65 points across 7 trials/342 patients (PMID:42176397), and the selumetinib franchise is expanding into low-grade glioma head-to-head vs carboplatin/vincristine (NCT04166409), granule formulations for ≥1 year olds (NCT05309668), and Chinese and post-marketing cohorts (NCT04590235, NCT06175637). The programme's job is therefore combination partners and post-MEKi resistance, not more MEKi monotherapy.\n\nWeak/deferred: P3 (PMID:42464674) frames NF1 skeletal disease as RAS/MAPK + PI3K/AKT dysregulation in bone remodelling — a real unmet need but the review offers no agent, so I hold it as a low-confidence lead only. P10 (PMID:41898726) names brigatinib, bevacizumab and a TβR1-RKIP axis, but the abstract does not cleanly assign these to NF1 versus NF2-SWN — flagged ambiguous, not built on. P6 (PMID:42583752) reports 61.1% transmission of NF1 mutant alleles across 322 families, proposing germline clonal selection of NF1-null cells — [GERMLINE], genetic-counselling relevant, no therapeutic lead.","leadChanges":[{"id":"L1","title":"FAK/PTK2 + RAF-MEK co-inhibition in chr8-gain MPNST","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"CDK4/6 inhibition in CDKN2A/B-deleted atypical neurofibromatous neoplasms (ANNUBP) as MPNST interception","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"MEK inhibition as the NF1 therapeutic backbone: pain/function endpoints and combination scaffold","level":"LEAD","status":"NEW","confidence":0.7},{"id":"L4","title":"RAS/MAPK-PI3K targeting for NF1 skeletal disease (pseudarthrosis, low BMD)","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["What fraction of NF1-associated versus sporadic MPNSTs carry chr8 gain, and does PTK2 expression or amplification (not just chr8 ploidy) predict FAKi/MEKi synergy?","Which resistance mechanisms dominate at MPNST progression on FAKi+RAF/MEKi in PDX — CRAF/ERK reactivation, YAP/TAZ, or RTK switching — and can a triplet or sequential schedule pre-empt them?","In NF1 ANNUBP, does abemaciclib response (NCT04750928) track with CDKN2A/B biallelic loss, and does it reduce conversion to MPNST rather than only stabilise volume?","What is the biology of plexiform neurofibroma progression on selumetinib, and are post-MEKi biopsies available to define the resistant state that combination arms must target?","Are the brigatinib, bevacizumab and TbR1-RKIP claims in PMID:41898726 NF1-specific or NF2-SWN-specific? Abstract is ambiguous and this must be resolved before any lead is built on them.","Do MEK inhibitors help or harm NF1 skeletal outcomes (BMD, pseudarthrosis healing) in children on chronic therapy?"],"nextQueries":["(\"malignant peripheral nerve sheath tumor\" AND (resistance OR \"focal adhesion kinase\" OR PTK2 OR \"chromosome 8\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"atypical neurofibroma\" OR ANNUBP OR \"plexiform neurofibroma\") AND (CDKN2A OR CDK4 OR \"CDK4/6\" OR abemaciclib OR ribociclib) AND SRC:MED","(\"neurofibromatosis type 1\" AND (selumetinib OR mirdametinib OR trametinib) AND (resistance OR relapse OR progression OR combination)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42343224","doi":"10.1186/s12865-026-00867-z","year":2026,"isNew":true,"title":"Hsa_circ_0077658 serves as a potential diagnostic biomarker for severe pneumonia in children and alleviates lipopolysaccharide-induced damage to bronchial epithelial cells by modul"},{"pmid":"42219284","doi":"10.1080/0886022x.2026.2667584","year":2026,"isNew":true,"title":"Combining bioinformatics and machine learning to analyze and validate sepsis-related cell senescence genes and potential drugs"},{"pmid":"42464674","doi":"10.3892/ijmm.2026.5929","year":2026,"isNew":true,"title":"Neurofibromin in bone disease: Mechanisms and therapeutic implications (Review)"},{"pmid":"42293475","doi":"10.1016/j.radcr.2026.05.028","year":2026,"isNew":true,"title":"Endovascular treatment of an intraosseous dural arteriovenous fistula of the greater wing of the sphenoid: A case report and literature review"},{"pmid":"42176397","doi":"10.1016/j.clineuro.2026.109478","year":2026,"isNew":true,"title":"Patient-reported pain outcomes following MEK inhibitor therapy in neurofibromatosis type 1-associated plexiform neurofibromas: A systematic review and meta-analysis"},{"pmid":"42583752","doi":"10.1016/j.gim.2026.102682","year":2026,"isNew":true,"title":"Transmission ratio distortion of NF1 mutant alleles in familial Neurofibromatosis type 1"},{"pmid":"42579369","doi":"10.1172/jci201331","year":2026,"isNew":true,"title":"Combined FAK and MEK inhibition suppresses chromosome 8 gain malignant peripheral nerve sheath tumors"},{"pmid":"42578230","doi":"10.1097/rc9.0000000000000707","year":2026,"isNew":true,"title":"Periampullary GIST in a neurofibromatosis type 1 patient with idiopathic thrombocytopenic purpura - a rare case report at a tertiary care center in Bangladesh"},{"pmid":"42559632","doi":"10.1097/gox.0000000000008001","year":2026,"isNew":true,"title":"Staged Resection and Reconstruction of a 60-kg Giant Plexiform Neurofibroma Involving the Posterior Trunk and Thigh"},{"pmid":"41898726","doi":"10.3390/ijms27062867","year":2026,"isNew":true,"title":"Emerging Molecular Insights and Therapeutic Directions in Neurofibromatosis Type 1 and NF2-Related Schwannomatosis"}],"trialsShown":[{"nct":"NCT04166409","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma"},{"nct":"NCT04590235","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study of Selumetinib in Chinese Paediatric and Adult Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas ("},{"nct":"NCT04750928","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type I (NF1) Related Atypical Neurofibromas"},{"nct":"NCT06880991","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Development of Patient-Reported Outcome Measures Assessing Tumor Visibility and Appearance Concerns in Neurofibromatosis Type 1: A Qualitati"},{"nct":"NCT05361811","phase":"NA","status":"RECRUITING","isNew":true,"title":"Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized "},{"nct":"NCT05309668","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Pharmacokinetics, Safety and Efficacy of the Selumetinib Granule Formulation in Children Aged ≥1 to <7 Years With NF1-related Symptomatic, I"},{"nct":"NCT02407405","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibroma"},{"nct":"NCT06175637","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Observational Study to Evaluate the Effect and Safety of Selumetinib in Pediatric Patients With NF1-PNs"}],"usage":{"input":8828,"output":4935},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"neurofibromatosis type 1\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"neurofibromatosis type 1\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42343224","PMID:42219284","PMID:42464674","PMID:42293475","PMID:42176397","PMID:42583752","PMID:42579369","PMID:42578230","PMID:42559632","PMID:41898726","NCT04166409","NCT04590235","NCT04750928","NCT06880991","NCT05361811","NCT05309668","NCT02407405","NCT06175637"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787173671139","cycle":121,"visit":1,"ts":"2026-08-19T21:07:51.139Z","cancer":{"key":"von hippel-lindau disease","name":"von Hippel-Lindau disease","mondo":{"id":"MONDO:0008667","name":"von Hippel-Lindau disease"}},"control":false,"modelLabel":"SCIENCE","summary":"Anchor the VHL programme on HIF-2α–ARNT blockade (belzutifan) across the VHL lesion spectrum and immediately build the resistance-pre-emption arm (HIF-α abundance reduction via translation/mTOR-eIF2α axis) plus compartment-specific adjuncts (intravitreal anti-VEGF for retinal hemangioblastoma; SSTR-","confidence":0.62,"notebook":"Visit 1 opens the programme with a pack that is heavy on consolidation and light on novelty: no negative trial, no mechanism refuted, but a clear statement that the field's centre of gravity is HIF-2α. VHL is [GERMLINE] causal, biallelic somatic inactivation in lesions; the protein's E3 role (ELOB/ELOC/CUL2/RBX1) makes it a classic non-druggable tumour suppressor, so every viable axis is downstream-node or synthetic-lethal (PMID:42593521). Belzutifan blocking HIF-2α–ARNT dimerization is now the anchor: phase III activity post-IO/TKI in ccRCC, first-line combination with cabozantinib, PPGL approval including ≥12 y, with on-target anaemia/hypoxia as the dose-limiting window (PMID:41569310); Japanese reimbursement now explicitly covers VHL hemangioblastomas alongside surgery/SRS (PMID:42604778), and LITESPARK-015 (NCT04924075) plus the extension protocol (NCT07405164) keep the VHL spectrum, pNET and PPGL arms live. Therapeutic window argument: HIF-2α is largely dispensable in adult tissue except erythropoiesis and carotid body/pulmonary sensing — hence anaemia and hypoxaemia, not organ toxicity, define tolerability [KNOWN].\n\nThree secondary axes are worth opening rather than one padded set. First, resistance pre-emption: PMID:42202639 argues chemically diverse HIF inhibitors converge on translation control (mTOR, eIF2α stress response) to lower HIF-α abundance, which is orthogonal to dimerization blockade; an abundance-plus-dimerization combination should be robust to EPAS1/HIF2A gatekeeper substitutions and to HIF-1α compensation [INFERRED/KNOWN]. Second, the ocular compartment: a retinal capillary hemangioblastoma case (with coincident NR2E3 ESCS confounder) regressed on focal laser plus intravitreal anti-VEGF (PMID:42254309), raising whether systemic HIF-2α blockade can spare intravitreal therapy or whether VEGF ligand blockade remains needed where drug penetration is limited. Third, theranostics: genotype-directed tracer selection is now standard in hereditary endocrine neoplasia (PMID:42274298), and VHL pseudohypoxic pNET/PPGL are SSTR-expressing, making 68Ga-DOTATATE selection for 177Lu-PRRT a rational partner or successor to belzutifan in unresectable endocrine lesions [KNOWN]. I also flag the KG anchor CCND1 [SOMATIC]: cyclin D1 is a HIF-2α-driven transcript in kidney lineage [KNOWN], so CDK4/6 inhibition is a candidate downstream node if HIF-2α blockade is escaped — lowest-confidence lead, held only as a hypothesis.\n\nNothing retires this visit. Notebook caution: PMID:42549347 and PMID:42186673 are non-VHL/sporadic case reports and carry no therapeutic signal; do not re-mine them. Next visit must find hard data on belzutifan resistance genotypes, hemangioblastoma-specific response durability, and whether HIF-independent VHL functions are actually druggable.","leadChanges":[{"id":"L1","title":"HIF-2α–ARNT dimerization blockade (belzutifan) as systemic backbone across the VHL lesion spectrum","level":"LEAD","status":"NEW","confidence":0.78},{"id":"L2","title":"Dual-axis HIF suppression: reduce HIF-α abundance (translation/mTOR-eIF2α) on top of dimerization blockade to pre-empt belzutifan escape","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L3","title":"Compartment-directed therapy for retinal capillary hemangioblastoma: intravitreal anti-VEGF plus focal laser as adjunct or alternative to systemic HIF-2α blocka","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"SSTR-directed theranostics for VHL pseudohypoxic pNET and pheochromocytoma/paraganglioma","level":"LEAD","status":"NEW","confidence":0.38},{"id":"L5","title":"CCND1/CDK4-6 as a downstream node after HIF-2α escape","level":"LEAD","status":"NEW","confidence":0.22}],"unverifiedCitations":0,"openQuestions":["What are the observed genomic mechanisms of acquired belzutifan resistance in VHL disease and ccRCC (EPAS1/HIF2A gatekeeper mutations, ARNT alterations, HIF-1α or VEGF-independent angiogenic switching), and at what frequency?","Is belzutifan activity in CNS/spinal hemangioblastoma durable enough to defer or replace resection, and does it penetrate cyst-associated lesions — what are the reported response and cyst-volume data?","Are any HIF-independent consequences of VHL loss (non-canonical substrates, activities independent of ubiquitin ligase function) druggable, and which are lesion-type specific?","Can HIF-α abundance reduction (mTOR/eIF2α-axis agents) be combined with dimerization blockade without unacceptable anaemia, and does it retain activity against EPAS1 gatekeeper mutants?","In VHL-associated pNET/PPGL, how does SSTR-directed 177Lu-PRRT compare or sequence with belzutifan, and does prior nephron loss preclude PRRT dosimetrically?","Does genotype (VHL missense vs truncating vs type 2C) predict lesion spectrum and response to HIF-2α blockade well enough to stratify trials?"],"nextQueries":["(\"belzutifan\" OR \"MK-6482\") AND (resistance OR \"EPAS1\" OR \"HIF-2alpha mutation\" OR biomarker) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"von Hippel-Lindau\" OR \"VHL disease\") AND (hemangioblastoma) AND (belzutifan OR \"HIF-2\" OR systemic therapy OR response) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"VHL\" AND (\"HIF-independent\" OR \"non-canonical\" OR \"synthetic lethal\" OR \"CRISPR screen\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42254309","doi":"10.1016/j.ajoc.2026.102606","year":2026,"isNew":true,"title":"Concurrent Von Hippel-Lindau disease and enhanced S-cone syndrome leading to a distinct retinal phenotype"},{"pmid":"42593521","doi":"10.1007/s10555-026-10370-x","year":2026,"isNew":true,"title":"Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD)"},{"pmid":"42604778","doi":"10.11477/mf.030126030540040811","year":2026,"isNew":true,"title":"[Treatment of von Hippel-Lindau Disease and Hemangioblastoma]"},{"pmid":"42549347","doi":"10.1055/a-2920-0717","year":2026,"isNew":true,"title":"Primary Cervicomedullary Hemangioblastoma with Extensive Caudal Cystic Extension into the Cervical Cord: A Case Report and Literature Review"},{"pmid":"42274298","doi":"10.1530/erc-25-0516","year":2026,"isNew":true,"title":"FROM DISCOVERY SCIENCE TO THE CLINIC - HERITABLE ENDOCRINE CANCERS AND RELATED DISORDERS: Functional imaging in hereditary endocrine neoplasms: evolving modalities and clinical imp"},{"pmid":"42264668","doi":"10.1016/j.nec.2026.03.002","year":2026,"isNew":true,"title":"Hemangioblastomas of the Spinal Cord"},{"pmid":"42202639","doi":"10.1016/j.redox.2026.104220","year":2026,"isNew":true,"title":"HIF inhibition: Current strategies and clinical challenges"},{"pmid":"42186673","doi":"10.1210/jcemcr/luag099","year":2026,"isNew":true,"title":"Clinical and biochemical variability in composite pheochromocytomas: a report of 3 cases"},{"pmid":"41569310","doi":"10.1007/s00280-025-04861-x","year":2026,"isNew":true,"title":"First-in-class HIF-2α therapy in genitourinary oncology: Belzutifan from von Hippel-Lindau disease to advanced renal cell carcinoma"},{"pmid":"41948715","doi":"10.15586/jkc.v13i1.420","year":2026,"isNew":true,"title":"Gastric Neuroendocrine Tumor Presenting Atypically in von Hippel-Lindau Disease: A Case Report"}],"trialsShown":[{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT07405164","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Extension Study for Participants in Studies That Include Belzutifan (MK-6482-043/LITESPARK-043)"},{"nct":"NCT00005902","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study of Brain and Spinal Cord Tumor Growth and Cyst Development in Patients With Von Hippel Lindau Disease"},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT00102544","phase":"NA","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Use of Tracking Devices to Locate Abnormalities During Invasive Procedures"},{"nct":"NCT01496625","phase":"n/a","status":"RECRUITING","isNew":true,"title":"National Eye Institute Biorepository for Retinal Diseases"},{"nct":"NCT05955014","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Data Collection Protocol for Patients With Von Hippel Lindau Disease"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":7706,"output":5909},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"von Hippel-Lindau disease\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"von Hippel-Lindau disease\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42254309","PMID:42593521","PMID:42604778","PMID:42549347","PMID:42274298","PMID:42264668","PMID:42202639","PMID:42186673","PMID:41569310","PMID:41948715","NCT00001238","NCT07405164","NCT00005902","NCT04924075","NCT00102544","NCT01496625","NCT05955014","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787173471977","cycle":120,"visit":12,"ts":"2026-08-19T21:04:31.977Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Prospective CD26+CD35- flow separation of BCR::ABL1+ LSCs from same-marrow normal HSCs gives the CML programme a sortable therapeutic-window assay and a diagnosis-time failure predictor, but CD26+ LSC burden does not predict TFR relapse — so residual-disease counts stay off the surrogate list while ","confidence":0.62,"notebook":"Fresh pack is thin on chemistry and rich on stem-cell phenotyping, and it moves the programme in one clear direction: the residual-disease compartment is now prospectively isolable, but its burden is not the thing that governs relapse.\n\nP1 (PMID:39503729) [NEW] separates BCR::ABL1+ LSCs from co-resident BCR::ABL1− HSCs within the same primitive fraction as CD26+CD35− versus CD26−CD35+, and shows that diagnosis-time abundance of molecularly primitive cells is higher in patients failing at 12 months. That is exactly the same-donor normal-HSPC window my LSC leads keep demanding, delivered as a sortable gate rather than an inference — I am rewriting the assay specification of L6/L11/L13/L14 around it (CD26+CD35− leukaemic versus CD26−CD35+ normal from one aspirate). It also gives L7 a mechanistic eligibility biomarker to sit beside the Morphoclinical image model, so L7 strengthens on a stratifier that is measurable at diagnosis by flow.\n\nP2 (PMID:40116978) [NEW] is the contradicting half and outranks enthusiasm: in 210 chronic-phase and 31 TFR patients, CD26+ LSC fell with DMR yet persisted in 19% of DMR patients, correlated only weakly with transcript level (r=0.187), and LSC recurrence in TFR did not track molecular relapse. So CD26+ LSC count is a poor surrogate — which is direct support for L5's premise that relapse timing is set by host surveillance rather than pre-cessation clone burden [INFERRED]; L5 strengthens, and open question 6 gains a burden-independent anchor. It also caps any CD26 lead: eradicating a compartment whose fluctuation does not predict relapse needs a hard clinical endpoint, not an MRD proxy.\n\nI open L15 anyway, because CD26/DPP4 is the only CML-restricted surface antigen in this programme (absent from healthy marrow and other myeloid neoplasms, PMID:40116978) and P1 confirms its selectivity against same-fraction normal HSCs — but at low confidence, with CD26's normal role on T cells (costimulation), kidney and gut epithelium as the binding window constraint [KNOWN].\n\nP3 (PMID:41917309) [NEW] is a 523-patient Japanese all-patient postmarketing surveillance: cumulative MMR 61.2%, MR4.0 42.3%, MR4.5 26.5% by week 48, responses including some baseline-mutant patients, vascular occlusive events 0.2%, no dosing above 80 mg. Independent real-world corroboration of L8's non-cross-resistant salvage claim and of the label-dose plateau underpinning L7/L9. The desk's control answer holds: direct/allosteric BCR-ABL1 inhibition remains the mechanism that works.\n\nThe targeted LSC query returned no TRIM28/SETDB1 or STAT5A regulon data in any CML atlas — L6 weakened for a second targeted silence, L13 likewise (retirement condition: one more empty visit). P4/P5/P6 are in-silico or non-CML; catalogued, not actioned.","leadChanges":[{"id":"L8","title":"Sequential ATP-site to allosteric switch: asciminib as non-cross-resistant salvage after ponatinib and in T315I disease","level":"DOSSIER","status":"STRENGTHENED","confidence":0.8},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.67},{"id":"L5","title":"Immune-readiness gating of TKI discontinuation: IL-6/MCP-1 cytokine signature plus innate-like CD8dim/NK effector clonality, with peg-IFN-alpha as expansion age","level":"LEAD","status":"STRENGTHENED","confidence":0.36},{"id":"L6","title":"TIF1beta/TRIM28-SETDB1 chromatin node as a BCR-ABL1-kinase-independent LSC-state dependency","level":"LEAD","status":"WEAKENED","confidence":0.24},{"id":"L15","title":"CD26 (DPP4) as a CML-restricted surface antigen for antibody- or cell-mediated eradication of the persistent BCR::ABL1+ LSC","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Does the diagnosis-time CD26+CD35- primitive-fraction gate (PMID:39503729) predict 12-month molecular failure in an independent prospective cohort, and how does its AUROC compare head-to-head with the Morphoclinical cytomorphology model and","Has any CD26/DPP4-directed depleting agent (antibody, ADC, CAR) been tested against primary CML LSCs, and what is the measured CD26 density differential versus activated normal T cells and CD34+ HSPCs?","What is the published kinase-domain mutation spectrum at asciminib failure beyond A337V/P465S — including in the Japanese postmarketing cohort's baseline-mutant responders and non-responders — and which ATP-site agent rescues each?","Can a DMR-specific asciminib Cmin floor be derived from ASC4FIRST/ASC4OPT PK once adherence/relative dose intensity is deconfounded, and does Cmax_2h outperform trough?","Does GRN inference on published CML single-cell/multiomic atlases show TRIM28/SETDB1 or STAT5A regulon enrichment in the persistent CD26+CD35- LSC state (retirement condition for L6/L13 if negative)?","Is there any reported concurrent asciminib + ATP-site TKI exposure with molecular depth, cytopenia and arterial-event data, given NCT03906292 remains silent for an eleventh visit?"],"nextQueries":["(\"chronic myeloid leukemia\" OR \"CML\") AND (CD26 OR DPP4 OR dipeptidyl-peptidase) AND (\"leukemic stem cell\" OR antibody OR CAR OR depletion) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"chronic myeloid leukemia\") AND (asciminib) AND (\"kinase domain\" OR mutation OR compound OR ponatinib OR olverembatinib) AND (failure OR resistance OR sequencing) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","(\"chronic myeloid leukemia\") AND (\"single-cell\" OR \"gene regulatory network\" OR SCENIC OR regulon) AND (TRIM28 OR SETDB1 OR STAT5 OR \"leukemic stem cell\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"39503729","doi":"10.7554/elife.92074","year":2024,"isNew":true,"title":"Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response"},{"pmid":"40116978","doi":"10.1007/s10238-025-01626-x","year":2025,"isNew":true,"title":"Evaluation of leukemic stem cell (CD26 +) in chronic myeloid leukemia patients with different molecular responses and in treatment-free remission"},{"pmid":"41917309","doi":"10.1007/s12185-026-04199-x","year":2026,"isNew":true,"title":"Postmarketing surveillance study of asciminib in patients with resistant/intolerant chronic myeloid leukemia in Japan"},{"pmid":"40868343","doi":"10.3390/bioengineering12080830","year":2025,"isNew":true,"title":"Regulation of Tetraspanin CD63 in Chronic Myeloid Leukemia (CML): Single-Cell Analysis of Asymmetric Hematopoietic Stem Cell Division Genes"},{"pmid":"42180517","doi":"10.3389/fgene.2026.1773468","year":2026,"isNew":true,"title":"Diverse roles of YTHDC1 in chromatin and blood cancers"},{"pmid":"41151234","doi":"10.1016/j.compbiolchem.2025.108744","year":2026,"isNew":true,"title":"Integrative multi-omics analysis of long non-coding RNA regulatory networks in chronic myeloid leukemia resistance and leukemic stem cell persistence"},{"pmid":"42284888","doi":"10.1016/j.biopha.2026.119652","year":2026,"isNew":false,"title":"Selective HDAC6 inhibition perturbs autophagy and enhances integrated stress response-mediated immunogenic apoptosis in chronic myeloid leukemia"},{"pmid":"41601208","doi":"10.1111/cas.70334","year":2026,"isNew":false,"title":"Roles of TIF1β in Leukemic Stem Cell Through SETDB1-Dependent and Independent Mechanisms"},{"pmid":"42463944","doi":"10.1038/s41375-026-02972-9","year":2026,"isNew":false,"title":"Asciminib monotherapy in patients with BCR::ABL1 T315I-mutated chronic-phase chronic myeloid leukemia: phase 1 trial final results"},{"pmid":"42090741","doi":"10.1016/j.leukres.2026.108239","year":2026,"isNew":false,"title":"Real-world data on the use of asciminib in chronic-phase chronic myeloid leukemia after two or more prior tyrosine kinase inhibitors: Results of the Turkish managed access program "}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":17356,"output":8935},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"chronic myeloid leukemia\") AND (asciminib) AND (resistance OR mutation OR \"kinase domain\" OR A337V OR P465S) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"chronic myeloid leukemia\") AND (\"leukemic stem cell\" OR \"CD34+CD38-\" OR \"long-term culture-initiating\") AND (STAT5 OR TRIM28 OR SETDB1 OR \"single-cell\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:39503729","PMID:40116978","PMID:41917309","PMID:40868343","PMID:42180517","PMID:41151234","PMID:42284888","PMID:41601208","PMID:42463944","PMID:42090741","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787173237835","cycle":119,"visit":1,"ts":"2026-08-19T21:00:37.835Z","cancer":{"key":"hereditary pheochromocytoma-paraganglioma","name":"hereditary pheochromocytoma-paraganglioma","mondo":{"id":"MONDO:0017366","name":"hereditary pheochromocytoma-paraganglioma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise HIF-2α blockade (belzutifan, NCT04924075) as the lead systemic hypothesis for cluster-1 pseudohypoxic hereditary PPGL, and demand SDHx-vs-VHL genotype-stratified response data plus SSTR2 co-expression mapping before designing a radioligand combination.","confidence":0.5,"notebook":"Programme opens on a pack that is diagnostically rich and therapeutically thin: mostly case reports, registries, and variant-interpretation infrastructure. Only one axis in the pack is a live drug hypothesis, and I am treating it as the spine of the programme.\n\nCluster-1 pseudohypoxia. SDHx/VHL/FH loss stabilises HIF-2α through succinate/fumarate-mediated inhibition of PHD2 (SDHx) or direct VHL loss [KNOWN]; the resulting HIF-2α transcriptional output (VEGFA, EPO, PDGFB, LOX) is the shared node linking the causal germline anchors (SDHA/B/C/D, SDHAF2, SLC25A11, DLST) to the correlated VHL/FH tumours. NCT04924075 is running belzutifan explicitly in advanced PPGL alongside VHL-associated tumours and SDH-deficient GIST, and NCT07167329 (BELIEVE-VHL) adds real-world plus pharmacogenetic readout; NCT00001238 supplies the VHL natural-history denominator. Therapeutic-window argument: HIF-2α in normal tissue drives renal EPO transcription and carotid-body chemoreception, so on-target anaemia and hypoxia-response blunting are the expected dose-limiting toxicities [KNOWN]. Anticipated resistance: HIF-1α compensation, HIF2A P-loop/PAS-B mutations that restore dimerisation despite drug (documented in belzutifan-treated ccRCC [KNOWN]), and VEGF-independent stromal rescue. Key unknown from abstracts alone: whether SDHx-mutant (succinate-driven, VHL-intact) tumours respond like VHL-null ones — the trial abstract does not stratify.\n\nSecond axis: SSTR2. Two independent pack cases show intense ⁶⁸Ga-DOTATATE avidity in PPGL, including a metastasis-mimicking multifocal VHL case (PMID:39253568) and an ACTH-cosecreting pheochromocytoma (PMID:42221407). Avidity is imaging, not efficacy, but it establishes target presence and makes ¹⁷⁷Lu-DOTATATE ± HIF-2α blockade a testable radioligand/radiosensitisation combination [INFERRED].\n\nThird: MAX. PMID:41685558 formalises MEN5 as germline MAX LOF with somatic second hit and parent-of-origin (paternal) penetrance; PMID:41446467 shows a pathogenic MAX variant missed on first-pass panel and only found after cortical-sparing recurrence. MAX loss releases MXD-mediated repression, leaving MYC–MGA/other partner complexes dominant — a tumour-suppressor loss, therefore synthetic-lethality territory, not direct inhibition [INFERRED]. Registered as a low-confidence mechanistic lead pending any functional dependency data.\n\nFourth: eligibility infrastructure. INT2GRATE|HPPGL (PMID:38473309, 8600 SDHx variants with paired somatic-inactivation evidence) and PMID:41030646 (an SDHB \"VUS\" that actually creates a splice site, confirmed by RT-PCR) both argue that the trial-eligible cluster-1 population is systematically undercounted. Novel SDHD frameshift in siblings (PMID:42005593) reinforces this.\n\nRecorded as not-a-lead: tipifarnib/HRAS (NCT03160274-adjacent pediatric MATCH, NCT04284774) has no PPGL rationale — cluster-2 disease runs through RET/NF1/TMEM127/MAX, not HRAS. Adrenal-sparing surgery (PMID:41809780) is a management question, not a target.","leadChanges":[{"id":"L1","title":"HIF-2α inhibition (belzutifan) in cluster-1 pseudohypoxic hereditary PPGL","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"SSTR2-directed radioligand therapy, with HIF-2α blockade as radiosensitising partner","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"MAX-null (MEN5) PPGL: synthetic-lethal dependencies downstream of lost MXD repression","level":"LEAD","status":"NEW","confidence":0.28},{"id":"L4","title":"Integrated germline+tumour interpretation (including splice-altering VUS) to define the trial-eligible cluster-1 population","level":"LEAD","status":"NEW","confidence":0.42}],"unverifiedCitations":0,"openQuestions":["Does belzutifan activity in NCT04924075 differ between SDHx-mutant (succinate-driven, VHL-intact) and VHL-null PPGL — i.e. is PHD2 inhibition by succinate sufficient to create HIF-2α dependence?","What are the reported acquired-resistance mechanisms to HIF-2α inhibitors in any pseudohypoxic tumour (HIF1A switch, HIF2A dimerisation-domain mutations, EGLN1 restoration), and are any detectable in PPGL?","Is there evidence that SDH/FH loss produces a homologous-recombination or 2-OG-dioxygenase-dependent repair defect ('BRCAness') that would justify PARP inhibitor or temozolomide/alkylator hypotheses in SDHB-mutant metastatic disease?","How does SSTR2 expression and DOTATATE SUVmax track with germline genotype, and is there any 177Lu-DOTATATE efficacy data specifically in SDHx-mutant metastatic PPGL?","Are there functional data (CRISPR screens, MAX-null models) identifying synthetic-lethal dependencies in MAX-deficient chromaffin tumours, and does MEN5 alter systemic therapy choice at all?","What is the recurrence rate in remnant adrenal tissue after cortical-sparing adrenalectomy stratified by germline gene, and does any medical therapy reduce it?"],"nextQueries":["(belzutifan OR \"HIF-2alpha\" OR \"HIF2A inhibitor\") AND (pheochromocytoma OR paraganglioma OR SDHB) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(SDHB OR SDHD OR \"succinate dehydrogenase\") AND (\"synthetic lethal\" OR PARP OR temozolomide OR \"homologous recombination\" OR \"DNA methylation\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"177Lu-DOTATATE\" OR \"peptide receptor radionuclide therapy\" OR SSTR2) AND (pheochromocytoma OR paraganglioma) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"40159592","doi":"10.1007/s10689-025-00457-9","year":2025,"isNew":true,"title":"The European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS): benefits for patients, families, and health care providers"},{"pmid":"39765842","doi":"10.3390/antiox13121514","year":2024,"isNew":true,"title":"Genetic and Functional Changes in Mitochondria in the Pituitary Adenoma: The Pathogenesis and Its Therapy"},{"pmid":"38473309","doi":"10.3390/cancers16050947","year":2024,"isNew":true,"title":"Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes"},{"pmid":"39253568","doi":"10.1210/jcemcr/luae160","year":2024,"isNew":true,"title":"Multiple Primary Paragangliomas in a Pediatric Patient With von Hippel Lindau: A Diagnostic Dilemma"},{"pmid":"42221407","doi":"10.1016/j.aed.2025.12.018","year":2026,"isNew":true,"title":"Ectopic Cushing Syndrome due to an Adrenocorticotropic Hormone-Producing Pheochromocytoma"},{"pmid":"42005593","doi":"10.1002/iju5.70179","year":2026,"isNew":true,"title":"Two Cases of Hereditary Paraganglioma-Pheochromocytoma Syndrome in Siblings, Caused by a Novel Succinate Dehydrogenase Complex Subunit D Variant"},{"pmid":"41809780","doi":"10.21037/tau-2025-683","year":2026,"isNew":true,"title":"Bilateral pheochromocytoma: case series and review of treatment strategies based on genetic mutations"},{"pmid":"41685558","doi":"10.1530/erc-25-0219","year":2026,"isNew":true,"title":"Multiple endocrine neoplasia type 5: emerging evidence and clinical perspectives"},{"pmid":"41446467","doi":"10.7759/cureus.97541","year":2025,"isNew":true,"title":"Pathogenic MAX Variant in Bilateral Adrenal Paragangliomas: The Dilemma of Cortical-Sparing Surgery"},{"pmid":"41030646","doi":"10.14740/wjon2631","year":2025,"isNew":true,"title":"Problems in Cancer Genome Medicine: Base Mutations Cause Intron Start Signals, Resulting in Unexpected Splicing"}],"trialsShown":[{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT04284774","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Trea"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT06573723","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Institutional Registry of Rare Diseases"},{"nct":"NCT07316075","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Multicenter Study on Cardiovascular and Metabolic Complications in Patients With Biochemically Silent Pheochromocytomas and Paragangliomas"},{"nct":"NCT03160274","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Genetic Analysis of Pheochromocytomas, Paragangliomas and Associated Conditions"},{"nct":"NCT07167329","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Real-World Effectiveness and Pharmacogenetics of Belzutifan in VHL Syndrome: The BELIEVE-VHL Trial"}],"usage":{"input":8124,"output":5893},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"hereditary pheochromocytoma-paraganglioma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"hereditary pheochromocytoma-paraganglioma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:40159592","PMID:39765842","PMID:38473309","PMID:39253568","PMID:42221407","PMID:42005593","PMID:41809780","PMID:41685558","PMID:41446467","PMID:41030646","NCT00001238","NCT04924075","NCT04284774","NCT03050268","NCT06573723","NCT07316075","NCT03160274","NCT07167329"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787173037725","cycle":118,"visit":1,"ts":"2026-08-19T20:57:17.725Z","cancer":{"key":"juvenile polyposis syndrome","name":"juvenile polyposis syndrome","mondo":{"id":"MONDO:0017380","name":"juvenile polyposis syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"In SMAD4/BMPR1A-germline juvenile polyposis the only drug-named hypothesis in current literature is rapalog (sirolimus) suppression of polyp burden and bleeding-related anaemia, supported so far by a single 2026 case report — next step is to find any cohort-level polyp-burden data on mTOR inhibition","confidence":0.34,"notebook":"Programme opens with a thin therapeutic pack: nine papers, one registry protocol, zero interventional trials in JPS. Four papers (P2, P4, P5, P6) mention JPS only as a list item in polyposis/gastric-cancer differentials and carry no mechanistic or therapeutic content for this desk — logged as non-informative so they are not re-mined. Anchor hygiene: SMAD4 and BMPR1A are [GERMLINE] loss-of-function predisposition genes (P9 confirms a heterozygous truncating SMAD4 c.1549_1550del in a 10-year-old with adenoma-bearing polyps); Monarch's \"correlated\" call on ENG is misleading — ENG is [GERMLINE] causal for HHT1 (P7), and its co-listing reflects the SMAD4 JPS–HHT overlap through the BMP9/10–ALK1–ENG–SMAD4 endothelial axis, not a somatic driver. PTEN [GERMLINE in PHTS] enters as a phenocopy, not a JPS somatic event.\n\nThree leads open. First, mTOR inhibition (sirolimus/everolimus) for polyp burden and refractory anaemia: P9 explicitly flags sirolimus as emerging therapy in SMAD4-JPS, and mechanistically [INFERRED] loss of BMP–SMAD4 restraint on PI3K/AKT/mTOR in the polyp stroma/epithelium converges on the same axis that makes rapalogs active in PTEN-hamartoma lesions [KNOWN]. This is the only lead in the pack with a named drug, but the evidence is a single case-report sentence with no dosing, no burden metric, no outcome — LEAD, low-moderate confidence, explicitly unverified. Window argument: chronic immunosuppression, stomatitis and growth effects in paediatric carriers set a high bar; a polyp-burden endpoint per surveillance endoscopy is the only realistic readout at this prevalence.\n\nSecond, modifier-directed chemoprevention. P8 is the single genuinely mechanistic entry: 260 F1 mice from 14 Collaborative Cross lines × Smad4-KO yield Ipsl1-3 (chr16/14/12) plus sex-specific loci, enriched for immune signalling, ubiquitin–proteasome and metabolic genes (STAM2, PSMD6, NAMPT, CACNB4). [SPECULATIVE] NAMPT and proteasome nodes are pharmacologically addressable; nothing is validated, and QTL intervals are wide. Value now is as a prioritisation substrate, not a target.\n\nThird, anti-angiogenic control of the SMAD4-JPS/HHT bleeding phenotype (P7, P9). Same ligand–receptor axis, VEGF-driven telangiectasia; embolisation is standard for PAVMs (P7) but GI telangiectatic bleeding is the dominant chronic morbidity. Framed honestly as morbidity control, not anticancer.\n\nTwo cautions recorded: P10 shows Rax-CreER^T2×BMPR1A^flox tanycyte ablation is methodologically unreliable — do not build conditional-BMPR1A tool claims on it — and BMPR1A's normal role in hypothalamic appetite/sympathetic control warns against systemic BMP-pathway agonism. P1 sets the feasibility frame: 3-year prevalence 0.15/100,000, ~188 Japanese patients; any trial must be registry-embedded (T1 NCT03050268).","leadChanges":[{"id":"L1","title":"Rapalog (sirolimus/everolimus) suppression of hamartomatous polyp burden in SMAD4/BMPR1A-germline JPS","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L2","title":"Modifier-locus-directed chemoprevention in Smad4-deficient polyposis (Ipsl1-3: immune, ubiquitin-proteasome, NAD-metabolic nodes)","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L3","title":"Anti-angiogenic control of the SMAD4-JPS/HHT overlap bleeding and anaemia phenotype","level":"LEAD","status":"NEW","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["Is there any cohort- or series-level evidence (not case reports) that sirolimus/everolimus reduces polyp number, size, or transfusion requirement in SMAD4/BMPR1A JPS, or in PTEN hamartoma tumour syndrome polyposis as the nearest phenocopy?","What are the somatic events in JPS polyps that progress to dysplasia/adenoma (second-hit SMAD4/BMPR1A LOH, KRAS, APC, TGFBR2) and does the epithelium or the stroma carry the driving lesion?","Can any Ipsl1-3 candidate (STAM2, PSMD6, NAMPT, CACNB4) be validated as a causal modifier, and does an orthologous human variant track with polyp burden in genotype-matched SMAD4 carriers?","Does immune-checkpoint or TGF-beta-axis pharmacology have a rationale in SMAD4-null GI neoplasia, given SMAD4 loss as an immune-evasion/stromal-remodelling node?","Given a prevalence of 0.15/100,000, what is the minimum viable trial architecture (registry-embedded n-of-few, polyp-burden endpoint, within-patient pre/post design) and which existing predisposition registries could supply the cohort?","Is BMP pathway agonism/restoration feasible at all, or does BMPR1A's normal role in hypothalamic appetite and sympathetic regulation preclude systemic agonists?"],"nextQueries":["(\"juvenile polyposis\" OR \"SMAD4\" OR \"BMPR1A\") AND (sirolimus OR everolimus OR rapamycin OR mTOR) AND SRC:MED","(\"SMAD4\" AND (\"loss\" OR \"deficient\")) AND (\"immune evasion\" OR \"TGF-beta\" OR \"checkpoint\" OR \"stroma\") AND PUB_YEAR:[2022 TO 2026] AND SRC:MED","(\"hamartomatous polyp\" OR \"juvenile polyp\") AND (\"somatic\" OR \"second hit\" OR \"loss of heterozygosity\" OR \"sequencing\") AND SRC:MED"],"papersShown":[{"pmid":"39623880","doi":"10.1111/jgh.16839","year":2025,"isNew":true,"title":"Prevalence and Incidence of Peutz-Jeghers Syndrome and Juvenile Polyposis Syndrome in Japan: A Nationwide Epidemiological Survey in 2022"},{"pmid":"41204315","doi":"10.1186/s13053-025-00318-7","year":2025,"isNew":true,"title":"The genetic puzzle of FAP: exploring novel diagnostic approaches for APC/MUTYH-negative case"},{"pmid":"42499747","doi":"10.1002/jpr3.70188","year":2026,"isNew":true,"title":"Endoscopic ischemic polypectomy for small intestinal polyps in a 7-year-old girl with juvenile polyposis syndrome"},{"pmid":"42419310","doi":"10.1016/j.suc.2026.03.006","year":2026,"isNew":true,"title":"Role of Genetics in Gastric Malignancy: Screening, Prevention and Treatment"},{"pmid":"42204638","doi":"10.1002/cam4.71848","year":2026,"isNew":true,"title":"Distinct Germline Mutation Landscape and Clinical Implications in Chinese Colorectal Cancer: A Large-Scale Genomic Analysis of 1094 Patients"},{"pmid":"42359212","doi":"10.7759/cureus.109578","year":2026,"isNew":true,"title":"Robot-Assisted Total Gastrectomy for Gastric Adenocarcinoma and Proximal Polyposis of the Stomach: A Case Report"},{"pmid":"42209023","doi":"10.1136/bcr-2026-273656","year":2026,"isNew":true,"title":"Hereditary haemorrhagic telangiectasia as a cause of exertional dyspnoea"},{"pmid":"42193864","doi":"10.3390/cells15100853","year":2026,"isNew":true,"title":"Mapping Genetic Modifiers of Polyp Formation in &lt;i&gt;Smad4&lt;/i&gt;-Deficient Juvenile Polyposis Using the Collaborative Cross Mouse Population"},{"pmid":"42110114","doi":"10.1002/jpr3.70143","year":2026,"isNew":true,"title":"Juvenile polyposis in a SMAD4-mutated child: A call for early surveillance"},{"pmid":"42040903","doi":"10.1096/fba.2025-00300","year":2026,"isNew":true,"title":"Methodological Challenges for Ablation of BMPR1A in Hypothalamic Tanycytes-A Cautionary Tale"}],"trialsShown":[{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":7205,"output":5464},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"juvenile polyposis syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"juvenile polyposis syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:39623880","PMID:41204315","PMID:42499747","PMID:42419310","PMID:42204638","PMID:42359212","PMID:42209023","PMID:42193864","PMID:42110114","PMID:42040903","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787172841927","cycle":117,"visit":1,"ts":"2026-08-19T20:54:01.927Z","cancer":{"key":"peutz-jeghers syndrome","name":"Peutz-Jeghers syndrome","mondo":{"id":"MONDO:0008280","name":"Peutz-Jeghers syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Anchor the PJS programme on COX-2 chemoprevention (randomised celecoxib trial NCT06722534) scored against the newly quantified cold-snare small-bowel polyp-burden endpoint, while treating LKB1-null/KRAS co-mutant lesions as immunotherapy-resistant and searching for STK11 synthetic-lethal partners.","confidence":0.42,"notebook":"Visit 1 opens the programme with a thin but usable pack: no mechanistic PJS biology, one genuine interventional trial, and several tangential case reports.\n\nThe single most actionable item is NCT06722534 — randomised celecoxib 400 mg vs placebo for \"prevention of progression\" in PJS (Air Force Military Medical University). This is the first pharmacologic prevention trial in the pack and it converts PJS from a purely endoscopic-management problem into a druggable one. Mechanistic rationale is off-pack and must be tagged: LKB1 loss de-represses mTORC1 via loss of AMPK signalling, and Lkb1+/− murine hamartomas show COX-2/PGE2 elevation, with celecoxib reducing polyp burden in mouse and small human pilots [KNOWN]. Window argument: COX-2 is largely inducible, minimally expressed in normal gut epithelium, but chronic celecoxib in children/young adults carries cardiovascular and renal liability [KNOWN] — so drug-holiday and dose-fractionation designs deserve explicit modelling. I make this LEAD, not higher: one trial, no results.\n\nTwo prospective/technical papers set the endpoint infrastructure the drug trial depends on. Cold snare polypectomy for 5–9 mm small-bowel polyps by double-balloon enteroscopy in 40 PJS patients, 187 polyps, 5.9% immediate bleeding (PMID:42544942), and endoscopic rescue of gastric outlet obstruction from a massive polyp in a 1-year-old (PMID:41843399), together define a quantifiable, repeatable readout — size-stratified polyp count, resection burden, bleeding events — that any chemoprevention arm should be scored against rather than against symptomatic laparotomy. This is a trial-design lead, and it is why I keep it separate from mechanism.\n\nPMID:40900228 is the only somatic-genotype signal: SMMN-FGT with a shared, likely somatic [SOMATIC] STK11 mutation across ovarian mucinous carcinoma and tubal metaplasia, plus site-divergent KRAS. That is a clonal-field pattern in which LKB1 loss precedes and KRAS follows [INFERRED]. STK11/KRAS co-mutation predicts poor single-agent PD-1 benefit in NSCLC [KNOWN], so I record now that anti-PD-1 monotherapy should not be proposed for LKB1-null PJS-spectrum tumours without an immune-priming partner. PMID:42286854 pharmacoprofiles 20 cervical lines with over-represented STK11 alterations and claims LoF-linked synthetic lethality, but the abstract is truncated and names no partner gene or drug — logged as a hypothesis-generating pointer only, confidence low.\n\nPancreatic interception registries (NCT02000089, NCT05692596) are surveillance-only for now; PJS carriers belong in them, but no interventional arm exists to strengthen.\n\nNext visit must supply the missing mechanism layer: rapamycin/everolimus and metformin evidence in Lkb1-null polyposis, and named STK11-synthetic-lethal partners (SIK1/2/3, HDAC, DHODH candidates [SPECULATIVE]).","leadChanges":[{"id":"L1","title":"COX-2 inhibition (celecoxib) as pharmacologic chemoprevention of STK11-germline hamartomatous polyposis","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"Size-stratified endoscopic polyp burden as the primary efficacy endpoint for PJS drug trials","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"LKB1-null / KRAS co-mutant PJS-spectrum tumours: avoid PD-1 monotherapy, prioritise MEK-plus-immune-priming combinations","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L4","title":"STK11 loss-of-function as a synthetic-lethal drug-response biomarker","level":"LEAD","status":"NEW","confidence":0.2}],"unverifiedCitations":0,"openQuestions":["What are the published rapamycin/everolimus and metformin data in Lkb1+/- murine polyposis and in human PJS pilots, and do they beat celecoxib on polyp burden?","Which specific gene/drug pair underlies the STK11-LoF synthetic lethality claim in PMID:42286854, and does it replicate in isogenic STK11-null models?","What is the immune contexture of PJS hamartomas and PJS-associated carcinomas (STING/interferon status), and does it justify innate priming plus MEK inhibition?","Is size-stratified polyp burden by double-balloon enteroscopy reproducible enough to serve as a randomised trial primary endpoint, and what bleeding rate is acceptable in children?","Do germline STK11 carriers in pancreatic interception registries (NCT02000089, NCT05692596) show lesion trajectories that could support an interventional prevention arm?","How often is STK11 mutation in mucinous gynaecologic and SMMN-FGT lesions germline versus somatic, and does KRAS co-mutation stratify outcome?"],"nextQueries":["(\"Peutz-Jeghers\" OR \"Lkb1\" OR \"STK11\") AND (rapamycin OR sirolimus OR everolimus OR metformin OR celecoxib) AND (polyp OR polyposis OR chemoprevention) AND SRC:MED","STK11 AND (\"synthetic lethal\" OR \"CRISPR screen\" OR \"salt-inducible kinase\" OR SIK) AND PUB_YEAR:[2022 TO 2026] AND SRC:MED","STK11 AND (STING OR interferon OR \"immune evasion\" OR \"PD-1 resistance\") AND PUB_YEAR:[2022 TO 2026] AND SRC:MED"],"papersShown":[{"pmid":"40900228","doi":"10.1007/s00428-025-04236-w","year":2026,"isNew":true,"title":"Synchronous mucinous metaplasia and neoplasia of the ovarium and fallopian tube with STK11 and KRAS mutations: a case report"},{"pmid":"42137457","doi":"10.3892/ol.2026.15627","year":2026,"isNew":true,"title":"Diagnostic and therapeutic challenges of locally advanced colon cancer complicated with acute lymphoblastic leukemia: A case report"},{"pmid":"41983269","doi":"10.1111/jcpe.70033","year":2026,"isNew":true,"title":"Gingival and Periodontal Diseases and Conditions in Children and Adolescents: Consensus Report"},{"pmid":"42286854","doi":"10.1002/cnr2.70599","year":2026,"isNew":true,"title":"Unveiling Candidate Markers for Drug Resistance or Synthetic Lethality in Cervical Cancer: Integrative Analysis of Genetic and Pharmacoprofiling"},{"pmid":"42204638","doi":"10.1002/cam4.71848","year":2026,"isNew":true,"title":"Distinct Germline Mutation Landscape and Clinical Implications in Chinese Colorectal Cancer: A Large-Scale Genomic Analysis of 1094 Patients"},{"pmid":"42095055","doi":"10.1016/j.gore.2026.102092","year":2026,"isNew":true,"title":"Malignant transformation of a testosterone-secreting ovarian steroid cell tumor: a case report"},{"pmid":"41843399","doi":"10.1007/s12328-026-02308-1","year":2026,"isNew":true,"title":"Gastric outlet obstruction secondary to Peutz-Jeghers syndrome successfully managed by polypectomy"},{"pmid":"42359212","doi":"10.7759/cureus.109578","year":2026,"isNew":true,"title":"Robot-Assisted Total Gastrectomy for Gastric Adenocarcinoma and Proximal Polyposis of the Stomach: A Case Report"},{"pmid":"42544942","doi":"10.14309/ajg.0000000000004176","year":2026,"isNew":true,"title":"Cold snare polypectomy for 5-9mm small-bowel polyps in patients with Peutz-Jeghers syndrome by double-balloon enteroscopy: a prospective clinical trial"},{"pmid":"42493218","doi":"10.1136/bcr-2026-272912","year":2026,"isNew":true,"title":"Gynaecomastia in a patient with Peutz-Jeghers syndrome"}],"trialsShown":[{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT05692596","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"The Pancreas Interception Center (PIC) for Early Detection, Prevention, and Novel Therapeutics"},{"nct":"NCT02775461","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Pancreas Registry and High Risk Registry"},{"nct":"NCT02000089","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"The Cancer of the Pancreas Screening-5 CAPS5)Study"},{"nct":"NCT06722534","phase":"NA","status":"RECRUITING","isNew":true,"title":"Celecoxib for Prevention of Progression in Peutz-Jeghers Syndrome"},{"nct":"NCT04095195","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Registry of Subjects at Risk of Pancreatic Cancer"}],"usage":{"input":7278,"output":5206},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Peutz-Jeghers syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Peutz-Jeghers syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:40900228","PMID:42137457","PMID:41983269","PMID:42286854","PMID:42204638","PMID:42095055","PMID:41843399","PMID:42359212","PMID:42544942","PMID:42493218","NCT03050268","NCT05692596","NCT02775461","NCT02000089","NCT06722534","NCT04095195"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787172646463","cycle":116,"visit":1,"ts":"2026-08-19T20:50:46.463Z","cancer":{"key":"birt-hogg-dube syndrome","name":"Birt-Hogg-Dube syndrome","mondo":{"id":"MONDO:0800444","name":"Birt-Hogg-Dube syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"In germline-FLCN renal tumours, dual PD-1/CTLA-4 blockade produced a durable complete pathologic response with clonal T-cell expansion (PMID:42527032), making immune-checkpoint sensitivity of FLCN-null renal neoplasia the programme's lead hypothesis, while new stromal-senescence/phospho-S6 data in f","confidence":0.38,"notebook":"Programme opens from zero. The pack is diagnostics-heavy — three papers (P2, P7, P9, P10) concern ascertainment, not therapy — but two items carry mechanistic weight and one registry sets the denominator.\n\nHighest-value item is P4 (PMID:42527032): first-line ipilimumab + nivolumab in locally advanced renal epithelioid angiomyolipoma on a germline FLCN background, with rapid symptomatic response, complete pathologic response at delayed nephrectomy, >5-year remission, and a shared expanded TCR clone in blood and tumour. That last detail matters: it argues a genuine clonal T-cell effector response rather than incidental regression. Mechanistically, E-AML is normally framed as a TSC1/TSC2–mTORC1 lesion treated with rapalogs, whose control is inconsistent (P4); a germline FLCN carrier reaching the same mTORC1-hyperactive perivascular epithelioid state via a different node [INFERRED] suggests that FLCN-null/TFE3-TFEB–driven renal tumours may be immunologically visible despite low mutational burden [SPECULATIVE — no TMB or PD-L1 data in the abstract, and n=1 case report]. Open lead, not more.\n\nSecond, P3 (PMID:42357990) re-frames fibrofolliculoma: all 13 lesions showed diastase-sensitive PAS+ dermal interstitial glycogen, with stromal GLB1/p53/phospho-S6 positivity and no CD68 — i.e. non-histiocytic stromal senescence plus mTORC1 activation in the *stromal*, not only epithelial, compartment. [KNOWN] Randomised topical rapamycin for BHD fibrofolliculomas was negative; I record that in the notebook so the desk never re-proposes topical rapalog monotherapy. The new compartmental data give a testable reason for that failure and a fresh angle: senescent-stroma-directed therapy (senolytic dasatinib+quercetin, or navitoclax) ± systemic/enhanced-penetration mTOR inhibition, with phospho-S6 and GLB1 as pharmacodynamic readouts on serial punch biopsy.\n\nThird, P1 (PMID:41823029) documents germline 17p11.2 deletion (FLCN+RAI1) plus a *somatic* FLCN splice-donor c.1300+1G>A — clean two-hit biallelic inactivation in an oncocytic/chromophobe-like renal tumour with patchy CK7/KIT. Tumour maintenance therefore rests on complete FLCN loss [SOMATIC second hit on a [GERMLINE] first hit], which is the licence for a synthetic-lethality search against the FLCN-null lysosomal/TFE3-TFEB transcriptional state rather than any attempt to drug the tumour suppressor. [KNOWN] The PRDM10 anchor converges on the same axis by reducing FLCN transcription — a dosage, not a structural, lesion; germline.\n\nP5 (PMID:42338237) quantifies stakes: BHD 18.1% of a 304-patient rare-ILD registry, pneumothorax 44.6% at diagnosis, low mortality (1.8%) but cancer in 25% during follow-up — a chemoprevention-shaped population. P8 flags cyst barotrauma (hyperbaric/diving) as a non-oncologic hazard. Trials T1–T4 are natural-history/counselling only: no interventional BHD trial exists to reference.\n\nNext visit: pressure-test whether FLCN-null renal tumours are intrinsically ICB-responsive, and find the FLCN-null dependency map.","leadChanges":[{"id":"L1","title":"Dual immune checkpoint blockade (ipilimumab + nivolumab) in FLCN-null renal neoplasia, including epithelioid angiomyolipoma","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L2","title":"Senescent-stroma-directed therapy for BHD fibrofolliculoma, not epithelial mTOR monotherapy","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L3","title":"Two-hit FLCN inactivation as the maintenance state to attack by synthetic lethality","level":"LEAD","status":"NEW","confidence":0.32}],"unverifiedCitations":0,"openQuestions":["Beyond the single case in PMID:42527032, is there any cohort-level evidence that FLCN-mutant renal tumours (E-AML, hybrid oncocytic/chromophobe, FLCN-RCC) respond to PD-1/CTLA-4 blockade, and what are their TMB, PD-L1 and CD8 spatial phenot","Was the index response driven by FLCN loss or by convergent mTORC1/TSC-pathway biology intrinsic to epithelioid angiomyolipoma — i.e. does germline FLCN status predict anything?","Which genes are selectively essential in FLCN-null renal cells (TFEB/TFE3 coactivators, V-ATPase, RagC/D axis, OXPHOS), and is any dependency drugged by an approved agent?","Do senolytics or senomorphics reduce stromal senescence markers and lesion burden in fibrofolliculoma, and does stromal (not epithelial) mTORC1 localisation explain the failed topical rapamycin trial?","Given cancer in 25% of BHD patients on registry follow-up (PMID:42338237) with pneumothorax in 44.6%, what is the tolerability threshold for any chronic chemopreventive agent in this largely asymptomatic, low-mortality population?","Is there a validated pharmacodynamic biomarker of FLCN pathway activity (GPNMB, phospho-S6, TFE3 nuclear localisation) usable as a trial endpoint in skin or renal lesions?"],"nextQueries":["(FLCN OR folliculin) AND (TFEB OR TFE3 OR \"RagC\" OR \"synthetic lethal\" OR \"CRISPR screen\" OR dependency) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(FLCN OR \"Birt-Hogg-Dube\") AND (\"immune checkpoint\" OR nivolumab OR ipilimumab OR \"tumor microenvironment\" OR \"tumor mutational burden\") AND SRC:MED","(fibrofolliculoma OR \"angiomyolipoma\") AND (sirolimus OR rapamycin OR senolytic OR senescence OR dasatinib OR quercetin) AND SRC:MED AND PUB_YEAR:[2015 TO 2026]"],"papersShown":[{"pmid":"41823029","doi":"10.1177/10668969251415520","year":2026,"isNew":true,"title":"&lt;i&gt;FLCN&lt;/i&gt;-Mutated Tumors in Smith-Magenis Syndrome: A Case Report of &lt;i&gt;FLCN&lt;/i&gt;-Associated Pathogenesis"},{"pmid":"41496737","doi":"10.1111/ijd.70247","year":2026,"isNew":true,"title":"Decoding Genetic Disease Through the Skin: Lessons From the UDN"},{"pmid":"42357990","doi":"10.1097/dad.0000000000003336","year":2026,"isNew":true,"title":"Dermal Interstitial Glycogenosis and Stromal Senescence-Associated Marker Expression in Fibrofolliculomas: Implications for Pathogenesis and mTOR-Targeted Therapy"},{"pmid":"42527032","doi":"10.1136/jitc-2026-015794","year":2026,"isNew":true,"title":"Complete response to dual immune checkpoint blockade in a patient with Birt-Hogg-Dubé syndrome and epithelioid angiomyolipoma"},{"pmid":"42338237","doi":"10.4046/trd.2026.0004","year":2026,"isNew":true,"title":"A Multicenter Registry for Rare Interstitial Lung Diseases in Korea: Baseline Characteristics and Clinical Outcomes"},{"pmid":"42333294","doi":"10.1093/omcr/omag109","year":2026,"isNew":true,"title":"A case of surgically treated recurrent spontaneous pneumothorax during pregnancy"},{"pmid":"42293364","doi":"10.1093/ckj/sfag143","year":2026,"isNew":true,"title":"Hereditary kidney tumor syndromes: structured evaluation of a questionnaire-based approach"},{"pmid":"42290582","doi":"10.28920/dhm56.2.198-202","year":2026,"isNew":true,"title":"Cerebral arterial oxygen embolism as a complication of hyperbaric oxygen treatment: a case report"},{"pmid":"42278264","doi":"10.3390/ijms27114731","year":2026,"isNew":true,"title":"Experience in Molecular Genetic Diagnostics of Birt-Hogg-Dubé Syndrome: Characteristics of Identified Mutations and Evolution of the Methodological Approach"},{"pmid":"41939121","doi":"10.1097/ms9.0000000000004884","year":2026,"isNew":true,"title":"CRISPR-Cas12a for Birt-Hogg-Dubé syndrome: a promising diagnostic tool for deep intronic variant detection"}],"trialsShown":[{"nct":"NCT00033137","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Genetic Analysis of Birt Hogg-Dube Syndrome and Characterization of Predisposition to Kidney Cancer"},{"nct":"NCT06330350","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling"},{"nct":"NCT06330324","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Reproductive Options in Inherited Skin Diseases"},{"nct":"NCT03749980","phase":"n/a","status":"RECRUITING","isNew":true,"title":"MyVHL: Patient Natural History Study"}],"usage":{"input":7709,"output":5646},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Birt-Hogg-Dube syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Birt-Hogg-Dube syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41823029","PMID:41496737","PMID:42357990","PMID:42527032","PMID:42338237","PMID:42333294","PMID:42293364","PMID:42290582","PMID:42278264","PMID:41939121","NCT00033137","NCT06330350","NCT06330324","NCT03749980"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787172445150","cycle":115,"visit":1,"ts":"2026-08-19T20:47:25.150Z","cancer":{"key":"gorlin syndrome","name":"Gorlin syndrome","mondo":{"id":"MONDO:0007187","name":"nevoid basal cell carcinoma syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Gorlin BCC management should be reframed around SMO-inhibitor tolerability and the ~13-month acquired-resistance ceiling documented in PMID:40492880 — prioritise skin-restricted patidegib gel (NCT06050122), SMO-independent PDT stacking (NCT06623201), and downstream PI3K/AKT+CDK4/6 salvage suggested ","confidence":0.6,"notebook":"Programme opens with a real-world efficacy/toxicity/resistance triangle rather than a target-discovery problem. P3 (PMID:40492880, 32 patients, Victoria, 8 years) is the anchor: oral Hedgehog inhibitors give 84% ORR in Gorlin/laBCC/mBCC, but 90% suffer QoL-limiting adverse effects and 77% (10/13) of la/mBCC develop acquired resistance at a median 13 months. So the therapeutic question for Gorlin is not \"does SMO blockade work\" — it does — but *how to keep the pathway suppressed in skin without systemic Hh withdrawal, and what to do at month 13*. [KNOWN] Systemic toxicity (muscle cramps, dysgeusia, alopecia, teratogenicity) is on-target: Hh signalling maintains hair-follicle cycling, taste-bud renewal, and skeletal/muscle homeostasis, so the window must come from compartmentalisation, intermittency, or downstream nodes.\n\nThree tractable strategies fall out. First, skin-restricted SMO inhibition: patidegib gel 2% is in phase 3 for facial BCC prevention in Gorlin (NCT06050122, active/not recruiting) — chemoprevention against germline PTCH1 haploinsufficiency [GERMLINE], where every follicular basal keratinocyte is one somatic hit from GLI derepression. Second, modality stacking that is SMO-independent: ALA blue-light PDT plus sonidegib in phase 1 (NCT06623201), rationalised by P6 (PMID:42511737), which names cyclic PDT as a tissue-sparing standby for Gorlin and flags hypoxia/optical thickness as PDT's failure mode — precisely what cytoreductive HHi could relieve. ROS killing does not care about SMO mutation or GLI2 amplification. Third, downstream/parallel salvage: P2 (PMID:41734992) shows a Gorlin-patient-derived neuroepithelial stem cell line and its SHH-medulloblastoma derivative, with the tumour derivative selectively sensitive to PI3K (BYL719)/AKT (AZD5363) and CDK4/6 (PD-0332991) single agents and synergistic/additive combinations in 2D and 3D. That is germline-PTCH1 background, non-canonical nodes, and a normal-cell comparator giving a window argument — but it is medulloblastoma, viability/apoptosis endpoints only, no in vivo, so extrapolation to BCC is [INFERRED].\n\nNoise recorded so the desk never re-chases it: Meier-Gorlin syndrome (PMID:42496035, PMID:42311582, NCT04569149) is an unrelated ORC/CDC6/GMNN replication-licensing dwarfism, not a Hh cancer syndrome; P1, P5, P9 and P4 (LC-OCT monitoring, PMID:42604114) are non-therapeutic. P8 (PMID:42462758) adds phenotypic/allelic spectrum for 11 PTCH1 patients including four novel variants but no genotype–therapy link.\n\nNext visit needs: the resistance genotype spectrum in Gorlin BCC (SMO point mutants vs GLI2/CCND1 amplification vs SUFU [SOMATIC] loss), whether patidegib gel's phase 3 read-out exists, and whether GLI-direct agents (arsenic trioxide, BET inhibitors) [KNOWN] have Gorlin-specific data.","leadChanges":[{"id":"L1","title":"Skin-compartment-restricted SMO inhibition (topical patidegib) as chemoprevention in germline PTCH1 Gorlin syndrome","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"SMO-independent modality stacking: cyclic ALA-photodynamic therapy combined with oral sonidegib","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L3","title":"Downstream/parallel-node salvage for SMO-inhibitor-resistant Hedgehog tumours: dual PI3K-AKT plus CDK4/6 inhibition","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L4","title":"Resistance-genotype mapping of Hedgehog-inhibitor failure in Gorlin BCC via prospective registries","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["What is the somatic genotype spectrum at HHi progression in Gorlin BCC specifically (SMO mutation vs GLI2/CCND1 amplification vs SUFU loss), and does germline PTCH1 vs SUFU status change it?","Has NCT06050122 (patidegib gel 2%) reported new-lesion-rate and systemic Hh-toxicity data, and do plasma levels confirm true skin compartmentalisation?","Does intermittent/pulsed oral HHi dosing preserve the 84% response rate while cutting the 90% adverse-effect burden, and does it delay or accelerate resistance?","Do PI3K/AKT and CDK4/6 inhibitors show the same tumour-selective window in Gorlin BCC-derived or HHi-resistant BCC models as in the tNES SHH-medulloblastoma model, and is there any in vivo evidence?","Is there Gorlin-specific evidence for GLI-direct agents (arsenic trioxide, BET/BRD4 inhibitors) or for immune-checkpoint blockade after HHi failure, given BCC's high mutational burden?","In Gorlin medulloblastoma (18% of PMID:42462758's cohort), is radiotherapy avoidance achievable with SMO or downstream inhibition, and what is the growth-plate risk in children?"],"nextQueries":["(\"basal cell carcinoma\") AND (vismodegib OR sonidegib) AND (resistance) AND (SMO OR GLI2 OR SUFU) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(patidegib OR \"topical hedgehog inhibitor\") AND (\"basal cell carcinoma\" OR \"Gorlin\") AND SRC:MED","(\"basal cell carcinoma\") AND (\"immune checkpoint\" OR cemiplimab OR pembrolizumab) AND (\"hedgehog inhibitor\" OR vismodegib OR sonidegib) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41496737","doi":"10.1111/ijd.70247","year":2026,"isNew":true,"title":"Decoding Genetic Disease Through the Skin: Lessons From the UDN"},{"pmid":"41734992","doi":"10.1002/1878-0261.70230","year":2026,"isNew":true,"title":"Dual PI3K/AKT and CDK4/6 inhibition reveals selective sensitivity in an SHH medulloblastoma stem cell model"},{"pmid":"40492880","doi":"10.1111/ajd.14544","year":2025,"isNew":true,"title":"Eight-Year Experience of Hedgehog Pathway Inhibitors at Three Tertiary Referral Centres in the Australian State of Victoria"},{"pmid":"42604114","doi":"10.1016/j.jdcr.2026.07.011","year":2026,"isNew":true,"title":"Line-field confocal optical coherence tomography for diagnosis and treatment monitoring of subtle basal cell carcinomas in a patient with nevoid basal cell carcinoma syndrome"},{"pmid":"41884229","doi":"10.1016/j.synbio.2026.02.013","year":2026,"isNew":true,"title":"Advances in vehicles for in situ delivery: From classical vectors to biologically inspired structures"},{"pmid":"42511737","doi":"10.3390/ijms27146396","year":2026,"isNew":true,"title":"Photodynamic Therapy for Keratinocytic Precancerous Lesions and Non-Melanoma Skin Cancer: A Narrative Review"},{"pmid":"42496035","doi":"10.1111/cen.70183","year":2026,"isNew":true,"title":"Endocrine Phenotypes and Hormonal Treatment in Meier-Gorlin Syndrome: Report of Two Cases and a Systematic Review of Literature"},{"pmid":"42462758","doi":"10.1055/a-2896-4106","year":2026,"isNew":true,"title":"PTCH1-Related Gorlin Syndrome: Expanding the Clinical and Molecular Spectrum in a Cohort of 11 Patients"},{"pmid":"41931068","doi":"10.1016/j.jid.2026.03.003","year":2026,"isNew":true,"title":"Building consensus in pediatric dermatology research"},{"pmid":"42311582","doi":"10.31486/toj.25.0048","year":2026,"isNew":true,"title":"Revision Anterior Cruciate Ligament Reconstruction in an Adult Twin With Meier-Gorlin Syndrome"}],"trialsShown":[{"nct":"NCT06050122","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Efficacy and Safety of Patidegib Gel 2% for Preventing Basal Cell Carcinomas on the Face of Adults With Gorlin Syndrome"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT06623201","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Blue-Light Photodynamic Therapy and Sonidegib for Multiple Basal Cell Carcinomas"},{"nct":"NCT04569149","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Primordial Dwarfism Registry"},{"nct":"NCT06330350","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling"},{"nct":"NCT06330324","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Reproductive Options in Inherited Skin Diseases"},{"nct":"NCT05463757","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Oral Hedgehog Inhibitors in the Treatment of Basal Cell Carcinoma in the Netherlands: a Prospective Registration Study"}],"usage":{"input":7259,"output":5430},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Gorlin syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Gorlin syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41496737","PMID:41734992","PMID:40492880","PMID:42604114","PMID:41884229","PMID:42511737","PMID:42496035","PMID:42462758","PMID:41931068","PMID:42311582","NCT06050122","NCT03050268","NCT06623201","NCT04569149","NCT06330350","NCT06330324","NCT05463757"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787172249915","cycle":114,"visit":1,"ts":"2026-08-19T20:44:09.915Z","cancer":{"key":"multiple endocrine neoplasia type 2","name":"multiple endocrine neoplasia type 2","mondo":{"id":"MONDO:0019003","name":"multiple endocrine neoplasia type 2"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise selpercatinib + MEK inhibitor (trametinib) as the lead vertical-block strategy for RET-inhibitor-resistant RET-mutant medullary thyroid carcinoma, and test whether NF1 loss/RAS-MAPK reactivation occurs in human post-progression MTC biopsies.","confidence":0.55,"notebook":"Programme opens with a genuinely actionable mechanism paper rather than a review. P10 (PMID:42258786) is the anchor: in a vandetanib-derived RET-mutant MTC resistance model, acquired resistance ran through RET copy-number gain plus the solvent-front-adjacent secondary mutation p.G810S, and, independently, a whole-genome CRISPR knockout screen identified NF1 loss → RAS/MAPK reactivation as sufficient for intrinsic resistance; selpercatinib + trametinib was active in preclinical animal models. Mechanistically this says RET-mutant MTC resistance is dominated by vertical MAPK re-flux, not by loss of RET dependence, so MEK co-inhibition is the rational vertical-block partner. P2 (PMID:41977363) independently frames resistance as secondary RET mutations plus MET/EGFR bypass, and P1/P8 confirm RAS-MAPK, PI3K-AKT and JAK-STAT as the RET output arms in MTC. Lead L1 (selpercatinib+trametinib) is created at LEAD, not higher — all supporting data are from this single visit and are preclinical; MTC-specific human data are absent. Therapeutic window is the main worry: [KNOWN] RET is required for enteric neurogenesis and nephrogenesis in development but adult dependence is limited, whereas MEK inhibition brings rash, ejection-fraction drop and ocular toxicity that stack with selpercatinib hypertension/transaminitis; a dose-attenuated or intermittent trametinib schedule is the trial design question. Expected escape from the combination: MEK1 P124/ERK amplification, PI3K/AKT or MET bypass (P2), RET G810 solvent-front expansion requiring next-generation RET agents [KNOWN, not in pack].\n\nSecond lead, weaker: MEN2A metastatic pheochromocytoma. P5 (PMID:42128848) reports 7.6 GBq ¹³¹I-MIBG in a p.C634Y [GERMLINE] MEN2A patient giving biochemical response (normetanephrine fall) without radiographic response — cytoreduction is not the realistic endpoint; hormonal control is. P8 proposes a treatment algorithm for metastatic pheo. Belzutifan (T1, NCT04924075) is recruiting in advanced PPGL, but [INFERRED] MEN2 RET-driven pheos are kinase-signalling (cluster 2) rather than pseudohypoxic, so HIF-2α dependence should not be assumed; whether MEN2A pheos carry a HIF-2α transcriptional signature is a testable, cheap question.\n\nThird: P4 (PMID:42541759) undercuts the MEN2/MTC GLP-1RA black-box as rodent-derived, with human registry/trial data conflicting. Recorded as a mechanism question (is GLP-1R expressed on human C-cell neoplasia at all?), which also gates any exendin-based radioligand idea. The semaglutide cardiometabolic papers (P6, P7, P9) and the PTC dedifferentiation case report (P3) are pack noise for MEN2 — logged so the desk does not re-chase them. NCT01660984 (NCI MTC natural history) is the likeliest source of paired pre/post-RET-inhibitor human tissue to test whether NF1 loss occurs clinically.","leadChanges":[{"id":"L1","title":"Vertical RET+MEK blockade (selpercatinib + trametinib) for RET-inhibitor-resistant MEN2-associated MTC","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"Radioligand-plus-systemic control of MEN2A metastatic pheochromocytoma, with cluster-2 vs pseudohypoxia target triage","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L3","title":"Does GLP-1R exist on human C-cell neoplasia? De-risking the MEN2/MTC GLP-1RA black box and testing GLP-1R as a ligand target","level":"LEAD","status":"NEW","confidence":0.2}],"unverifiedCitations":0,"openQuestions":["Does NF1 loss or other RAS-MAPK reactivation actually occur in human MTC biopsies/ctDNA at progression on selpercatinib or pralsetinib, or is it an in vitro CRISPR artefact?","What is the tolerable schedule for selpercatinib plus a MEK inhibitor in MTC, and is intermittent MEK dosing sufficient to suppress pERK rebound?","For RET G810S/solvent-front resistance specifically, does MEK co-inhibition help at all, or is a next-generation RET inhibitor the only route — and are there published MTC data on such agents?","Do MEN2-associated (RET-driven) pheochromocytomas show any HIF-2alpha transcriptional dependence that would justify belzutifan, or should they be treated purely as cluster-2 kinase-driven disease?","Is GLP-1R expressed in human MTC and C-cell hyperplasia, and does GLP-1RA exposure alter calcitonin kinetics in RET mutation carriers?","Are MET or EGFR bypass tracks (flagged in PMID:41977363) documented in MTC as opposed to RET-fusion lung cancer, i.e. is the bypass literature transferable to MEN2?"],"nextQueries":["(\"medullary thyroid carcinoma\") AND (selpercatinib OR pralsetinib) AND (resistance OR \"G810\" OR \"acquired\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"medullary thyroid\" OR \"multiple endocrine neoplasia type 2\") AND (\"MEK inhibitor\" OR trametinib OR selumetinib OR NF1) AND SRC:MED","(pheochromocytoma) AND (\"cluster 2\" OR RET OR \"HIF-2\" OR belzutifan OR \"177Lu-DOTATATE\" OR MIBG) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"41930492","doi":"10.3892/mmr.2026.13874","year":2026,"isNew":true,"title":"Mechanism of and research progress on alterations in the RET gene in thyroid cancer (Review)"},{"pmid":"41977363","doi":"10.3390/ijms27073180","year":2026,"isNew":true,"title":"RET Signaling Pathway in Human Cancer: Oncogenic Mechanisms, Selective Inhibitors, and Emerging Resistance Strategies"},{"pmid":"42327507","doi":"10.1016/j.radcr.2026.05.080","year":2026,"isNew":true,"title":"Squamous dedifferentiation and differentiated high-grade transformation of papillary thyroid carcinoma in metastatic lymph nodes: Two cases and literature review"},{"pmid":"42541759","doi":"10.1093/ejendo/lvag135","year":2026,"isNew":true,"title":"Safety of glucagon-like peptide-1 receptor agonists in neuroendocrine neoplasms"},{"pmid":"42128848","doi":"10.1507/endocrj.ej25-0486","year":2026,"isNew":true,"title":"Efficacy of iodine-131-metaiodobenzylguanidine therapy for multiple endocrine neoplasia type 2A-associated metastatic pheochromocytoma: case report and literature review"},{"pmid":"42046181","doi":"10.1111/dom.70746","year":2026,"isNew":true,"title":"Semaglutide 2.4 mg Cardiometabolic Long-Term Effects in Patients With Obesity or Overweight in a Real-World Setting: A Retrospective Cohort Study in the United States (SMILE)"},{"pmid":"41994903","doi":"10.1111/dom.70770","year":2026,"isNew":true,"title":"Semaglutide Treatment in Young Adults Living With Type 2 Diabetes: A Post Hoc Analysis From the SUSTAIN and PIONEER Clinical Trials"},{"pmid":"42297674","doi":"10.1016/j.beem.2026.102135","year":2026,"isNew":true,"title":"Multiple endocrine neoplasia type 2: From molecular genetics to precision therapy"},{"pmid":"42291047","doi":"10.1016/j.ajpc.2026.101521","year":2026,"isNew":true,"title":"Association between semaglutide 2.4 mg and risk of cardiovascular events in people with overweight or obesity without atherosclerotic cardiovascular disease in the real-world: The "},{"pmid":"42258786","doi":"10.1200/po-26-00091","year":2026,"isNew":true,"title":"Combination of Selpercatinib and Trametinib Overcomes Resistance to RET Inhibitors in RET-Mutant Medullary Thyroid Carcinoma"}],"trialsShown":[{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT07285044","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"The Cancer Connected Access and Remote Expertise Beyond Walls Program to Provide In-Home Cancer Treatment and Improve Treatment Satisfaction"},{"nct":"NCT07492680","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Study of BMS-986504 Monotherapy and in Combination With Other Agents in Participants With Advanced and/or Metastatic Solid Tumors With Hom"},{"nct":"NCT07303894","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Study of Isoquercetin in People With Ovarian Cancer"},{"nct":"NCT01660984","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Natural History Study of Children and Adults With Medullary Thyroid Cancer"},{"nct":"NCT05142189","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Clinical Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced No"},{"nct":"NCT02867592","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumor"},{"nct":"NCT03655223","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Early Check: Expanded Screening in Newborns"}],"usage":{"input":8808,"output":5018},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"multiple endocrine neoplasia type 2\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"multiple endocrine neoplasia type 2\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41930492","PMID:41977363","PMID:42327507","PMID:42541759","PMID:42128848","PMID:42046181","PMID:41994903","PMID:42297674","PMID:42291047","PMID:42258786","NCT04924075","NCT07285044","NCT07492680","NCT07303894","NCT01660984","NCT05142189","NCT02867592","NCT03655223"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787172038736","cycle":113,"visit":2,"ts":"2026-08-19T20:40:38.736Z","cancer":{"key":"multiple endocrine neoplasia type 1","name":"multiple endocrine neoplasia type 1","mondo":{"id":"MONDO:0007540","name":"multiple endocrine neoplasia type 1"}},"control":false,"modelLabel":"SCIENCE","summary":"Promote the menin-loss/p27-p18 G1 axis to CANDIDATE on independent endocrine-tumour evidence (MEN1-mutant, CDK4-amplified, cell-cycle-altered ACC subtype plus germline CDKN1B/MEN4 confirmation), pre-screening for RB protein loss as an exclusion biomarker, and formally bar menin-KMT2A inhibitors from","confidence":0.32,"notebook":"The pack is thin and largely off-target (fat-containing soft-tissue tumours, chordoid glioma, fezolinetant, BNT116 — irrelevant; the ClinicalTrials return contained no MEN1-actionable interventional arm, only NCT04969926, a NIDDK parathyroid natural-history study that is worth flagging as a possible biobank/recruitment substrate for the L4 question rather than as evidence). Two signals nonetheless move the programme.\n\nFirst, the G1/RB axis (L2) gains its first independent, endocrine-tumour-specific corroboration. Integrated WES/RNA/CNV of 61 adrenocortical carcinomas finds recurrent somatic MEN1 mutation in 8% alongside focal CDK4 amplification, and defines a \"cell cycle-altered\" subtype (22%, chromosomal instability, cell-cycle gene overexpression) for which the authors explicitly nominate CDK4/6 inhibition (PMID:42550593). This is cross-tumour extrapolation — ACC is not a canonical MEN1-syndrome lesion and the abstract does not report whether the MEN1-mutant cases fall in the CCA cluster — so it corroborates the axis, not the MEN1-specific dependency. PMID:42141904 independently confirms CDKN1B as an established germline pituitary-predisposition gene (MEN4) [GERMLINE], anchoring p27 as a genuine rate-limiting brake in this lineage rather than an inferred one. PMID:42245474 supplies the pre-specified exclusion biomarker: RB protein loss by IHC in a somatotropinoma, i.e. RB-null endocrine adenomas exist and would be intrinsically CDK4/6i-refractory [INFERRED]. L2 → CANDIDATE at 0.35; the isogenic MEN1-null palbociclib IC50 experiment (open question 2) is still unanswered by literature and remains the gate to any higher tier.\n\nSecond, a notebook-level negative to protect the desk: menin–KMT2A inhibitors (revumenib/ziftomenib class) are reviewed as targeted therapeutics for KMT2A-rearranged myeloid disease (PMID:40181550, PMID:41051795) where menin is a required cofactor. In MEN1 tumours menin is biallelically lost [GERMLINE first hit / SOMATIC second]; pharmacological menin inhibition is directionally wrong and potentially tumour-promoting [KNOWN/INFERRED]. Never propose it here. The residual legitimate epigenetic play is the mirror image — loss-of-menin creating dependence on other chromatin writers (PRC2/EZH2, PRMT5, DOT1L) in low-mutational-burden, epigenetically driven NETs (PMID:42252277, PMID:39601374) — opened as L5 at 0.2 and explicitly hypothesis-only, since no MEN1-null screen data appear in the pack.\n\nL3 gets weak lateral support: ACC's immune-suppressed subtype (40%, TCR downregulation, HLA-II deletions, worst DFS) reproduces the immune-cold endocrine phenotype and again argues against checkpoint monotherapy (PMID:42550593). L1 and L4 unchanged — no MET or thymectomy evidence arrived.","leadChanges":[{"id":"L2","title":"Menin-loss to p27/p18 G1 dysregulation as a CDK4/6-inhibitor dependency in MEN1 tumours","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.35},{"id":"L3","title":"Stroma/immune-exclusion-directed combination rather than checkpoint monotherapy in MEN1 panNET","level":"LEAD","status":"STRENGTHENED","confidence":0.25},{"id":"L5","title":"Chromatin-writer dependency created by menin loss (PRC2/EZH2, PRMT5, DOT1L) — and explicit exclusion of menin-KMT2A inhibitors","level":"LEAD","status":"NEW","confidence":0.2}],"unverifiedCitations":0,"openQuestions":["In the MEN1-mutant adrenocortical and MEN1-syndromic panNET/parathyroid tumours, does somatic MEN1 loss co-segregate with the cell cycle-altered/CDK4-amplified phenotype, and is RB1/p16 status retained often enough to support an RB-intact C","Is there any published isogenic, organoid or PDX evidence that MEN1-null endocrine cells show a palbociclib/ribociclib/abemaciclib IC50 shift versus MEN1-WT, and does p27/p18 restoration abolish it?","Beyond CDK4/6, which chromatin-writer dependencies (EZH2/PRC2, PRMT5 with MTAP co-deletion, DOT1L, KDM1A) are documented in menin-null endocrine models, and are any screens published rather than reviewed?","Do MEN1-germline panNETs share the immune-excluded, CAF-rich, MHC-low topology of sporadic panNET and of immune-suppressed adrenocortical carcinoma, or do they differ in CD8 infiltration and HLA copy number?","Does c-MET IHC positivity in MEN1 NETs correspond to MET amplification/exon-14 events or HGF autocrine signalling, and is any cabozantinib response in a MEN1 patient published?","Is the cervical-thymectomy cure benefit reproducible with surgeon volume and resection extent controlled, and what is the permanent hypoparathyroidism penalty — can NCT04969926-type parathyroid natural-history cohorts adjudicate this?"],"nextQueries":["(MEN1 OR menin) AND (isogenic OR organoid OR \"cell line\" OR xenograft) AND (palbociclib OR ribociclib OR abemaciclib OR \"CDK4/6\") AND SRC:MED","(\"pancreatic neuroendocrine\" OR parathyroid OR \"pituitary adenoma\") AND (\"single-cell\" OR \"spatial transcriptomics\" OR \"tumour microenvironment\") AND MEN1 AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(MEN1 OR menin) AND (\"CRISPR screen\" OR PRMT5 OR EZH2 OR MTAP OR \"replication stress\" OR ATR) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"papersShown":[{"pmid":"40181550","doi":"10.1002/ijc.35389","year":2026,"isNew":true,"title":"Therapeutic targeting of chromatin alterations in leukemia and solid tumors"},{"pmid":"39601374","doi":"10.1080/17501911.2024.2430169","year":2025,"isNew":true,"title":"Cancer epigenetic therapy: recent advances, challenges, and emerging opportunities"},{"pmid":"41537447","doi":"10.1002/ctm2.70586","year":2026,"isNew":true,"title":"Synthetic lethality in cancer therapy: Mechanisms, models and clinical translation for overcoming therapeutic resistance"},{"pmid":"41051795","doi":"10.1021/acs.chemrev.5c00231","year":2025,"isNew":true,"title":"Chromatin Regulatory Targets for Anticancer Therapeutics"},{"pmid":"42550593","doi":"10.1530/erc-25-0342","year":2026,"isNew":true,"title":"Molecular subtyping of adrenocortical carcinoma reveals distinct subtypes with prognostic and therapeutic implications"},{"pmid":"42245474","doi":"10.1210/jcemcr/luag146","year":2026,"isNew":true,"title":"Growth hormone-secreting adenoma with lack of retinoblastoma protein expression"},{"pmid":"42141904","doi":"10.1210/clinem/dgag195","year":2026,"isNew":true,"title":"The germline landscape of pituitary adenomas: established and emerging predisposition genes"},{"pmid":"41714734","doi":"10.1007/s00256-026-05160-z","year":2026,"isNew":true,"title":"Fat-containing soft-tissue tumors: Imaging findings and pathologic correlation"},{"pmid":"42342947","doi":"10.1007/s10143-026-04375-x","year":2026,"isNew":true,"title":"Surgical strategies and long-term survival for third ventricle chordoid gliomas: a systematic review and clinical algorithm"},{"pmid":"42252277","doi":"10.1111/jne.70211","year":2026,"isNew":true,"title":"Neuroendocrine tumours through an epigenetic lens: Emerging insights for diagnosis and treatment"}],"trialsShown":[{"nct":"NCT06957691","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Proof-of-Concept Trial to Assess the Efficacy and Safety of Fezolinetant in Improving Vasomotor Symptoms in Men With Prostate Cancer Undergo"},{"nct":"NCT04969926","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Natural History Study of Parathyroid Disorders"},{"nct":"NCT06781983","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Safety and Tolerability of IPH4502 in Patients With Advanced Solid Tumors"},{"nct":"NCT05142189","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Clinical Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced No"},{"nct":"NCT05250284","phase":"n/a","status":"RECRUITING","isNew":false,"title":"The Intersection of Oncology Care and Worker Well-Being"},{"nct":"NCT06834204","phase":"NA","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Advancing Care Coordination Between Cancer and Primary Care Teams for Complex Cancer Survivors"},{"nct":"NCT03655223","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Early Check: Expanded Screening in Newborns"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":9747,"output":6249},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(MEN1 OR menin) AND (CDK4/6 OR palbociclib OR ribociclib OR CDKN1B OR p27 OR p18) AND SRC:MED AND PUB_YEAR:[2015 TO 2026]","(\"menin\" OR MEN1) AND (\"synthetic lethal\" OR EZH2 OR PRMT5 OR \"replication stress\" OR ATR OR HDAC) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"evidenceIds":["PMID:40181550","PMID:39601374","PMID:41537447","PMID:41051795","PMID:42550593","PMID:42245474","PMID:42141904","PMID:41714734","PMID:42342947","PMID:42252277","NCT06957691","NCT04969926","NCT06781983","NCT05142189","NCT05250284","NCT06834204","NCT03655223","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787171839452","cycle":112,"visit":2,"ts":"2026-08-19T20:37:19.452Z","cancer":{"key":"hereditary diffuse gastric cancer","name":"hereditary diffuse gastric cancer","mondo":{"id":"MONDO:0007648","name":"hereditary diffuse gastric adenocarcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Run DepMine-style CDH1/CTNNA1 cancer-profile queries against public CRISPR dependency data before any wet-lab synthetic-lethal screen, and prioritise CLDN18.2 and integrin αvβ6 (not HER2-low) as the surface targets worth quantifying in poorly cohesive/signet-ring HDGC tumours.","confidence":0.42,"notebook":"This visit's pack was largely off-target: the CDH1/synthetic-lethal/spindle query returned no gastric CDH1- or CTNNA1-isogenic dependency data at all. That absence matters. L1 is therefore **weakened** (0.35→0.30): after two evidence-bearing visits there is still no published druggable dependency downstream of adherens-junction loss, and the ROS1/PI3K claims remain [KNOWN]-only. The one tractable gain is methodological — DepMine (PMID:42203685; DOI:10.5281/zenodo.19570601) allows CDH1-mutant/CTNNA1-mutant \"cancer profiles\" to be queried against existing CRISPR dependency data and refined to biomarker definitions, so Q1 can be answered in silico before any wet screen. I also note PMID:42190666 as a modelling template: appendiceal organoid orthotopic intraperitoneal xenografts recapitulate diffuse peritoneal carcinomatosis and reveal dedifferentiation to intestinal-stem/fetal-progenitor states — the same axis PMID:41517846 implicates via progenitor displacement in E-cadherin loss [SPECULATIVE]; this is the right assay format for DGC peritoneal tropism, and RMC-7977/WNTinib are noted as appendiceal-specific, not HDGC leads.\n\nL3 is **strengthened** by independent SRCC evidence: PMID:41250973 confirms a stromal-rich, immunosuppressive GSRCC microenvironment (dysfunctional infiltrate, CAF activation, ECM remodelling, complement dysregulation) and explicitly attributes checkpoint-inhibitor resistance to it, converging with PMID:41902313's TLS/CXCL13 deficit from a different dataset. It adds a second axis: physical stromal/ECM exclusion of drug (PMID:42125068), so any TLS-induction arm should be co-designed with ECM/CAF modulation and complement-pathway readouts. Two independent visits, three citations → CANDIDATE.\n\nL4 is narrowed rather than confirmed. PMID:42512297 states that actionable targets are absent, heterogeneous, or lost precisely in high-grade diffuse/poorly cohesive/signet-ring carcinomas — direct evidence against my HER2-low ADC sub-arm, which I retire. Conversely PMID:41250973 names CLDN18.2 among the key GSRCC biomarkers, so the CLDN18.2 arm survives on new, SRCC-specific ground.\n\nNew lead L5: integrin αvβ6 radiotheranostics. αvβ6 is epithelial-specific, minimally expressed in normal adult tissue and TGF-β-inducible during invasion (PMID:42512297) — a genuine therapeutic window, and mechanistically attractive as a candidate compensatory adhesion receptor in E-cadherin/αE-catenin-null epithelium [SPECULATIVE]. The abstract is truncated: no prevalence figures for the 53 cases and no poorly-cohesive breakdown are visible, so Q3 remains open.\n\nParked: MAP3K6 — two visits, zero supporting evidence; the KG anchor is now formally treated as unsupported for both predisposition and maintenance. cfDNA (NCT06726642) still unaddressed; no pT1a sensitivity data.","leadChanges":[{"id":"L1","title":"Spindle-orientation dependency as synthetic lethal partner of adherens-junction loss in CDH1/CTNNA1-null gastric epithelium","level":"LEAD","status":"WEAKENED","confidence":0.3},{"id":"L3","title":"TLS-induction / Treg-depletion combination required for any immunotherapy in diffuse and signet-ring gastric cancer","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.5},{"id":"L4","title":"Surface-antigen payload delivery (HER2-low ADC, CLDN18.2) as genotype-agnostic systemic option in diffuse gastric cancer","level":"LEAD","status":"STRENGTHENED","confidence":0.35},{"id":"L5","title":"Integrin alphavbeta6 as a histopathology-selectable radiotheranostic target in poorly cohesive/signet-ring and HDGC-derived gastric cancer","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":1,"openQuestions":["Does a DepMine-style query of CDH1-mutant and CTNNA1-mutant/low cancer profiles against public CRISPR dependency data return any convergent, druggable dependency (mitotic, cytoskeletal or other), and if not should L1 be retired?","What fraction of poorly cohesive/signet-ring gastric adenocarcinomas in PMID:42512297 were integrin alphavbeta6-positive, and is alphavbeta6 induced by CDH1 or CTNNA1 loss in isogenic gastric epithelium?","What is the measured CLDN18.2 (and GRIN2D, AGR2, MSMB) prevalence specifically in HDGC-derived and pT1a SRCC lesions, and does adherens-junction loss change CLDN18.2 surface density or antibody internalisation?","Which agent class can measurably mature tertiary lymphoid structures or restore CXCL13 in a stromal-rich, complement-dysregulated signet-ring gastric model, and does CAF/ECM modulation improve delivery of that agent?","Can cfDNA or methylation assays (NCT06726642) detect intramucosal pT1a SRCC in CDH1/CTNNA1 carriers, or is this lead to be pre-emptively retired on burden grounds?","Do CTNNA1-null DGCs reproduce the spindle misorientation/progenitor displacement phenotype of E-cadherin loss, or is it CDH1-specific?"],"nextQueries":["(\"integrin alphavbeta6\" OR ITGB6) AND (gastric OR \"signet ring\" OR \"poorly cohesive\" OR \"diffuse gastric\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(CDH1 OR CTNNA1) AND (DepMap OR \"gene dependency\" OR \"CRISPR screen\" OR \"synthetic lethal\") AND (gastric OR \"lobular breast\" OR organoid) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(CLDN18.2 OR zolbetuximab OR \"claudin 18.2 CAR\") AND (\"signet ring\" OR \"poorly cohesive\" OR \"diffuse type\") AND (prevalence OR expression OR response) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42190666","doi":"10.1016/j.devcel.2026.04.014","year":2026,"isNew":true,"title":"An appendiceal cancer organoid biobank identifies phenotypic evolution and druggable dependencies of peritoneal carcinomatosis"},{"pmid":"42100092","doi":"10.1016/j.xinn.2026.101300","year":2026,"isNew":true,"title":"Neuro-immune interactions in gastrointestinal oncology: Mechanisms, challenges, and therapeutic potential"},{"pmid":"41250973","doi":"10.1111/cts.70424","year":2025,"isNew":true,"title":"Gastric Signet Ring Cell Carcinoma: Tumor Microenvironment Reprogramming and Novel Therapeutic Targets With Emphasis on GRIN2D"},{"pmid":"42183023","doi":"10.1016/j.ncrna.2026.01.007","year":2026,"isNew":true,"title":"Functional role of long non-coding RNA MALAT1 and HOTAIR in lung cancer"},{"pmid":"42203685","doi":"10.1093/bioinformatics/btag337","year":2026,"isNew":true,"title":"Using cancer profiles to identify synthetic lethal therapeutic targets and predictive biomarkers in cancer gene dependency data"},{"pmid":"42346204","doi":"10.3390/curroncol33060304","year":2026,"isNew":true,"title":"Molecular Tumor Board-Directed Treatment for Patients with Advanced-Stage Solid Tumors: A Case-Control Real-World Study"},{"pmid":"42125068","doi":"10.1002/mco2.70763","year":2026,"isNew":true,"title":"Targeting Tumor Stroma: Current Challenges and Future Directions"},{"pmid":"42122259","doi":"10.3390/cancers18091463","year":2026,"isNew":true,"title":"The HGF/MET Axis in Advanced Prostate Cancer: From Context-Dependent Biology to Biomarker-Driven Therapeutic Strategies"},{"pmid":"42082461","doi":"10.1038/s41392-026-02705-5","year":2026,"isNew":true,"title":"Pancreatic ductal adenocarcinoma: integrating molecular insights for targeted interventions"},{"pmid":"42512297","doi":"10.3390/cancers18142231","year":2026,"isNew":true,"title":"Immunohistochemical Evaluation of Integrin αvβ6 Expression in Gastric and Gastroesophageal Junction Adenocarcinoma as a Histopathology-Driven Biomarker for Integrin αvβ6-Targeted R"}],"trialsShown":[{"nct":"NCT05126290","phase":"n/a","status":"RECRUITING","isNew":false,"title":"CTNNA1 Familial Expansion Study"},{"nct":"NCT06726642","phase":"n/a","status":"RECRUITING","isNew":false,"title":"CfDNA in Hereditary And High-risk Malignancies 2"}],"usage":{"input":9992,"output":7120},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(CDH1 OR \"E-cadherin\") AND (\"synthetic lethal\" OR ROS1 OR crizotinib OR entrectinib OR \"spindle orientation\") AND gastric AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(CLDN18.2 OR \"claudin 18.2\" OR \"HER2-low\") AND (\"diffuse gastric\" OR \"signet ring\" OR \"poorly cohesive\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:42190666","PMID:42100092","PMID:41250973","PMID:42183023","PMID:42203685","PMID:42346204","PMID:42125068","PMID:42122259","PMID:42082461","PMID:42512297","NCT05126290","NCT06726642"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787171629288","cycle":111,"visit":2,"ts":"2026-08-19T20:33:49.288Z","cancer":{"key":"hereditary breast and ovarian cancer syndrome","name":"hereditary breast and ovarian cancer syndrome","mondo":{"id":"MONDO:0003582","name":"hereditary breast ovarian cancer syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Gate PARP inhibitors in non-BRCA HBOC genes on demonstrated biallelic inactivation plus a functional HR readout (RAD51 foci), not on germline panel label: niraparib benefit in the ATM/CHEK2/PALB2/BRCA pancreatic trial fell entirely to biallelic cases, and PALB2 is the only non-BRCA gene with consist","confidence":0.62,"notebook":"The pack's decisive item is P3 (PMID:41686836, NCT03601923): niraparib in advanced pancreatic cancer selected by germline/somatic PV in BRCA1/2, PALB2, ATM or CHEK2 met its 6-month PFS bar (25%, 90% CI 13–41%) but with median PFS of only 2 months and ORR 14% — i.e. the panel-label population is largely non-responsive, and all six patients with ≥6-month PFS and evaluable zygosity carried **biallelic** DNA-repair inactivation. That is direct clinical support for L1's central claim: monoallelic carrier status is not the actionable unit; biallelic loss with demonstrable HR failure is. ATM was the largest cohort (n=14) yet the aggregate PFS is short, consistent mechanistically with ATM/CHEK2 acting in checkpoint signalling rather than strand invasion [KNOWN]; the abstract gives no per-gene response breakdown, so ATM-specific failure remains inferred, not proven. P10 (PMID:42589411) independently concludes that PALB2 shows the strongest, most consistent PARPi benefit across ovarian/breast/prostate/pancreas while other non-BRCA HR genes are heterogeneous — converging with the filament-loading vs checkpoint split. L1 therefore moves to CANDIDATE (new, independent evidence this visit; 0.72).\n\nP7 (PMID:41520277) supplies both an assay and a negative: RAD51 immunofluorescence was used for HRD classification in patient-ascites-derived HGSC lines/organoids, but *concurrent* carboplatin+olaparib/niraparib produced no viability gain over carboplatin alone, with sequence-dependence in sequential arms. Recorded so the desk does not re-propose simultaneous platinum–PARPi as a novel schedule; the open scheduling question is induction-then-maintenance ordering. New lead L6 for schedule/gap biology, anchored also on P2 (PMID:39927794), whose replicative-ssDNA-gap model reframes sensitivity as gap load rather than HR status per se — predicting that gap-inducing partners (POLQ, USP1, ATR/WEE1) and PARP-trapping capacity, not HRD scars, should be the functional readout [INFERRED].\n\nResistance reviews P1/P4/P5 partition acquired resistance into HR restoration/reversion, reduced PARP trapping (PARP1 mutation, PARG loss), efflux, and fork protection, with >40% of BRCA1/2-altered patients resisting (P4). No primary ctDNA lead-time data in this pack, so my Q3 stays open; I open L5 as an explicitly instrumented surveillance lead rather than a therapeutic claim.\n\nL4 (founder-allele cohorts) hit its pre-registered kill criterion — no functional or pharmacodynamic data attached this visit — and is retired. L2 and L3 received no new evidence and stand unchanged at low confidence.","leadChanges":[{"id":"L1","title":"Functional-HRD gating, not gene label, for PARPi in non-BRCA1/2 HBOC genes","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.72},{"id":"L5","title":"Longitudinal ctDNA resistance-mechanism triage on PARPi: reversion vs trapping loss vs efflux vs fork protection","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L6","title":"Replicative-gap load, not HRD scar, as the functional PARPi biomarker - and sequence-dependence of platinum/PARPi","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L4","title":"Founder-allele cohorts as ready-made, genotype-uniform interception and pharmacodynamic populations","level":"LEAD","status":"RETIRED","confidence":0.1}],"unverifiedCitations":1,"openQuestions":["What are the per-gene, zygosity-stratified PARPi response rates for PALB2, RAD51C, RAD51D, BARD1, ATM and CHEK2 in ovarian and breast cancer - does the biallelic-only benefit seen in NCT03601923 pancreatic data replicate?","Is there any prospective clinical evidence that ATM- or CHEK2-mutant HBOC tumours respond to ATR (ceralasertib/camonsertib) or WEE1 inhibition after failing or bypassing PARPi?","What is the concordance of RAD51-foci immunofluorescence with resolved biallelic status and with genomic HRD scar in non-BRCA HBOC genes, and has any lab reported analytical validation for treatment gating?","In serial ctDNA, how much lead time do reversion alleles, PARP1/PARG alterations or ABCB1 upregulation give over radiographic progression, and is mechanism-matched switching feasible?","Do POLQ/Pol-theta, USP1 or ATR inhibitor combinations with PARPi have 2023-2026 clinical readouts in HRD or PARPi-resistant disease, and does gap load predict response better than HRD scar?","Do the circulating BRCAness classifiers (plasma metabolome, serum miRNA) survive strict independent-cohort validation (L2 still unaddressed)?"],"nextQueries":["(PALB2 OR RAD51C OR RAD51D OR BARD1 OR ATM OR CHEK2) AND (biallelic OR zygosity OR \"loss of heterozygosity\") AND (\"PARP inhibitor\" OR olaparib OR niraparib OR talazoparib OR rucaparib) AND (\"response rate\" OR \"progressio","(\"ATR inhibitor\" OR ceralasertib OR camonsertib OR \"WEE1 inhibitor\" OR adavosertib OR \"POLQ\" OR \"polymerase theta\" OR \"USP1 inhibitor\") AND (ATM OR CHEK2 OR BRCA1 OR BRCA2) AND (\"clinical trial\" OR \"phase I\" OR \"phase II","(\"circulating tumor DNA\" OR ctDNA) AND (\"reversion mutation\" OR \"reversion allele\") AND (BRCA1 OR BRCA2 OR PALB2 OR RAD51C) AND (\"PARP inhibitor\" OR platinum) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"40442774","doi":"10.1186/s12943-025-02355-1","year":2025,"isNew":true,"title":"Clinical approaches to overcome PARP inhibitor resistance"},{"pmid":"39927794","doi":"10.1042/bst20241633","year":2025,"isNew":true,"title":"'Where is my gap': mechanisms underpinning PARP inhibitor sensitivity in cancer"},{"pmid":"41686836","doi":"10.1158/1078-0432.ccr-24-3766","year":2026,"isNew":true,"title":"A Phase II Trial of Niraparib in Patients with Advanced Pancreatic Cancer Harboring Pathogenic Variants in ATM, BRCA1, BRCA2, PALB2, and CHEK2"},{"pmid":"41900841","doi":"10.3390/pharmaceutics18030355","year":2026,"isNew":true,"title":"Interplay Between Poly(ADP-ribosyl)ation and Specific Inner Cellular Events That Suggest Combination Strategies for Overcoming PARP Inhibitor Resistance"},{"pmid":"41772736","doi":"10.1186/s40364-026-00908-0","year":2026,"isNew":true,"title":"Clinical application of PARP inhibitors and emerging strategies to overcome resistance: a pan-cancer perspective"},{"pmid":"41879036","doi":"10.1080/15384047.2026.2644667","year":2026,"isNew":true,"title":"Molecular mechanisms and therapeutic strategies: DNA methylation in pancreatic cancer"},{"pmid":"41520277","doi":"10.1080/15384047.2025.2611602","year":2026,"isNew":true,"title":"Evaluating carboplatin and PARP inhibitor combination efficacy using high-grade serous carcinoma spheroids and organoids"},{"pmid":"41395847","doi":"10.1080/14756366.2025.2598478","year":2026,"isNew":true,"title":"Antitumor activity and structure-activity relationship of poly (ADP-ribose) polymerase (PARP)-based dual inhibitors"},{"pmid":"42133170","doi":"10.1007/s12010-026-05720-y","year":2026,"isNew":true,"title":"Decoding the Genetic Hallmarks of Breast Cancer: Molecular Signatures, Prognostic and Therapeutic Perspectives"},{"pmid":"42589411","doi":"10.3390/ijms27156754","year":2026,"isNew":true,"title":"PARP Inhibitor Sensitivity in Tumors Harboring Non-BRCA Homologous Recombination Gene Alterations: Current Evidence Across Ovarian, Breast, Prostate, and Pancreatic Cancers"}],"trialsShown":[{"nct":"NCT02302742","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry"},{"nct":"NCT03246841","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes."},{"nct":"NCT02760849","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations"},{"nct":"NCT04494945","phase":"NA","status":"RECRUITING","isNew":false,"title":"Identifying and Caring for Individuals With Inherited Cancer Syndrome"},{"nct":"NCT06914726","phase":"NA","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Patient Centered Clinical Decision Support for Hereditary Cancer Syndromes"},{"nct":"NCT02012699","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Integrated Cancer Repository for Cancer Research"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT04009148","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Cascade Testing in Families With Newly Diagnosed Hereditary Breast and Ovarian Cancer Syndrome"}],"usage":{"input":11087,"output":6566},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(PALB2 OR RAD51C OR RAD51D OR BARD1) AND (\"PARP inhibitor\" OR olaparib OR niraparib OR talazoparib) AND (response OR sensitivity OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"BRCA1\" OR \"BRCA2\") AND (\"reversion mutation\" OR \"53BP1\" OR shieldin OR \"restored homologous recombination\") AND (\"PARP inhibitor resistance\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:40442774","PMID:39927794","PMID:41686836","PMID:41900841","PMID:41772736","PMID:41879036","PMID:41520277","PMID:41395847","PMID:42133170","PMID:42589411","NCT02302742","NCT03246841","NCT02760849","NCT04494945","NCT06914726","NCT02012699","NCT03050268","NCT04009148"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787171423198","cycle":110,"visit":2,"ts":"2026-08-19T20:30:23.198Z","cancer":{"key":"familial adenomatous polyposis","name":"familial adenomatous polyposis","mondo":{"id":"MONDO:0021055","name":"classic familial adenomatous polyposis"}},"control":false,"modelLabel":"SCIENCE","summary":"FAP-associated desmoid now has a pack-supported drug hierarchy (nirogacestat > sorafenib > methotrexate/vinblastine), promoting the desmoid lead to CANDIDATE and generating two new mechanistic hypotheses: nirogacestat's Notch blockade as a possible adenoma-differentiation agent, and TTI1/TTT-complex","confidence":0.5,"notebook":"Fresh pack answered open question 4 decisively and opened two mechanistically new fronts; it added nothing on eRapa, FOG-001, REC-4881 or ONC201 despite a targeted mTOR/MEK query, so L1/L3/L4 stand unchanged with no new data.\n\nDesmoid pharmacology now exists in-pack. Nirogacestat has phase I ORR 71.4% in desmoid, pivotal DeFi phase III showing 71% reduction in progression risk with PFS/ORR benefit, FDA (Nov 2023) and EC (Aug 2025) approval for progressing desmoid requiring systemic therapy (PMID:40888418); a review of systemic classes places NSAIDs, anthracycline-based chemotherapy, sorafenib and γ-secretase inhibitors in an algorithm explicitly encompassing germline APC/FAP-associated disease (PMID:42192882); and a 24-year-old post-colectomy FAP patient with a 17 cm obstructive abdominopelvic desmoid responded substantially to vinblastine/methotrexate (PMID:42211606), with a further case reiterating nirogacestat's role (PMID:42326221). L5 therefore stops being an unmet-need placeholder: it becomes drug-nominated and moves to CANDIDATE. The programme-level argument is now testable — does early systemic desmoid therapy in FAP reduce the rate of mesenteric obstruction/intestinal transplantation (PMID:42324901, PMID:42577576)? [INFERRED] Case reports are the weakest tier and neither is FAP-randomised; DeFi was not FAP-restricted.\n\nSecond: γ-secretase inhibition in FAP may not be desmoid-only. Notch blockade in intestinal epithelium drives secretory/goblet conversion of proliferative crypt cells [KNOWN], and Notch–Wnt crosstalk is the stated rationale for repurposing nirogacestat in Wnt-driven neoplasia (PMID:40888418, PMID:42192882) — so an approved drug already given to FAP desmoid patients might be assessable for polyp-burden effect as a secondary endpoint. New L6, speculative, cheap to test.\n\nThird: PMID:42283915 identifies TTI1 as a direct β-catenin/TCF target that stabilises ATM/ATR via the TTT complex; depletion or piperlongumine sensitises Apc-mutant patient-derived organoids and Apc-mutant models to 5-FU/oxaliplatin. This is the synthetic-lethality reframe the desk wants for an undruggable tumour suppressor: hit a Wnt-output effector rather than the pathway, sparing crypt/bone Wnt dependence. New L7. It also argues, by the authors' own framing, that global Wnt blockade carries avoidable toxicity — combined with a second visit yielding zero FOG-001 human PD/safety data, L2 weakens to 0.40.\n\nUnresolved: microbiome evidence remains CRC-generic (Peptostreptococcus oral–gut axis PMID:42186437; microbiota–stem cell axis PMID:41427927) with nothing APC-germline-specific and no decolonisation data; NSAID review PMID:42357259 gives no FAP combination endpoints; sulforaphane synergy (PMID:42201192) is cell-line-level and not FAP-anchored — none support a lead yet.","leadChanges":[{"id":"L5","title":"FAP-associated intra-abdominal desmoid: pharmacological control to displace multivisceral/intestinal transplantation","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.6},{"id":"L6","title":"Nirogacestat repurposed for duodenal/colorectal adenoma burden in FAP via Notch-blockade-induced secretory differentiation","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L7","title":"TTI1/TTT-complex suppression as Wnt-output synthetic lethality in APC-mutant neoplasia (chemo/ATR sensitisation without global Wnt blockade)","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L2","title":"Direct beta-catenin:TCF interface blockade (FOG-001) as node-matched therapy for APC-null neoplasia","level":"LEAD","status":"WEAKENED","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["In FAP-associated intra-abdominal desmoid, does first-line nirogacestat versus observation/anthracycline change obstruction-free survival and intestinal transplant listing rates, and what is the ovarian/GI toxicity burden in this young post","Does gamma-secretase inhibition alter duodenal or pouch adenoma burden in FAP patients treated for desmoid, and does crypt immunohistochemistry show secretory differentiation (MUC2/CHGA up, HES1/OLFM4 down)?","Is TTI1/TTT-complex dependence selective for APC-null adenoma organoids over matched normal FAP crypt organoids, and can a clinical-grade ATR inhibitor substitute for piperlongumine?","Does the eRapa duodenal signal replicate in NCT06950385, and is daily-dose inferiority explained by feedback pAKT(S473)/pS6 reactivation in paired crypt biopsies?","For REC-4881 in FAP, is pERK suppression epithelial (adenoma crypt) or stromal/immune, and are there any interim polyp-burden data?","Is there any APC-germline-specific (not CRC-generic) evidence that pks+ E. coli, ETBF, F. nucleatum or Peptostreptococcus accelerates adenoma progression, and has decolonisation or a defined dietary intervention been tested with polyp endpo"],"nextQueries":["(\"desmoid\" AND (\"familial adenomatous polyposis\" OR \"germline APC\")) AND (nirogacestat OR \"gamma-secretase\" OR outcomes OR obstruction OR transplantation) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"Apc(Min)\" OR \"APC-mutant\" OR \"familial adenomatous polyposis\") AND (\"gamma-secretase\" OR Notch OR HES1 OR \"goblet cell\" OR differentiation) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"familial adenomatous polyposis\" OR \"Apc(Min)\" OR \"APC-mutant organoid\") AND (microbiome OR colibactin OR \"pks+\" OR \"Fusobacterium\" OR \"Bacteroides fragilis\" OR ATR OR \"TTT complex\") AND SRC:MED AND PUB_YEAR:[2021 TO 20"],"papersShown":[{"pmid":"42201192","doi":"10.3390/medicines13020016","year":2026,"isNew":true,"title":"Sulforaphane Synergies with Phytochemicals and Pharmaceuticals: Implications for Healthspan"},{"pmid":"42186437","doi":"10.1080/21505594.2026.2673632","year":2026,"isNew":true,"title":"The \"oral-gut axis\" transmission of microorganisms in colorectal cancer: Insights from &lt;i&gt;Peptostreptococcus'&lt;/i&gt; perspective"},{"pmid":"41427927","doi":"10.1080/19490976.2025.2606477","year":2026,"isNew":true,"title":"Impact of gut microbiota on host stem cells across the gastrointestinal tract"},{"pmid":"42283915","doi":"10.1186/s43556-026-00475-8","year":2026,"isNew":true,"title":"TELO2-interacting protein 1 (TTI1), a novel Wnt/β-catenin target gene, decreases chemo-sensitivity in colorectal cancer by modulating DNA damage responses"},{"pmid":"42102822","doi":"10.1016/j.stemcr.2026.102898","year":2026,"isNew":true,"title":"Human organoids: Fit for drug discovery?"},{"pmid":"42357259","doi":"10.3390/pharmaceutics18060643","year":2026,"isNew":true,"title":"The Effect of Anti-Inflammatory Drugs on the Incidence of Colorectal Cancer"},{"pmid":"42192882","doi":"10.3390/cancers18101521","year":2026,"isNew":true,"title":"Systemic Therapies for Desmoid Tumors: A Review of Past, Present, and Future Treatments"},{"pmid":"42326221","doi":"10.7759/cureus.109286","year":2026,"isNew":true,"title":"Extra-abdominal Desmoid Tumor in a 23-Year-Old Male: A Case Report"},{"pmid":"42211606","doi":"10.7759/cureus.107811","year":2026,"isNew":true,"title":"Huge Abdominal Desmoid Tumor Successfully Managed by Chemotherapy in a Young Patient With Familial Adenomatous Polyposis: A Case Report"},{"pmid":"40888418","doi":"10.1080/14796694.2025.2550826","year":2025,"isNew":true,"title":"Repurposing nirogacestat, a gamma secretase enzyme inhibitor in desmoid tumors"}],"trialsShown":[{"nct":"NCT05919264","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"FOG-001 in Locally Advanced or Metastatic Solid Tumors"},{"nct":"NCT07726771","phase":"NA","status":"RECRUITING","isNew":false,"title":"Evaluation of the Ileo-anal Pouch in FAP (ENDOPOL)"},{"nct":"NCT02012699","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Integrated Cancer Repository for Cancer Research"},{"nct":"NCT07066046","phase":"NA","status":"RECRUITING","isNew":false,"title":"Artificial Intelligence-assisted Colonoscopy in the Detection and Characterization of Colorectal Lesions"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT05630794","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Testing for Safety and Colorectal Cancer Preventive Effects of ONC201"},{"nct":"NCT05552755","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Evaluate REC-4881 in Participants With Familial Adenomatous Polyposis (FAP)"},{"nct":"NCT06950385","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Phase 3 Trial of eRapa in Patients With Familial Adenomatous Polyposis"}],"usage":{"input":10300,"output":6061},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"familial adenomatous polyposis\" OR \"Apc(Min)\") AND (rapamycin OR sirolimus OR mTOR OR \"MEK inhibitor\" OR REC-4881) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"desmoid\" AND (\"familial adenomatous polyposis\" OR FAP)) AND (nirogacestat OR \"gamma-secretase\" OR sorafenib OR \"systemic therapy\") AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"evidenceIds":["PMID:42201192","PMID:42186437","PMID:41427927","PMID:42283915","PMID:42102822","PMID:42357259","PMID:42192882","PMID:42326221","PMID:42211606","PMID:40888418","NCT05919264","NCT07726771","NCT02012699","NCT07066046","NCT03050268","NCT05630794","NCT05552755","NCT06950385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787171220129","cycle":109,"visit":2,"ts":"2026-08-19T20:27:00.129Z","cancer":{"key":"lynch syndrome","name":"Lynch syndrome","mondo":{"id":"MONDO:0005835","name":"Lynch syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Neoadjuvant ICI organ preservation in dMMR colorectal cancer is now corroborated by four independent 2025-26 syntheses (dual PD-1/CTLA-4 for colon, PD-1 alone for rectal, with protocolised pseudoresidue adjudication), and Nous-209 frameshift-peptide vaccination gains a mechanistic prevention window ","confidence":0.66,"notebook":"**Visit 2 notebook.** The pack is dominated by neoadjuvant/organ-preservation literature and by one high-value primary paper on prevention; nothing new on aspirin, so L1 stands unchanged with its verification debt (OQ1) intact.\n\nL2 moves up. Four independent 2025–2026 syntheses now converge: a PRISMA systematic review of eight prospective phase 2 trials (n=352, stage II–III) reports pCR 41–90%, highest with dual PD-1+CTLA-4 blockade in colon (nivolumab+ipilimumab 90% pCR, 95% MPR) and 100% cCR with dostarlimab in rectal disease (PMID:41343101); a dedicated review of the surgical dilemma reports equivalent oncological outcomes and 100% DFS at 2–3 years in complete responders, but flags pseudoprogression and \"pseudoresidue\" as concrete failure modes of conventional imaging-based response assessment (PMID:41097680); and two overviews confirm ICI now permits omission of chemoradiation and surgery in most locally advanced dMMR rectal cancer, and that ICI added to adjuvant chemotherapy substantially improves DFS in node-positive dMMR colon cancer (PMID:41710674, PMID:41196394). Mechanistically this is the frameshift-neoantigen argument holding at the pre-metastatic stage. Caveats I record rather than bury: these are reviews, not new primary data; no Lynch-versus-sporadic (MLH1-hypermethylated) subgroup is reported anywhere; follow-up is 2–3 years, short against Lynch's metachronous-cancer clock; and PMID:41710674 explicitly states a subset derives limited or no benefit. Promoted to CANDIDATE at 0.74. Practical refinement: dual blockade for colon, single-agent PD-1 for rectal, with response adjudication protocolised against pseudoresidue.\n\nL3 gains its first real biology. In 62 precancerous lesions from 26 MLH1/MSH2 carriers, Nous-209-targeted frameshift mutations track MSI acquisition, not MMR loss: 15–57 mutations in dMMR/MSI-H lesions, 6–19 in dMMR/MSI-low, 0–2 in MSS lesions; 58% of adenomas and 83% of advanced adenomas were dMMR but only 66% of dMMR adenomas were MSI-H (PMID:42108525). So the antigenic window opens mid-sequence — a shared off-the-shelf FSP vaccine can plausibly intercept the adenoma→carcinoma transition but will be blind to early dMMR/MSI-low crypts, which is exactly the compartment aspirin might cover [INFERRED]; that asymmetry is now a testable combination rationale rather than hand-waving. Promoted to CANDIDATE at 0.5. Still no human immunogenicity or adenoma-incidence endpoint data (PMID:42213481, PMID:41912995 give only platform-level context).\n\nNew L5, deliberately low confidence: salvage for primary/acquired ICI-refractory dMMR disease (MHC-I-null B2M/JAK1 escape), where neither PD-1 nor FSP vaccines can work by definition — oncolytic and NK-directed platforms are the MHC-I-independent options (NCT02978625, PMID:42082461, PMID:41740058).\n\nL4 unchanged; no corroborating literature appeared.","leadChanges":[{"id":"L2","title":"Genotype-agnostic neoadjuvant / immuno-ablative PD-1 blockade as an organ-sparing strategy in Lynch-associated MSI-H tumours","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.74},{"id":"L3","title":"Frameshift-peptide neoantigen vaccination for primary/secondary prevention in MMR carriers","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.5},{"id":"L5","title":"MHC-I-independent salvage for ICI-refractory dMMR/MSI-H disease (B2M/JAK-null escape)","level":"LEAD","status":"NEW","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["CaPP3 per-dose dMMR cancer incidence, non-inferiority margin and GI-bleed rates: is 100 mg non-inferior to 600 mg, and does effect differ by MMR gene or BMI?","Beyond 3 years, what is the local regrowth and metachronous-cancer rate under watch-and-wait specifically in germline Lynch carriers (versus sporadic MLH1-hypermethylated dMMR), and does ctDNA/stool testing detect regrowth before imaging?","What immunogenicity, adenoma-incidence or dMMR-crypt-clearance data exist from Nous-209 or other FSP vaccines in unaffected MMR carriers, and can a vaccine + aspirin factorial cover the MSI-low adenoma gap?","What is the prevalence of B2M, JAK1/2 truncation and HLA LOH in Lynch-associated versus sporadic MSI-H tumours, and does it differ before versus after ICI exposure?","Does dual PD-1/CTLA-4 blockade add pCR over PD-1 alone in dMMR rectal cancer at acceptable irAE cost, or is single-agent already at ceiling?","Is there any primary-literature support (not my inference) that tumour TGFBR2 A10 frameshift status predicts benefit from TGF-beta-pathway-edited effector cells in MSI-H disease?"],"nextQueries":["(\"Lynch syndrome\" OR \"mismatch repair\") AND aspirin AND (CAPP3 OR chemoprevention OR dose) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"MSI-H\" OR dMMR) AND (B2M OR \"beta-2 microglobulin\" OR JAK1 OR \"HLA loss of heterozygosity\") AND (resistance OR escape OR \"checkpoint\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"Nous-209\" OR \"frameshift peptide vaccine\" OR \"shared neoantigen vaccine\") AND (\"Lynch syndrome\" OR carriers OR immunogenicity OR \"phase 1\") AND SRC:MED"],"papersShown":[{"pmid":"41710674","doi":"10.1136/bmjonc-2025-000980","year":2026,"isNew":true,"title":"Deficient mismatch repair/microsatellite instability-high colorectal cancer: current treatment paradigms, limitations and future perspectives"},{"pmid":"41097680","doi":"10.3390/cancers17193153","year":2025,"isNew":true,"title":"Immunotherapy-Induced Complete Response in dMMR Rectal Cancer-A Surgical Dilemma?"},{"pmid":"41740058","doi":"10.1002/advs.202518960","year":2026,"isNew":true,"title":"Combination Immunotherapy as a Promising Strategy to Overcome Immunotherapy Resistance: From Emergence to Next-Generation Approaches"},{"pmid":"41196394","doi":"10.1007/s00262-025-04223-9","year":2025,"isNew":true,"title":"Biology and evolving management of resectable dMMR/MSI-H cancers: current status and future perspectives"},{"pmid":"41343101","doi":"10.1007/s12029-025-01358-x","year":2025,"isNew":true,"title":"Neoadjuvant Immune Checkpoint Inhibition in MSI-H/dMMR Colorectal Cancer: A Systematic Review of Prospective Trials Evaluating Efficacy, Pathologic Response, and Surgical Outcomes"},{"pmid":"42108525","doi":"10.1158/1940-6207.capr-25-0388","year":2026,"isNew":true,"title":"Mutations Targeted by Nous-209 Immunotherapy Occur Early in Lynch Syndrome Carriers' Precancer Lesions with Microsatellite Instability"},{"pmid":"42213481","doi":"10.1093/bjsopen/zrag041","year":2026,"isNew":true,"title":"Cancer vaccines: comprehensive review"},{"pmid":"42082461","doi":"10.1038/s41392-026-02705-5","year":2026,"isNew":true,"title":"Pancreatic ductal adenocarcinoma: integrating molecular insights for targeted interventions"},{"pmid":"41912995","doi":"10.1007/s40291-026-00842-9","year":2026,"isNew":true,"title":"Neoantigen Targeting as a Novel Approach for Therapy-Resistant Tumors"},{"pmid":"42032169","doi":"10.1007/s12672-026-05030-z","year":2026,"isNew":true,"title":"The mechanisms and clinical prospects of combining chemotherapy with immunotherapy for advanced pancreatic cancer"}],"trialsShown":[{"nct":"NCT05410977","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Collecting Blood and Stool Samples to Detect Colorectal Cancer or Advanced Neoplasia in Lynch Syndrome Patients"},{"nct":"NCT03805919","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Men at High Genetic Risk for Prostate Cancer"},{"nct":"NCT02978625","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers"},{"nct":"NCT02912559","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair"},{"nct":"NCT07411599","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Dual Administration Of Intraperitoneal And Intravenous TROP2-Directed CAR-NK With TGF-Beta Receptor 2 (TGFBR2) Knock Out (KO) Therapy For Co"},{"nct":"NCT07106359","phase":"NA","status":"RECRUITING","isNew":false,"title":"Initial Testing of a Behavioral Intervention About Genetic Services for Families at Risk of Lynch Syndrome"},{"nct":"NCT02359565","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas,"},{"nct":"NCT04494945","phase":"NA","status":"RECRUITING","isNew":false,"title":"Identifying and Caring for Individuals With Inherited Cancer Syndrome"}],"usage":{"input":11151,"output":5693},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"Lynch syndrome\" OR \"mismatch repair deficient\") AND (\"frameshift peptide\" OR \"neoantigen vaccine\" OR Nous-209) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"MSI-H\" OR dMMR) AND (\"neoadjuvant\" OR \"organ preservation\" OR \"watch and wait\") AND (pembrolizumab OR dostarlimab OR nivolumab) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41710674","PMID:41097680","PMID:41740058","PMID:41196394","PMID:41343101","PMID:42108525","PMID:42213481","PMID:42082461","PMID:41912995","PMID:42032169","NCT05410977","NCT03805919","NCT02978625","NCT02912559","NCT07411599","NCT07106359","NCT02359565","NCT04494945"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787171023800","cycle":108,"visit":11,"ts":"2026-08-19T20:23:43.800Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Visit 11 returned no CML-specific evidence: retire the ILK niche lead, weaken the frontline dual-site combination (NCT03906292 silent for a tenth visit), the HDAC6/Beclin 1 axis and the MDM2-degrader extension, and redirect next visit to asciminib-failure mutation spectra and primary CD34+CD38- pers","confidence":0.42,"notebook":"Visit 11 is an evidentially empty visit for this disease. Both Europe PMC queries — MDM2/p53-restoration in CML stem cells, and ricolinostat/citarinostat with autophagy/Beclin 1/MCL1 — returned ten items, nine of which are pan-cancer reviews (biomarkers PMID:38763973, HSPs PMID:39232809, PCD pathways PMID:40377777, KDMs PMID:40940894, methylation PMID:41673722, BMX PMID:42212521, c-Myc PMID:42059277, AML therapy PMID:41995989, cardio-oncology sex differences PMID:42279262) with no CML-specific experimental content. The single primary paper, PMID:40256307, is a new tetrahydro-β-carboline HDAC6 inhibitor (9c, IC50 7 nM) validated by selective α-tubulin acetylation, apoptosis with Bcl-2 downregulation and reduced non-tumour cytotoxicity — but in triple-negative breast cancer, with only a pooled NCI-60 GI50; no CML line is reported separately and no autophagy/Beclin 1 readout appears. It confirms only that selective HDAC6 chemistry is now abundant while the CML-relevant experiment (clinical-grade HDAC6i + asciminib on primary CD34+CD38− LSCs versus same-donor HSPCs) remains undone. L11 is therefore weakened for silence, not contradicted.\n\nCalibration note for this control cadence: nothing in this pack touches BCR::ABL1 [SOMATIC], and the programme's centre of mass remains exactly the solved mechanism — allosteric plus ATP-site inhibition of the fusion kinase (L8 DOSSIER), with the live questions being exposure (L9), de-escalation (L7) and non-mutational persistence (L6/L13). That is the correct convergence; this visit adds nothing to it.\n\nTrials repeat prior states. NCT03906292 (frontline asciminib combination) is ACTIVE_NOT_RECRUITING without readout for a tenth consecutive visit — L1 weakened again, and the desk should now treat \"await NCT03906292\" as a dead branch rather than a plan. NCT02689440 likewise still silent, which reinforces the two retired venetoclax leads; do not revive. The other trials are Ph+ ALL (NCT03147612), CMML/MDS (NCT03147612 aside: NCT06566742, NCT05600894, NCT07033598), neoantigen TCR (NCT06904066) and mismatched-donor transplant (NCT06001385) — none CML-chronic-phase relevant.\n\nL12 (ILK) reaches its prespecified retirement condition: two consecutive visits with zero CML-specific ILK expression, regulon or same-donor sparing data, against a review-level negative on niche-directed strategies in CML. Retired. L14 (MDM2 degrader) is weakened: the query designed to find CML MDM2/p53 data found none, so the 105-sample window remains AML-only.\n\nI am also retiring open question 1 as unanswerable by literature search (three null queries on BH3 profiling in asciminib/ponatinib-resistant LSCs); it becomes a bench specification inside L11 rather than a search target. Next visit must pull asciminib-failure mutation spectra and any primary CML-LSC epigenetic/STAT5 replication.","leadChanges":[{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"WEAKENED","confidence":0.35},{"id":"L11","title":"HDAC6-selective inhibition plus asciminib: autophagy blockade to maladaptive ISR, MCL-1 loss and BCL-xL-dependent apoptosis in CML","level":"CANDIDATE","status":"WEAKENED","confidence":0.4},{"id":"L14","title":"MDM2 degradation (PROTAC) to restore wild-type p53 in TP53-intact CML LSCs alongside BCR-ABL1 blockade","level":"LEAD","status":"WEAKENED","confidence":0.2},{"id":"L12","title":"ILK as a microenvironment-coupled, kinase-independent resistance node in CML LSCs","level":"LEAD","status":"RETIRED","confidence":0.05}],"unverifiedCitations":0,"openQuestions":["What is the published spectrum and frequency of kinase-domain mutations at asciminib failure beyond A337V/P465S, and which ATP-site agent (ponatinib, olverembatinib, dasatinib) rescues each?","Can a DMR-specific asciminib Cmin floor be derived from ASC4FIRST/ASC4OPT PK once adherence/relative dose intensity is deconfounded from true exposure, and does Cmax_2h outperform trough?","Is TRIM28/SETDB1 or STAT5A regulon activity demonstrably enriched in primary CD34+CD38- TKI-persistent chronic-phase cells in published single-cell atlases, and is any same-donor normal-HSPC window shown?","Does the Morphoclinical cytomorphology model (or any image-derived marker) predict TFR success and safe de-escalation, not just MMR attainment?","Has NCT03906292 or any registry reported concurrent asciminib + ATP-site TKI exposure with molecular depth, cytopenia and arterial-event data?","In forced-discontinuation cohorts (pregnancy), does relapse timing track host immune markers rather than pre-cessation transcript burden?"],"nextQueries":["(\"chronic myeloid leukemia\") AND (asciminib) AND (resistance OR mutation OR \"kinase domain\" OR A337V OR P465S) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"chronic myeloid leukemia\") AND (\"leukemic stem cell\" OR \"CD34+CD38-\" OR \"long-term culture-initiating\") AND (STAT5 OR TRIM28 OR SETDB1 OR \"single-cell\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"chronic myeloid leukemia\") AND (\"treatment-free remission\" OR discontinuation) AND (prediction OR nomogram OR \"machine learning\" OR cytomorphology) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"38763973","doi":"10.1038/s41392-024-01823-2","year":2024,"isNew":true,"title":"Tumor biomarkers for diagnosis, prognosis and targeted therapy"},{"pmid":"39232809","doi":"10.1186/s13045-024-01601-1","year":2024,"isNew":true,"title":"Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies"},{"pmid":"40377777","doi":"10.1007/s12672-025-02592-2","year":2025,"isNew":true,"title":"Specific signaling pathways mediated programmed cell death in tumor microenvironment and target therapies"},{"pmid":"40940894","doi":"10.3390/cancers17172798","year":2025,"isNew":true,"title":"The Targeted Inhibition of Histone Lysine Demethylases as a Novel Promising Anti-Cancer Therapeutic Strategy-An Update on Recent Evidence"},{"pmid":"42279262","doi":"10.3390/cancers18111677","year":2026,"isNew":true,"title":"Sex Differences in Cancer and Cardiotoxicity: Mechanisms, Outcomes, and Clinical Implications Across Solid and Hematological Malignancies"},{"pmid":"40256307","doi":"10.1039/d5md00086f","year":2025,"isNew":true,"title":"Development of potent and selective tetrahydro-β-carboline-based HDAC6 inhibitors with promising activity against triple-negative breast cancer"},{"pmid":"41673722","doi":"10.1186/s40164-026-00760-w","year":2026,"isNew":true,"title":"Targeting epigenetic methylation: emerging diagnosis and therapeutic strategies in cancer"},{"pmid":"42212521","doi":"10.1080/14756366.2026.2677282","year":2026,"isNew":true,"title":"Targeting the BMX in cancer: molecular mechanisms and emerging therapeutic strategies"},{"pmid":"41995989","doi":"10.1007/s10147-026-03038-7","year":2026,"isNew":true,"title":"The new era of AML therapy: current standards and emerging targets"},{"pmid":"42059277","doi":"10.3892/mmr.2026.13892","year":2026,"isNew":true,"title":"Oncogene c‑Myc: From molecular mechanism to targeted therapy (Review)"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":17138,"output":5830},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"chronic myeloid leukemia\" OR CML) AND (MDM2 OR \"p53 restoration\" OR nutlin OR idasanutlin OR PROTAC) AND (\"CD34\" OR \"leukemic stem cell\" OR \"stem cell\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"chronic myeloid leukemia\") AND (ricolinostat OR citarinostat OR \"HDAC6 inhibitor\") AND (autophagy OR \"Beclin 1\" OR MCL1 OR \"BCL-xL\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:38763973","PMID:39232809","PMID:40377777","PMID:40940894","PMID:42279262","PMID:40256307","PMID:41673722","PMID:42212521","PMID:41995989","PMID:42059277","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787170824561","cycle":107,"visit":2,"ts":"2026-08-19T20:20:24.561Z","cancer":{"key":"li-fraumeni syndrome","name":"Li-Fraumeni syndrome","mondo":{"id":"MONDO:0018875","name":"Li-Fraumeni syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"FH deficiency co-occurring with biallelic TP53 inactivation in Li-Fraumeni uterine smooth muscle tumours (PMID:42312930) defines a tissue-verified, p53-independent metabolic/redox vulnerability (NRF2-glutathione-glycolysis) that should be prioritised for FH IHC screening across LFS mesenchymal tumou","confidence":0.5,"notebook":"**Visit 2 notebook.** The pack contains one genuinely informative LFS-tissue paper and several negatives/constraints; no lead is killed, one gains a metabolic branch, and two new hypotheses open.\n\nPMID:42312930 (10 LFS patients, 8 sequenced uterine smooth muscle tumours) is the highest-value item. It partially answers Q1: three STUMPs showed *biallelic* TP53 inactivation, confirming that the classic somatic second hit occurs in LFS mesenchymal lesions; but \"p53-aberrant by IHC\" in 6/8 does not distinguish overexpressed missense from null pattern in the abstract, so the reactivator-eligible fraction remains unresolved. The unexpected finding is **fumarate hydratase loss with inactivating FH variants in three uSMT** — a second metabolic tumour-suppressor hit co-occurring with germline TP53. Whether these FH events are somatic or reflect co-inherited HLRCC alleles is not stated and is now a germline/somatic discipline question [INFERRED]. Mechanistically FH loss creates a defined, druggable state independent of p53: fumarate accumulation, succination of glutathione/KEAP1, constitutive NRF2, pseudohypoxic HIF signalling and glycolysis/HMOX1 addiction [KNOWN] — i.e. a *redox-collapse* target class overlapping L4's TrxR1 axis but with a tissue-verified biomarker (FH IHC). New lead L5. Also noted: one biallelic-TP53 STUMP carried CIN plus ATRX and RB1 loss, consistent with L2's instability phenotype.\n\nL2 is strengthened only in framework, not in LFS tissue: PMID:41516322 explicitly nominates WEE1/ATR G2/M inhibition plus the mitotic kinases PLK1 and TTK/MPS1 as the synthetic-lethal set for TP53-mutant breast cancer, and PMID:41537447/PMID:42098732 add resistance-oriented SL translation. I add PLK1 and MPS1 to the node panel; the LFS-specific gap flagged last visit persists.\n\nL1 gains nuance rather than support. PMID:42289459 finds only slightly elevated ex vivo lymphocyte radiosensitivity (breaks/metaphase) in breast-cancer risk-gene carriers, indistinguishable from breast-cancer controls, with 24.5% above a dose-reduction cutoff and no TP53-specific data. So the radiation-sparing argument for LFS must rest on clinical second-malignancy incidence, not on a generic carrier radiosensitivity phenotype; a per-patient B/M assay is the testable bridge. Confidence held.\n\nNegatives recorded so the desk never re-proposes them: chronic high-fat diet in Trp53^R270H/+ mice (359 animals, two cohorts) did **not** alter survival, tumour burden or spectrum except lung, with adipose-only inflammation (PMID:42165629) — obesity/dietary or systemic anti-inflammatory chemoprevention is dead as an LFS-wide strategy. And somatic TP53 alteration predicts poor remission/EFS after CD19 CAR-T in paediatric B-ALL (PMID:41935222), a caution for cell-therapy-first designs in LFS-associated leukaemia and a partial damper on Q6.\n\nNew speculative lead L6: PMID:42283896's homozygous exon-4 last-nucleotide synonymous variant causing aberrant splicing and partial p53 loss implies splice-switching oligonucleotides could restore wild-type-sequence p53 in hypomorphic splice alleles — a class that no reactivator addresses.","leadChanges":[{"id":"L1","title":"ERBB2 amplification as the only recurrent actionable co-driver in germline TP53 breast cancer","level":"LEAD","status":"WEAKENED","confidence":0.55},{"id":"L2","title":"Short-amplicon chromosomal instability as a synthetic-lethal handle (ATR/WEE1/PKMYT1/KIF18A) in TP53-null LFS tumours","level":"LEAD","status":"STRENGTHENED","confidence":0.47},{"id":"L5","title":"FH-deficient, fumarate-driven metabolic vulnerability in germline-TP53 mesenchymal tumours","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L6","title":"Splice-switching restoration of hypomorphic germline TP53 splice-region alleles","level":"LEAD","status":"NEW","confidence":0.22}],"unverifiedCitations":0,"openQuestions":["Are the FH-inactivating events in LFS uterine smooth muscle tumours somatic second hits or co-inherited HLRCC germline alleles, and how often does FH loss co-occur with germline TP53 across LFS sarcomas and leiomyomas?","Among LFS tumours with biallelic TP53 inactivation, what fraction retain a stable missense protein (reactivator-eligible) versus null pattern — resolvable only by pairing p53 IHC pattern with allele-level sequencing?","Does short-amplicon/CIN burden predict sensitivity to PLK1 and TTK/MPS1 inhibition better than to ATR/WEE1 in germline-TP53 models, and better than TP53 status alone?","Is lymphocyte radiosensitivity (breaks/metaphase) genuinely elevated specifically in germline TP53 carriers, and should radiation avoidance be universal or assay-directed?","Given that somatic TP53 alteration predicts poor CD19 CAR-T outcomes in paediatric B-ALL, do germline-TP53 haematological malignancies fail cellular immunotherapy for the same reason (impaired apoptotic execution after T-cell engagement), a","Does the P47S-PIN1 tubulin vulnerability generalise to canonical LFS missense alleles?"],"nextQueries":["(\"fumarate hydratase\" OR \"FH-deficient\" OR \"HLRCC\") AND (\"TP53\" OR \"Li-Fraumeni\" OR leiomyosarcoma) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"germline TP53\" OR \"Li-Fraumeni\") AND (\"p53 immunohistochemistry\" OR \"missense\" OR \"null pattern\" OR \"allele-specific\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"TP53\" AND (\"PLK1\" OR \"TTK\" OR \"MPS1\" OR \"onvansertib\")) AND (\"chromosomal instability\" OR \"synthetic lethal\" OR sarcoma) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41516322","doi":"10.3390/ijms27010450","year":2025,"isNew":true,"title":"Overcoming Therapeutic Resistance in Triple-Negative Breast Cancer: Targeting the Undrugged Kinome"},{"pmid":"42293463","doi":"10.1002/hem3.70403","year":2026,"isNew":true,"title":"EHA Guidelines on management of chronic lymphocytic leukemia and Richter transformation"},{"pmid":"41537447","doi":"10.1002/ctm2.70586","year":2026,"isNew":true,"title":"Synthetic lethality in cancer therapy: Mechanisms, models and clinical translation for overcoming therapeutic resistance"},{"pmid":"42312930","doi":"10.1111/his.70201","year":2026,"isNew":true,"title":"Clinicopathological and molecular features of uterine smooth muscle tumours in patients with Li-Fraumeni syndrome"},{"pmid":"42289459","doi":"10.1038/s41598-026-57275-x","year":2026,"isNew":true,"title":"Breast cancer risk genes affecting individual radiosensitivity"},{"pmid":"42283896","doi":"10.1007/s10689-026-00580-1","year":2026,"isNew":true,"title":"Homozygous TP53 alterations: a case of a biallelic splice variant and a brief review of the literature"},{"pmid":"42281857","doi":"10.5500/wjt.v16.i2.117357","year":2026,"isNew":true,"title":"Immunosenescence and cancer predisposition in pediatric transplant recipients: An emerging paradigm"},{"pmid":"42165629","doi":"10.1158/2767-9764.crc-25-0280","year":2026,"isNew":true,"title":"Chronic High-Fat Diet Does Not Alter Overall Cancer Incidence in Trp53R270H/+ Mice"},{"pmid":"41935222","doi":"10.1038/s41409-026-02838-9","year":2026,"isNew":true,"title":"Impact of TP53 alterations on outcomes in pediatric and young adult patients with relapsed / refractory B-cell acute lymphoblastic leukemia after CD19-CAR T-Cell therapy"},{"pmid":"42098732","doi":"10.1186/s12964-026-02932-x","year":2026,"isNew":true,"title":"Synthetic lethality in cancer: mechanism exploration and therapeutic applications"}],"trialsShown":[{"nct":"NCT06888388","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Long-term Safety of Nipple Sparing Mastectomy in Women With High Penetrance Breast Cancer Susceptibility Genes in Breast Cancer"},{"nct":"NCT01143454","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Characterization of Patients With Uncommon Presentations and/or Uncommon Diseases Associated With the Cardiovascular System"},{"nct":"NCT01443468","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Clinical and Genetic Studies of Li-Fraumeni Syndrome"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT03176836","phase":"NA","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Li-Fraumeni Syndrome Imaging Study"},{"nct":"NCT05126810","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Willingness to Participate in a Trial Comparing Standard Genetic Counseling Versus Personalized Genetic Counseling"},{"nct":"NCT04541654","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress"},{"nct":"NCT02950987","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Screening With Whole Body MRI For Detection Of Primary Tumors In Children And Adults With Li-Fraumeni Syndrome (LFS) And Other Cancer Predis"}],"usage":{"input":11197,"output":7956},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"germline TP53\" OR \"Li-Fraumeni\") AND (\"loss of heterozygosity\" OR \"second hit\" OR \"biallelic\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"TP53\" AND (\"KIF18A\" OR \"PKMYT1\" OR \"WEE1\" OR \"ATR inhibitor\") AND (\"chromosomal instability\" OR \"synthetic lethal\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41516322","PMID:42293463","PMID:41537447","PMID:42312930","PMID:42289459","PMID:42283896","PMID:42281857","PMID:42165629","PMID:41935222","PMID:42098732","NCT06888388","NCT01143454","NCT01443468","NCT03050268","NCT03176836","NCT05126810","NCT04541654","NCT02950987"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787170597433","cycle":106,"visit":2,"ts":"2026-08-19T20:16:37.433Z","cancer":{"key":"systemic mastocytosis","name":"systemic mastocytosis","mondo":{"id":"MONDO:0016586","name":"systemic mastocytosis"}},"control":false,"modelLabel":"SCIENCE","summary":"PATHFINDER 4-year data show AdvSM progression on avapritinib is driven predominantly by the associated hematologic neoplasm, so the desk's priority shifts to co-targeting the SRSF2/ASXL1/TET2/DNMT3A co-mutant myeloid clone (HMA ± venetoclax added to KIT D816V blockade) while peripherally restricted ","confidence":0.72,"notebook":"PATHFINDER's 4-year update (PMID:41604606) is the most consequential item in this pack and it cuts two ways. It confirms durable single-agent activity of KIT D816V blockade in AdvSM (ORR 73%, median DOR 58 months, PFS 51, OS 62 months) — the deepest validation yet that D816V [SOMATIC] is the maintenance driver — while simultaneously localising failure: 20% progressed, \"predominantly in SM-AHN and largely driven by the AHN.\" That is direct, non-inferential support for L2's core prediction that the SRSF2/ASXL1/RUNX1/TET2/CBL co-mutant compartment is KIT-independent and rate-limiting for survival; L2 moves to CANDIDATE. PMID:42004892 adds an independent (small, n=24, targeted 66-gene NGS) cohort in which TET2, SRSF2 P95 and DNMT3A R882H cluster in mastocytosis — DNMT3A is new to the desk's anchor set. PMID:41378161 (aCML) reinforces the pharmacological pessimism: for the same lesion set no agent is disease-modifying, so the combination question is HMA/venetoclax-shaped, and PMID:40950415 supplies a single anecdotal SM-AHN/AML case in which azacitidine–venetoclax reduced mast cell burden (KIT-wildtype SM, so uninterpretable for KIT-mutant clones).\n\nL1 also strengthens but with sharper framing: cognitive effects 34% (8% grade ≥3) and intracranial bleeds 4% on avapritinib are now cited, not recollected, which is the entire rationale for peripherally restricted elenestinib/bezuclastinib in ISM. Counterweight: PMID:41961082 shows avapritinib achieving CSF molecular remission in KIT D816V CNS-involved AML, with loss and recapture of response on discontinuation/rechallenge — CNS penetration is an asset where disease is intracranial, so peripheral restriction is a window argument specific to indolent disease, not a general improvement. PMID:41701410 supplies a usable ISM endpoint: KIT TKIs may cut anaphylaxis risk through both KIT- and FcεRI-dependent signalling, so anaphylaxis/mediator-event rate belongs alongside VAF and tryptase in HARBOR/Summit readouts. PMID:42174092 (CML TFR) frames the unanswered question of whether any SM molecular response depth permits discontinuation — doubtful if D816V sits in an HSC [INFERRED].\n\nL3 is retired as pre-committed. The pack's T-BsAb review (PMID:42049030) covers myeloid targets with no mast cell data and emphasises myelotoxicity/target-specificity failure; NCT05362773 records no SM cohort. No CD30 ADC evidence surfaced. Logged as retired so the desk does not re-propose CD123 engagers or CD30 ADCs in SM without new primary data.\n\nNew L4: BTK inhibition. Acalabrutinib monotherapy produced SM response in SM-with-CLL (PMID:41376555) — confounded by the lymphoid AHN, but mechanistically coherent with FcεRI/BTK dependence of mast cell activation (PMID:41701410).","leadChanges":[{"id":"L1","title":"D816V-selective, CNS-restricted KIT inhibition to extend targeted therapy into indolent SM","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.85},{"id":"L2","title":"Co-mutant myeloid clone (SRSF2/ASXL1/RUNX1/TET2/CBL) as a KIT-independent compartment in advanced SM and SM-AHN","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.7},{"id":"L3","title":"Surface-antigen (CD30 / CD123) targeting of neoplastic mast cells","level":"LEAD","status":"RETIRED","confidence":0.05},{"id":"L4","title":"BTK inhibition as an FcEpsilonRI-axis-directed strategy in mast cell neoplasms, starting with SM plus lymphoid AHN","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["In HARBOR (NCT04910685) and Summit (NCT05186753), do elenestinib and bezuclastinib match avapritinib's KIT D816V VAF and tryptase reduction while eliminating the 34% cognitive-effect and 4% intracranial-bleed signals seen in PATHFINDER (PMI","Since PATHFINDER progression was largely AHN-driven, is there any published or trial-embedded experience of a KIT D816V inhibitor combined with azacitidine or venetoclax in SM-AHN, and what is the observed cytopenia burden?","Do serial per-mutation VAF data show that KIT inhibition leaves SRSF2/ASXL1/RUNX1/TET2/CBL/DNMT3A clone VAF unchanged, and does the co-mutant clone reside in the same cell as KIT D816V?","What are the documented acquired resistance lesions at progression on avapritinib/bezuclastinib in SM (secondary KIT substitutions vs RAS-MAPK vs BCL2/MCL1 dependence), and is any pharmacologically addressable?","Is any degree of molecular response in SM compatible with treatment discontinuation, or does D816V persistence in the HSC compartment make treatment-free remission unattainable on the CML template (PMID:42174092)?","Beyond the confounded SM-CLL case (PMID:41376555), is there preclinical or clinical evidence that BTK inhibition reduces mast cell burden or anaphylaxis frequency in mastocytosis?"],"nextQueries":["(\"systemic mastocytosis\" OR \"mast cell leukemia\") AND (avapritinib OR bezuclastinib OR elenestinib OR midostaurin) AND (azacitidine OR decitabine OR venetoclax OR \"hypomethylating\") AND SRC:MED","(\"systemic mastocytosis\" OR \"mast cell\") AND (\"acquired resistance\" OR \"secondary mutation\" OR \"RAS\" OR \"MCL1\" OR \"BCL2\") AND (KIT AND D816V) AND SRC:MED","(\"mastocytosis\" OR \"mast cell activation\") AND (ibrutinib OR acalabrutinib OR zanubrutinib OR \"Bruton tyrosine kinase\") AND SRC:MED"],"papersShown":[{"pmid":"41376555","doi":"10.3324/haematol.2025.289116","year":2026,"isNew":true,"title":"Is Bruton tyrosine kinase a potential target to treat mast cell neoplasms? Systemic mastocytosis associated with chronic lymphoid leukemia successfully treated with acalabrutinib m"},{"pmid":"42174092","doi":"10.1038/s41375-026-02984-5","year":2026,"isNew":true,"title":"From fatal disease to functional cure: 25 years of tyrosine kinase inhibition in chronic myeloid leukemia"},{"pmid":"42049030","doi":"10.1016/j.xcrm.2026.102772","year":2026,"isNew":true,"title":"T cell-engaging bispecific antibodies for myeloid malignancies: Targets, formats, and clinical challenges"},{"pmid":"41604606","doi":"10.1182/bloodadvances.2025017519","year":2026,"isNew":true,"title":"Efficacy and safety of avapritinib in advanced systemic mastocytosis: 4-year follow-up of the PATHFINDER study"},{"pmid":"41961082","doi":"10.1007/s00277-026-06953-x","year":2026,"isNew":true,"title":"Avapritinib for targeting KIT D816V-mutated acute myeloid leukemia relapsed after allogeneic hematopoietic stem cell transplant with extramedullary and central nervous system invol"},{"pmid":"41793580","doi":"10.1007/s11899-026-00775-4","year":2026,"isNew":true,"title":"Molecular Pathogenesis and Targeted Therapies for Myeloproliferative Hypereosinophilic Neoplasms"},{"pmid":"41701410","doi":"10.1007/s11882-026-01257-6","year":2026,"isNew":true,"title":"Systemic Mastocytosis, KIT and the Effects of KIT Tyrosine Kinase Inhibitors on Mast Cell and Basophil Activation"},{"pmid":"42004892","doi":"10.2147/jaa.s594281","year":2026,"isNew":true,"title":"Clonal Mast Cell Disorders and Mutation Profile in Adults Initially Presenting with Mast Cell Activation (Anaphylaxis) versus Non-Anaphylactic Presentations: A Joint Allergy-Hemato"},{"pmid":"40950415","doi":"10.1155/crom/3563591","year":2025,"isNew":true,"title":"KIT-Negative Systemic Mastocytosis Associated With Acute Myeloid Leukemia"},{"pmid":"41378161","doi":"10.1002/hem3.70270","year":2025,"isNew":true,"title":"Atypical chronic myeloid leukemia: From diagnosis to molecular features and therapeutic options"}],"trialsShown":[{"nct":"NCT00935090","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"3'-Deoxy-3'-[18F] Fluorothymidine PET Imaging in Patients With Cancer"},{"nct":"NCT07264959","phase":"n/a","status":"RECRUITING","isNew":false,"title":"An Observational Study in Participants With Indolent Systemic Mastocytosis (ISM)"},{"nct":"NCT04910685","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis"},{"nct":"NCT04996875","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"(Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis"},{"nct":"NCT03779854","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Naive T Cell Depletion for Preventing Chronic Graft-versus-Host Disease in Children and Young Adults With Blood Cancers Undergoing Donor Ste"},{"nct":"NCT05362773","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of MGD024 in Patients With Relapsed or Refractory Hematologic Malignancies"},{"nct":"NCT01137825","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Registry of Older Patients With Cancer"},{"nct":"NCT05186753","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"(Summit) A Study to Evaluate the Efficacy and Safety of CGT9486 Versus Placebo in Patients With Indolent or Smoldering Systemic Mastocytosis"}],"usage":{"input":10388,"output":6558},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"systemic mastocytosis\" OR \"mast cell leukemia\") AND (avapritinib OR elenestinib OR bezuclastinib OR midostaurin) AND (resistance OR \"variant allele frequency\" OR \"molecular response\") AND SRC:MED","\"systemic mastocytosis\" AND (SRSF2 OR ASXL1 OR RUNX1 OR TET2 OR CBL) AND (prognosis OR clone OR \"associated hematologic neoplasm\" OR azacitidine OR venetoclax) AND SRC:MED"],"evidenceIds":["PMID:41376555","PMID:42174092","PMID:42049030","PMID:41604606","PMID:41961082","PMID:41793580","PMID:41701410","PMID:42004892","PMID:40950415","PMID:41378161","NCT00935090","NCT07264959","NCT04910685","NCT04996875","NCT03779854","NCT05362773","NCT01137825","NCT05186753"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787170391694","cycle":105,"visit":2,"ts":"2026-08-19T20:13:11.694Z","cancer":{"key":"primary myelofibrosis","name":"primary myelofibrosis","mondo":{"id":"MONDO:0009692","name":"primary myelofibrosis"}},"control":false,"modelLabel":"SCIENCE","summary":"Mutant-CALR-directed immunotherapy is now the programme's lead subtype strategy — a mutCALR CAR T selectively depletes patient MF stem cells and retains potency in a fibrotic human chimeroid TME, while an mRNA vaccine ORF for the shared CALR exon 9 C-terminus provides an off-the-shelf second modalit","confidence":0.55,"notebook":"This visit was mostly about CALR. P7 (PMID:42384776) is the strongest single piece of evidence the desk has seen for L1: a mutCALR-specific CAR T construct that depleted mutCALR+ stem cells from myelofibrosis patient samples while sparing healthy CD34+ HSC, extended survival in mutCALR leukaemia xenografts, and — critically for the fibrosis objection I raised at visit 1 — retained full killing potency in a human \"chimeroid\" model engineered to mimic fibrotic marrow, i.e. the hostile stromal TME did not blunt cytotoxicity. It also reports a method to upregulate surface mutCALR on CD34+ cells from accelerated/blast-phase MPN, which is exactly the antigen-density problem that would otherwise limit engager/CAR approaches [INFERRED]. P6 (PMID:42509808) independently nominates a single CALR exon 9 ORF encoding the shared novel C-terminus of type 1/2 mutations as a pre-manufactured HLA-matched mRNA vaccine target under a cancer-cell-only criterion (clonal, recurrent, absent from essential normal tissue), giving a cheaper, off-the-shelf modality alongside cell therapy. Two independent new lines, both mechanism-consistent with the surface mutCALR–TpoR complex, so L1 moves to CANDIDATE. Eligibility ceiling is unchanged: ~1/3 of MPN is CALR-driven (P7), so this is a subtype strategy, and P4/P5 (NK-cell and TCE platform reviews) are generic — no MF-specific data — so they inform modality choice only, not confidence.\n\nL3 gets its primary source: P2 (PMID:41785311) is the SENTRY/XPORT-MF-034 phase 1 that fed last visit's pooled figure. Real numbers are SVR35 79% and TSS50 58% at selinexor 60 mg in 24 JAKi-naive patients, no DLTs, with anaemia, thrombocytopenia and nausea as expected on-target XPO1 toxicities. That is lower than the 92% pooled estimate and still uncontrolled, so I raise confidence only slightly; no TP53 correlative data reported, so open question 3 stands unanswered and now has a named randomised test (phase 3 portion of NCT04562389).\n\nNew lead L6 from P10 (PMID:42337564): JAK2V617F drives HIF-1-dependent glycolytic rewiring with dependency on GLUT1/GLUT3; CRISPR knockout impairs fitness, pharmacological GLUT1/3 inhibition works in SET-2/HEL, primary cells and a Jak2V617F knock-in mouse, and combines with ruxolitinib. This is the first metabolic lead in the programme and covers the JAK2-mutant majority that L1 cannot address. The therapeutic-window argument is the whole risk: GLUT1 is the erythrocyte and blood–brain-barrier transporter [KNOWN], so isoform selectivity or GLUT3-biased agents matter.\n\nP1 and P3 reinforce the framing that current JAKi are anti-inflammatory without survival/progression impact, and list pelabresib/navitoclax/imetelstat/bomedemstat as candidate fibrosis-modifying agents — modest support for L2. P8 (cold plasma) and P9 (in-transit melanoma) are pack noise; recorded as such.","leadChanges":[{"id":"L1","title":"Mutant CALR neoepitope-directed immunotherapy in CALR-mutant PMF","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.72},{"id":"L3","title":"XPO1 inhibition (selinexor) with ruxolitinib in JAKi-naive MF","level":"LEAD","status":"STRENGTHENED","confidence":0.5},{"id":"L2","title":"BET bromodomain inhibition (pelabresib) added to ruxolitinib","level":"LEAD","status":"STRENGTHENED","confidence":0.57},{"id":"L6","title":"GLUT1/GLUT3 glucose-transport dependency downstream of HIF-1 in JAK2V617F MPN","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["What is the first-in-human path for mutCALR CAR T — dose, lymphodepletion in a cytopenic fibrotic marrow, and does mutCALR VAF fall with marrow fibrosis regression rather than just spleen response?","Does the shared CALR exon 9 mRNA vaccine construct elicit measurable CD8 responses and VAF decline in lower-risk CALR-mutant patients, and which HLA alleles present the novel C-terminus?","In randomised SENTRY (NCT04562389), does selinexor+ruxolitinib SVR35/TSS50 survive a control arm, and does response segregate by TP53 wild-type status?","Is GLUT1/GLUT3 dependency specific to JAK2V617F or shared by CALR/MPL-mutant and triple-negative MF, and can any tool compound achieve marrow-selective GLUT blockade without erythrocyte/CNS toxicity?","Does the pelabresib phase 3 (NCT07357727) deliver fibrosis-grade or VAF change, and at what haemoglobin cost?","Can IL-1beta/NLRP3 blockade or HO-1 induction reverse established fibrosis in a mammalian PMF model without unacceptable infection risk (L4 still model-organism only)?"],"nextQueries":["(\"mutant calreticulin\" OR mutCALR) AND (\"CAR T\" OR \"chimeric antigen receptor\" OR \"bispecific\" OR vaccine) AND (myelofibrosis OR \"myeloproliferative\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","myelofibrosis AND (GLUT1 OR SLC2A1 OR GLUT3 OR SLC2A3 OR \"HIF-1\" OR glycolysis) AND (JAK2V617F OR \"myeloproliferative\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(selinexor OR pelabresib OR navitoclax OR imetelstat) AND myelofibrosis AND (randomized OR \"phase 3\" OR \"placebo-controlled\") AND (\"bone marrow fibrosis\" OR \"allele burden\" OR TP53) AND SRC:MED AND PUB_YEAR:[2025 TO 2026"],"papersShown":[{"pmid":"40062529","doi":"10.1002/ajh.27658","year":2025,"isNew":true,"title":"Targeted Therapies in Myelofibrosis: Present Landscape, Ongoing Studies, and Future Perspectives"},{"pmid":"41785311","doi":"10.1182/bloodadvances.2025018706","year":2026,"isNew":true,"title":"Selinexor plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: a multicenter, open-label, phase 1 study"},{"pmid":"40192154","doi":"10.1002/hon.70053","year":2025,"isNew":true,"title":"Managing Myelofibrosis: Matching Advances in Treatments With Clinical Unmet Needs"},{"pmid":"42033215","doi":"10.1080/15384047.2026.2658896","year":2026,"isNew":true,"title":"Advances in natural killer cell immunotherapy for hematologic malignancies"},{"pmid":"41700001","doi":"10.1080/2162402x.2026.2632421","year":2026,"isNew":true,"title":"Trial Watch - bispecific T cell engagers and higher-order multispecific immunotherapeutics"},{"pmid":"42509808","doi":"10.3390/biom16071015","year":2026,"isNew":true,"title":"Sequence-Anchored Shared Tumor-Specific Epitopes for Pre-Manufactured HLA-Matched mRNA Cancer Vaccine Libraries: A Pan-Cancer Framework"},{"pmid":"42384776","doi":"10.1126/scitranslmed.adz3553","year":2026,"isNew":true,"title":"CAR T cell therapy selectively depletes disease-driving mutant calreticulin cells in xenotransplants and human organoid models of myelofibrosis"},{"pmid":"42143970","doi":"10.1016/j.redox.2026.104162","year":2026,"isNew":true,"title":"A dual-index framework for cold atmospheric plasma dosing: A meta-analysis of parametric control from volumetric redox flux to redox homeostatic status"},{"pmid":"42346244","doi":"10.3390/curroncol33060344","year":2026,"isNew":true,"title":"The Evolving Role of Intralesional Therapy in In-Transit Melanoma"},{"pmid":"42337564","doi":"10.1186/s12964-026-03018-4","year":2026,"isNew":true,"title":"Glucose transport dependency defines a therapeutic vulnerability in JAK2V617F-driven myeloproliferative neoplasms"}],"trialsShown":[{"nct":"NCT06661915","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)"},{"nct":"NCT07228624","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Ruxolitinib Before, During and After Hematopoietic Cell Transplant in Older Patients With Myelofibrosis and Myelodysplastic Syndrome/Myelopr"},{"nct":"NCT07357727","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF)"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"},{"nct":"NCT07302776","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"TACrolimus Targeted Immunosuppression Cessation in ALlogeneic HCT"},{"nct":"NCT07443306","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Clinical Trial of Flonoltinib Maleate Tablets in the Treatment of JAK Inhibitor Refractory/Relapsed/Intolerant Patients With Intermediate "},{"nct":"NCT07317700","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Clinical Trial of Flonoltinib Maleate for Intermediate or High-Risk Myelofibrosis"},{"nct":"NCT06468033","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"P1101 in Treating Patients With Early PMF or Overt PMF at Low or Intermediate-1 Risk"}],"usage":{"input":11258,"output":6068},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"calreticulin\" OR CALR) AND (neoantigen OR neoepitope OR \"bispecific\" OR \"CAR-T\" OR vaccine OR antibody) AND (myelofibrosis OR \"myeloproliferative\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","myelofibrosis AND (pelabresib OR selinexor OR siremadlin OR navitoclax OR bomedemstat) AND (\"bone marrow fibrosis\" OR \"allele burden\" OR \"disease modification\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:40062529","PMID:41785311","PMID:40192154","PMID:42033215","PMID:41700001","PMID:42509808","PMID:42384776","PMID:42143970","PMID:42346244","PMID:42337564","NCT06661915","NCT07228624","NCT07357727","NCT06001385","NCT07302776","NCT07443306","NCT07317700","NCT06468033"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787170189064","cycle":104,"visit":2,"ts":"2026-08-19T20:09:49.064Z","cancer":{"key":"essential thrombocythemia","name":"essential thrombocythemia","mondo":{"id":"MONDO:0005029","name":"essential thrombocythemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Mutant-CALR is now validated as a clone-restricted surface target across three independent modalities (mAb, CAR T, mRNA vaccine), so the desk should prioritise reversible-exposure mutCALR agents (INCA033989-class antibody/TCE) with allele-burden endpoints in chronic-phase CALR-mutant ET, reserving C","confidence":0.6,"notebook":"The pack's decisive item is P7 (PMID:42384776): a mutCALR-specific CAR T construct that depletes mutCALR⁺ stem cells from patient marrow while sparing healthy HSCs, retains killing in a fibrotic \"chimeroid\" TME, and extends survival in mutCALR leukemia xenografts — plus a method to upregulate surface mutCALR in CD34⁺ cells from accelerated/blast-phase MPN. This is an independent modality validating the same target logic as INCA033989 (mutCALR–TpoR complex externalised only on clonal cells), so L1 moves to CANDIDATE. P6 (PMID:42509808) adds a third format — an mRNA construct encoding the shared CALR exon 9 type 1/2 novel C-terminus — and, usefully, states the escape criterion explicitly: targets must be sufficiently clonal. [INFERRED] In ET, where the mutant clone often occupies a smaller fraction of haematopoiesis than in MF and life expectancy is near-normal, the surface-density and CRS/lymphodepletion arithmetic favours reversible-exposure formats (mAb, TCE) in chronic-phase ET, reserving CAR T for MF/accelerated phase; the surface-boosting trick from P7 is the natural way to rescue low-epitope-density ET targets. [SPECULATIVE] Combining a mutCALR agent with interferon (which drives quiescent clones into cycle) may raise both epitope display and clone vulnerability.\n\nInterferon evidence this visit is real but PV-anchored: P2 and P3 push durable complete molecular remission as a treatment goal and establish ropegIFN superiority over HU and over phlebotomy-only in PV, and P1 reports the HIDAT high-initial-dose/accelerated-titration schedule giving rapid JAK2V617F VAF fall and high CMR. None of this is ET, and none reports per-genotype (CALR/MPL) molecular response — my open question 2 remains unanswered. L3 stays LEAD with only a nudge; the actionable new sub-hypothesis is dose-intensity (HIDAT) rather than genotype.\n\nNew lead from P10 (PMID:42337564): JAK2V617F induces HIF-1-dependent glycolytic rewiring with GLUT1/GLUT3 dependency; CRISPR loss and pharmacological GLUT1/3 blockade impair JAK2V617F cells and synergise with ruxolitinib. Window is the whole argument — germline SLC2A1 haploinsufficiency causes GLUT1-deficiency encephalopathy and GLUT3 is neuronal [KNOWN] — so CNS-sparing or partial inhibition is mandatory; also genotype-restricted (CALR/MPL ET excluded).\n\nNotebook negatives: pelabresib's new phase 3 (NCT07357727) is MF-only, not ET; ruxolitinib in ET remains unproven pending Ruxo-BEAT (NCT02577926) and should not be re-proposed as monotherapy for count control. Bomedemstat phase 3 (NCT06079879) is now closed to accrual with efficacy still unreported — L2 unchanged. P8/P9 (cold plasma, intralesional melanoma) are pack noise.","leadChanges":[{"id":"L1","title":"Mutant-CALR neoepitope-directed immunotherapy in CALR-mutant ET","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.72},{"id":"L3","title":"Ropeginterferon alfa-2b as driver-agnostic clonal control backbone in ET","level":"LEAD","status":"STRENGTHENED","confidence":0.62},{"id":"L5","title":"HIF-1-driven GLUT1/GLUT3 glucose-transport dependency in JAK2V617F ET","level":"LEAD","status":"NEW","confidence":0.33}],"unverifiedCitations":0,"openQuestions":["In chronic-phase ET (not MF), what surface mutCALR density is achievable, and does an antibody/TCE format lower CALR VAF at doses tolerable in a disease with near-normal life expectancy - versus the CAR T risk-benefit that only justifies it","What are the bomedemstat MK-3543-006 (NCT06079879) efficacy, allele-burden and grade 3/4 cytopenia results versus BAT now that accrual is closed?","Does ropeginterferon molecular response in ET differ by JAK2 V617F vs CALR vs MPL genotype, and does a HIDAT-style dose-intensified schedule improve ET molecular response without added toxicity?","Which escape routes actually emerge under mutCALR-directed pressure - epitope-negative CALR clones, MPL/TpoR downregulation, or outgrowth of TET2/ASXL1-mutant CALR-wild-type clones?","Is there any ET-specific (not MF) evidence that any agent delays post-ET myelofibrosis or leukemic transformation, and will Ruxo-BEAT (NCT02577926) high-risk ET arm add anything to the negative ruxolitinib-in-ET record?","Can HIF-1/GLUT1 blockade be made haematopoietically selective enough to avoid GLUT1-deficiency-type CNS and erythrocyte toxicity in JAK2V617F ET?"],"nextQueries":["(bomedemstat OR \"MK-3543\" OR \"IMG-7289\") AND (\"essential thrombocythemia\" OR thrombocythaemia) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"mutant calreticulin\" OR \"mutCALR\" OR \"CALR exon 9\") AND (\"T cell engager\" OR antibody OR \"CAR T\" OR \"immune escape\" OR \"epitope loss\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"essential thrombocythemia\") AND (ropeginterferon OR \"interferon alfa\") AND (\"molecular response\" OR \"allele burden\" OR CALR OR MPL) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"40646417","doi":"10.1007/s11899-025-00752-3","year":2025,"isNew":true,"title":"Highlights from MPN Asia 2025: Advances in Molecular Pathogenesis and Therapeutic Strategies in Myeloproliferative Neoplasms"},{"pmid":"41060606","doi":"10.1007/s11899-025-00758-x","year":2025,"isNew":true,"title":"Emerging Significance and Implications of a Durable Complete Molecular Remission in the Treatment of Polycythemia Vera"},{"pmid":"41951941","doi":"10.1038/s41375-026-02882-w","year":2026,"isNew":true,"title":"A paradigm shift in the treatment of patients with polycythemia vera. The initial early use of recombinant interferon-alpha"},{"pmid":"42033215","doi":"10.1080/15384047.2026.2658896","year":2026,"isNew":true,"title":"Advances in natural killer cell immunotherapy for hematologic malignancies"},{"pmid":"41700001","doi":"10.1080/2162402x.2026.2632421","year":2026,"isNew":true,"title":"Trial Watch - bispecific T cell engagers and higher-order multispecific immunotherapeutics"},{"pmid":"42509808","doi":"10.3390/biom16071015","year":2026,"isNew":true,"title":"Sequence-Anchored Shared Tumor-Specific Epitopes for Pre-Manufactured HLA-Matched mRNA Cancer Vaccine Libraries: A Pan-Cancer Framework"},{"pmid":"42384776","doi":"10.1126/scitranslmed.adz3553","year":2026,"isNew":true,"title":"CAR T cell therapy selectively depletes disease-driving mutant calreticulin cells in xenotransplants and human organoid models of myelofibrosis"},{"pmid":"42143970","doi":"10.1016/j.redox.2026.104162","year":2026,"isNew":true,"title":"A dual-index framework for cold atmospheric plasma dosing: A meta-analysis of parametric control from volumetric redox flux to redox homeostatic status"},{"pmid":"42346244","doi":"10.3390/curroncol33060344","year":2026,"isNew":true,"title":"The Evolving Role of Intralesional Therapy in In-Transit Melanoma"},{"pmid":"42337564","doi":"10.1186/s12964-026-03018-4","year":2026,"isNew":true,"title":"Glucose transport dependency defines a therapeutic vulnerability in JAK2V617F-driven myeloproliferative neoplasms"}],"trialsShown":[{"nct":"NCT06661915","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)"},{"nct":"NCT07357727","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF)"},{"nct":"NCT02577926","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"The Ruxo-BEAT Trial in Patients With High-risk Polycythemia Vera or High-risk Essential Thrombocythemia"},{"nct":"NCT06079879","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of Bomedemstat (IMG-7289/MK-3543) Compared to Best Available Therapy (BAT) in Participants With Essential Thrombocythemia and an Ina"},{"nct":"NCT05320198","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Study of DISC-0974 (RALLY-MF) in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia"},{"nct":"NCT05936359","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neop"},{"nct":"NCT06361641","phase":"NA","status":"RECRUITING","isNew":false,"title":"Functional and Phenotypic Characterization of Monocytes in Myeloproliferative Syndromes"},{"nct":"NCT00935090","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"3'-Deoxy-3'-[18F] Fluorothymidine PET Imaging in Patients With Cancer"}],"usage":{"input":10336,"output":5542},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"calreticulin\" OR CALR) AND (neoepitope OR antibody OR \"CAR-T\" OR \"bispecific\" OR vaccine) AND (myeloproliferative OR thrombocythemia) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"essential thrombocythemia\") AND (\"allele burden\" OR \"molecular response\" OR clonal) AND (interferon OR ropeginterferon OR bomedemstat OR LSD1) AND SRC:MED"],"evidenceIds":["PMID:40646417","PMID:41060606","PMID:41951941","PMID:42033215","PMID:41700001","PMID:42509808","PMID:42384776","PMID:42143970","PMID:42346244","PMID:42337564","NCT06661915","NCT07357727","NCT02577926","NCT06079879","NCT05320198","NCT05936359","NCT06361641","NCT00935090"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787169992097","cycle":103,"visit":2,"ts":"2026-08-19T20:06:32.097Z","cancer":{"key":"polycythemia vera","name":"polycythemia vera","mondo":{"id":"MONDO:0009891","name":"acquired polycythemia vera"}},"control":false,"modelLabel":"SCIENCE","summary":"Hepcidin agonism (rusfertide/divesiran/sapablursen) is the most tractable PV lever and rises to CANDIDATE, but must be judged on thrombotic events rather than hematocrit because iron restriction can mask an expanded microcytic red-cell mass; meanwhile ropeginterferon shows no molecular-response adva","confidence":0.5,"notebook":"Visit 2 turns the programme from registry-derived speculation toward endpoint discipline, and one prior assumption breaks.\n\nThe hepcidin axis is now the strongest thing on the desk. P3 (PMID:41100735) states directly that hepcidin is *relatively low* in PV despite low systemic iron — i.e. the pathophysiology is permissive iron avidity, not iron overload — and names three hepcidin agonists in clinical development (rusfertide, divesiran, sapablursen), while confirming DISC-0974 as the opposite-direction MF agent exactly as banked. L4 moves to CANDIDATE (independent new literature, second evidence-bearing visit). But P5 (PMID:42381746) is a mechanistic caution I will not discount: an iron-deficiency-masked JAK2+ PV presented with extensive bilateral PE at Hct 45.9%, MCV 66.5 fL. [INFERRED] Iron restriction normalises hematocrit while leaving an expanded, microcytic, rheologically abnormal red-cell mass and an untouched clone; hematocrit may therefore be a corrupted surrogate under precisely the intervention being developed. Thrombotic-event endpoints, not phlebotomy counts, are the only acceptable read-out.\n\nL1 weakens. P1 (PMID:41907306) reviews next-generation JAK selectivity but locates the tractable covalent handle at JAK3 Cys909, not JAK2, and does not identify BEBT-507 — open question 1 remains open, so BEBT-507 stays [SPECULATIVE]. Worse, P9 (PMID:42176929) says V617F allele burden links to thrombosis, phenotype and fibrosis \"not uniformly across disease subtypes,\" with assay standardisation still unsettled. Allele fraction as the molecular-response endpoint for flonoltinib/NCT07232290 needs pre-specified dPCR/NGS methodology and a demonstrated VAF-to-event link before it can arbitrate class superiority.\n\nThe interferon molecular-response paradigm takes a real hit and I am recording it so the desk never re-proposes it unselected: P8 (PMID:42566639), 3 RCTs/522 patients, found ropeginterferon no better than hydroxyurea for CHR, partial molecular response, or JAK2 VAF reduction — benefit appeared only versus phlebotomy alone. P6's EXCEED-ET is single-arm and in ET. New lead L6: interferon is a selection problem (low baseline VAF, absent TET2/DNMT3A/ASXL1 co-mutations, long exposure), not a universal disease-modifier.\n\nP2 (PMID:41761659) supports L3 laterally — BET inhibitor BMS-986158 plus ruxolitinib gave SVR35 90% in JAKi-naïve MF — and generates L5: MDM2 inhibition (siremadlin 45% SVR35 post-JAKi; idasanutlin previously PV-tested with GI-limiting toxicity [KNOWN]) as p53 reactivation in TP53-wildtype JAK2 V617F PV, with TP53-mutant subclone selection as the named resistance/hazard. P4 anchors the clinical target: 38.3% thrombotic burden, 87% of events at/before diagnosis, arterial 90.7% — early-window arterial protection is the prize. L2 unchanged.","leadChanges":[{"id":"L1","title":"Selectivity-optimized JAK2 inhibition for molecular (allele-burden) response in JAK2 V617F PV","level":"LEAD","status":"WEAKENED","confidence":0.4},{"id":"L3","title":"BET/NF-kB inhibition added to JAK inhibition — test extension from myelofibrosis into high-risk PV","level":"LEAD","status":"STRENGTHENED","confidence":0.4},{"id":"L4","title":"Hepcidin/hemojuvelin axis as a pharmacologic lever on PV erythrocytosis","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.5},{"id":"L5","title":"MDM2 inhibition (p53 reactivation) in TP53-wildtype JAK2 V617F PV","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L6","title":"Interferon in PV is a patient-selection problem, not a universal disease-modifier","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["Do rusfertide/divesiran/sapablursen reduce thrombotic EVENTS in PV, or only phlebotomy frequency — and does the iron-restricted microcytic state itself carry residual thrombotic risk at hematocrit <45% (as PMID:42381746 suggests)?","What is BEBT-507's molecular target and class (NCT07012109) — still undisclosed after a dedicated JAK-selectivity review?","Is JAK2 V617F VAF change a validated surrogate for thrombosis-free or fibrosis-free survival in PV, and what standardised dPCR/NGS thresholds should trials pre-specify?","Which subgroup, if any, achieves true molecular response on ropeginterferon (baseline VAF, co-mutation status, treatment duration), given no pooled advantage over hydroxyurea?","In TP53-wildtype PV, can MDM2 inhibition deplete the JAK2-mutant clone without selecting TP53-mutant subclones, and what is the GI/thrombocytopenia ceiling?","Since 87% of thrombotic events occur at or before PV diagnosis and 90% are arterial, is any cytoreductive or clone-directed agent testable in the pre-diagnostic/early window, or is antithrombotic optimisation the only accessible lever there"],"nextQueries":["(\"polycythemia vera\") AND (rusfertide OR divesiran OR sapablursen) AND (thrombosis OR thromboembolic OR \"red cell mass\" OR viscosity) AND SRC:MED","(\"myeloproliferative\" OR \"polycythemia vera\") AND (idasanutlin OR siremadlin OR \"MDM2 inhibitor\" OR navtemadlin) AND SRC:MED","(\"polycythemia vera\") AND (\"allele burden\" OR \"variant allele frequency\") AND (thrombosis OR \"progression-free\" OR surrogate OR \"digital PCR\") AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41907306","doi":"10.1016/j.pscia.2026.100116","year":2026,"isNew":true,"title":"Next-generation Janus kinase inhibitors: Integrating synthetic innovation, structural biology, and computational design for precision drug discovery"},{"pmid":"41761659","doi":"10.1080/07853890.2026.2634532","year":2026,"isNew":true,"title":"Efficacy and safety of Ruxolitinib-based combination therapy in the patients with Myelofibrosis (MF): a systematic review and meta-analysis"},{"pmid":"41100735","doi":"10.1182/blood.2025028643","year":2026,"isNew":true,"title":"Modulators of the hepcidin pathway in polycythemia vera and myelofibrosis"},{"pmid":"42262970","doi":"10.1080/07853890.2026.2682982","year":2026,"isNew":true,"title":"Thrombotic burden and longitudinal outcomes in Thai patients with polycythemia vera"},{"pmid":"42381746","doi":"10.1016/j.radcr.2026.06.035","year":2026,"isNew":true,"title":"Extensive bilateral pulmonary embolism revealing iron deficiency-masked JAK2-positive polycythemia vera: A case report"},{"pmid":"42306077","doi":"10.1016/j.lana.2026.101529","year":2026,"isNew":true,"title":"Ropeginterferon alfa-2b-njft treatment in essential thrombocythemia across different driver mutations: results from a North American, single-arm, multicentre study (EXCEED-ET)"},{"pmid":"42575681","doi":"10.1136/bcr-2025-271701","year":2026,"isNew":true,"title":"First Philippine report of myeloproliferative neoplasms with concurrent &lt;i&gt;JAK2&lt;/i&gt; and &lt;i&gt;BCR::ABL1&lt;/i&gt; mutations"},{"pmid":"42566639","doi":"10.1097/md.0000000000050143","year":2026,"isNew":true,"title":"Ropeginterferon alfa-2b in Polycythemia Vera: A systematic review and meta-analysis"},{"pmid":"42176929","doi":"10.1016/j.cca.2026.121116","year":2026,"isNew":true,"title":"JAK2 V617F as a diagnostic and prognostic biomarker in myeloproliferative neoplasms"},{"pmid":"41902804","doi":"10.1016/j.mayocp.2026.01.008","year":2026,"isNew":true,"title":"Polycythemia vera"}],"trialsShown":[{"nct":"NCT06661915","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)"},{"nct":"NCT07357727","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF)"},{"nct":"NCT07012109","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Study of BEBT-507 Injection in Subjects With Polycythemia Vera (PV)"},{"nct":"NCT07232290","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Phase IIa Study of Flonoltinib Maleate Tablets in the Treatment of Patients With Polycythemia Vera"},{"nct":"NCT02577926","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"The Ruxo-BEAT Trial in Patients With High-risk Polycythemia Vera or High-risk Essential Thrombocythemia"},{"nct":"NCT05320198","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Study of DISC-0974 (RALLY-MF) in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia"},{"nct":"NCT06361641","phase":"NA","status":"RECRUITING","isNew":false,"title":"Functional and Phenotypic Characterization of Monocytes in Myeloproliferative Syndromes"},{"nct":"NCT00935090","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"3'-Deoxy-3'-[18F] Fluorothymidine PET Imaging in Patients With Cancer"}],"usage":{"input":11102,"output":7967},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"polycythemia vera\") AND (\"allele burden\" OR \"molecular response\" OR \"JAK2 V617F\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"polycythemia vera\") AND (rusfertide OR hepcidin OR \"iron restriction\" OR ropeginterferon) AND SRC:MED"],"evidenceIds":["PMID:41907306","PMID:41761659","PMID:41100735","PMID:42262970","PMID:42381746","PMID:42306077","PMID:42575681","PMID:42566639","PMID:42176929","PMID:41902804","NCT06661915","NCT07357727","NCT07012109","NCT07232290","NCT02577926","NCT05320198","NCT06361641","NCT00935090"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787169765193","cycle":102,"visit":2,"ts":"2026-08-19T20:02:45.193Z","cancer":{"key":"hodgkin lymphoma","name":"Hodgkin lymphoma","mondo":{"id":"MONDO:0004952","name":"Hodgkins lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Reframe the antigen-presentation axis in cHL: germline-instrumented high soluble β2M raises HL risk (PMID:39434879) rather than evidencing a somatic B2M-null subgroup, so demote the NK/missing-self lead and pivot to PD-1/LAG-3 co-blockade and extracellular-release CD30 ADCs for MHC-II-loss and CD30-","confidence":0.55,"notebook":"This visit's pack is HL-thin but not empty, and it forces one correction and two new hypotheses.\n\nThe single HL-specific datum is P1 (PMID:39434879): a bidirectional two-sample MR/GWMA in which genetically predicted circulating β2M raises Hodgkin lymphoma risk (UKB OR 2.27, 95% CI 1.53–3.38; FinnGen OR 1.58), with no reverse effect. Direction matters: this is *elevated* soluble β2M as a germline-instrumented risk factor, not somatic *loss* of B2M in HRS cells. It therefore does not evidence the B2M/HLA-I-null subgroup that L3 requires as its entry criterion; if anything it points the other way (higher HLA-I turnover/immune activation) [INFERRED]. Two consecutive visits have now failed to yield HL-restricted NK or B2M-null data — the NK lead is weakened to 0.24, kept alive only because P1's novel β2M loci include NLRC5, the CITA transactivator of HLA class I [KNOWN], which is a genuine new handle on antigen-presentation genetics in HL, and because P2 (PMID:41993707) supplies a concrete, repurposable NK-rescue mechanism (CD36-driven lipid loading → ferroptosis → exhaustion, reversed by NMN/NR) that is DLBCL-only and must be tested in HL before it earns anything.\n\nNew lead from P4 (PMID:41846252): PD-1/LAG-3 co-blockade in checkpoint-refractory cHL. cHL is the archetype of a tumour where MHC class II loss (CIITA/B2M rearrangement) accompanies expansion of LAG-3⁺ CD4 T cells in the HRS rosette [KNOWN]; the relatlimab-class bispecific/combination is already approved in melanoma per P4, so this is repurposing-first, testable as nivolumab+relatlimab in post-PD-1 relapse stratified by MHC-I/II status. Expected resistance: FGL1/galectin-3 ligand redundancy, TIM-3/TIGIT compensation, IFN-γ pathway loss making any T-cell-dependent strategy moot.\n\nSecond new lead from P3 (PMID:41866709): CD30-low/endocytosis-impaired relapse after brentuximab is precisely the failure mode non-internalizing, extracellularly-cleaved ADCs were designed for. Since HL is paucicellular and payload bystander diffusion into the reactive infiltrate is part of BV's mechanism (PMID:42070121), a protease- or redox-triggered extracellular-release CD30 conjugate is mechanistically well matched to the R/R population where BV benefit attenuated after adjustment (PMID:42432844). Preclinical only; confidence 0.3.\n\nL1 and L2 stand unchanged — nothing in the pack addresses CD30 IHC/9p24.1 stratification in NCT05675410 or NCT01896999, and no spatial-pathology data arrived. P5, P6, P7, P8, P9, P10 are off-target for HL except P6's EBV immune-evasion framing, which I log as a question (EBV⁺ vs EBV⁻ cHL as distinct checkpoint-response strata) rather than a lead.","leadChanges":[{"id":"L3","title":"NK-directed targeting of MHC-I-deficient HRS cells (CD30 NK engagers / CAR-NK)","level":"LEAD","status":"WEAKENED","confidence":0.24},{"id":"L4","title":"PD-1/LAG-3 co-blockade for checkpoint-refractory classical Hodgkin lymphoma stratified by MHC class I/II status","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L5","title":"Non-internalizing / extracellularly-cleaved CD30 ADC for CD30-low or endocytosis-impaired relapse after brentuximab vedotin","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does a somatic B2M/HLA class I-null cHL subgroup exist at measurable prevalence, and is it enriched among PD-1 blockade failures — or is the antigen-presentation lesion in cHL predominantly MHC class II/CIITA rather than class I?","Is NLRC5 (CITA) genotype or HRS expression associated with HL risk, HLA-I surface level, or checkpoint-inhibitor response, given its emergence as a novel β2M locus (PMID:39434879)?","What is the density and spatial distribution of LAG-3+ T cells relative to HRS cells in PD-1-refractory versus PD-1-sensitive cHL, and does it track with MHC class II loss?","Do EBV+ and EBV- cHL behave as distinct checkpoint-response strata, and is LMP1/2-directed T-cell therapy or EBV-specific T cells viable in checkpoint-refractory EBV+ cases?","Does CD30 IHC intensity, 9p24.1 copy number, or B2M/HLA-I status predict benefit from BV+nivolumab over ABVD-type chemotherapy in NCT05675410 and NCT01896999?","At what CD30 expression threshold does brentuximab vedotin fail in cHL, and is CD30 loss or MDR1 efflux the dominant acquired mechanism in serial biopsies?"],"nextQueries":["(\"Hodgkin lymphoma\" AND (LAG-3 OR LAG3 OR CIITA OR \"MHC class II\") AND (\"PD-1\" OR nivolumab OR pembrolizumab OR refractory)) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"Hodgkin\" AND (CD30 AND (\"antigen loss\" OR downregulation OR \"MDR1\" OR \"ABCB1\" OR \"brentuximab resistance\"))) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"Hodgkin lymphoma\" AND (\"spatial transcriptomics\" OR \"imaging mass cytometry\" OR \"digital pathology\" OR \"multiplex immunofluorescence\") AND (macrophage OR CD8 OR \"PD-L1\")) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"papersShown":[{"pmid":"39434879","doi":"10.3389/fimmu.2024.1448476","year":2024,"isNew":true,"title":"Causal relationship between beta-2 microglobulin and B-cell malignancies: genome-wide meta-analysis and a bidirectional two-sample Mendelian randomization study"},{"pmid":"41993707","doi":"10.1016/j.pscia.2026.100111","year":2026,"isNew":true,"title":"NAD&lt;sup&gt;+&lt;/sup&gt; precursor supplementation reverses CD36-mediated lipid accumulation and ferroptosis to restore antitumor function of NK cells in DLBCL"},{"pmid":"41866709","doi":"10.1080/10717544.2026.2645769","year":2026,"isNew":true,"title":"Extracellular payload release from non-internalizing antibody-drug conjugates: mechanisms and linker technologies"},{"pmid":"41846252","doi":"10.1080/07853890.2026.2643042","year":2026,"isNew":true,"title":"Research progress on the molecular mechanisms of PD-1 and LAG-3 synergy in regulating T cell exhaustion and immunotherapy"},{"pmid":"41179303","doi":"10.32604/or.2025.067445","year":2025,"isNew":true,"title":"Universal CAR-T Cell Therapy for Cancer Treatment: Advances and Challenges"},{"pmid":"42112354","doi":"10.3389/fimmu.2026.1791347","year":2026,"isNew":true,"title":"Epstein-Barr virus-associated tumors: commonalities in pathogenesis and the tumor immune microenvironment"},{"pmid":"41318108","doi":"10.1002/cnr2.70416","year":2025,"isNew":true,"title":"Prognostic Role of Beta-2 Microglobulin in Diffuse Large B-Cell Lymphoma: Systematic Review and Meta-Analysis of Observational Studies"},{"pmid":"41956548","doi":"10.1080/21645515.2026.2654318","year":2026,"isNew":true,"title":"Second primary cancers following hematologic malignancies: Epidemiology, pathobiology and clinical management"},{"pmid":"41800605","doi":"10.1080/07853890.2026.2640457","year":2026,"isNew":true,"title":"Preclinical advances and mechanistic insights of CAR-T therapy for acute myeloid leukemia: from target iteration to microenvironment regulation"},{"pmid":"42196444","doi":"10.3390/ijms27104464","year":2026,"isNew":true,"title":"Serum Protein Profiling of Patients at Risk to Develop Gastric Disease Based on a DSC Test"}],"trialsShown":[{"nct":"NCT01896999","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma"},{"nct":"NCT06724237","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Testing Whether High Dose Chemotherapy and Infusion of the Patients' Own Stem Cells Improves Survival in Patients With Peripheral T-cell Lym"},{"nct":"NCT00740805","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Veliparib, Cyclophosphamide, and Doxorubicin Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Non-Hodgkin "},{"nct":"NCT07630545","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Phase I Study in Healthy Volunteers and Parkinson's Disease (PD) Patients."},{"nct":"NCT03876769","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients"},{"nct":"NCT06549595","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study of Surovatamig (AZD0486) Plus Rituximab in Previously Untreated Follicular Lymphoma Patients"},{"nct":"NCT05675410","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study to Compare Standard Therapy to Treat Hodgkin Lymphoma to the Use of Two Drugs, Brentuximab Vedotin and Nivolumab"},{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"}],"usage":{"input":10602,"output":6957},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"Hodgkin lymphoma\" AND (\"9p24.1\" OR PD-L1 OR \"JAK2\") AND (resistance OR \"acquired resistance\" OR biomarker)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"Hodgkin lymphoma\" AND (B2M OR \"beta-2 microglobulin\" OR \"HLA class I\" OR \"antigen presentation\" OR \"natural killer\")) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"evidenceIds":["PMID:39434879","PMID:41993707","PMID:41866709","PMID:41846252","PMID:41179303","PMID:42112354","PMID:41318108","PMID:41956548","PMID:41800605","PMID:42196444","NCT01896999","NCT06724237","NCT00740805","NCT07630545","NCT03876769","NCT06549595","NCT05675410","NCT05006716"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787169549273","cycle":101,"visit":2,"ts":"2026-08-19T19:59:09.273Z","cancer":{"key":"mantle cell lymphoma","name":"mantle cell lymphoma","mondo":{"id":"MONDO:0018876","name":"mantle cell lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Eprenetapopt + palbociclib is synergistic in TP53-mutant/deleted, cyclin D1-driven MCL via ROS/DNA damage and UHRF1 loss (PMID:42068675) — prioritise this genotype-matched combination and test whether UHRF1 depletion demethylates the miR-146a promoter, while treating ATM/ATR synthetic lethality in M","confidence":0.5,"notebook":"This visit's pack is asymmetric: one MCL-specific primary paper and five pan-cancer DDR reviews. The reviews (PMID:38279263, PMID:39492835, PMID:40422251, PMID:38539474, PMID:41402978) confirm the general logic behind open question 2 — ATM-CHK2 inactivation forces dependence on ATR-CHK1, and CCNE1/MYC amplification or CDK4/6 blockade adds replication stress — but none contains MCL data. Record that as a negative search result: two visits of targeted querying have produced zero MCL-specific ATR/CHK1/WEE1 evidence, so any ATM-synthetic-lethality lead here rests on borrowed pan-cancer reasoning and must stay low-confidence until an MCL line/PDX panel is run. Likewise, the miR-146a/methylation query returned nothing new; L1 still stands on a single primary report and is weakened accordingly (not retired — its multi-model design remains the pack's best mechanistic work).\n\nThe substantive change is PMID:42068675: eprenetapopt (APR-246) plus palbociclib is synergistic in TP53-mutant/deleted MCL cells and CDX, with increased ROS, comet-assay DNA damage, apoptosis and no gross toxicity, and with UHRF1 identified as mediator by rescue/knockdown. Mechanistically this joins both remaining KG anchors to a druggable axis: CCND1 [SOMATIC] translocation makes cyclin D1-CDK4/6 the proliferative engine, palbociclib both arrests and — per PMID:38279263 — degrades repair/replication fidelity, while APR-246 depletes glutathione and raises ROS, so the lesions inflicted cannot be resolved. It also answers open question 3 in the affirmative for a defined genotype, and reframes it: the CDK4/6 partner may not be BTKi or venetoclax but a redox/p53-directed agent. New lead L6, 0.5, single paper.\n\nUHRF1 is the unexpected bridge. UHRF1 is the DNMT1 partner required for maintenance methylation [KNOWN], so a UHRF1-lowering combination should be tested for promoter demethylation — specifically whether it restores miR-146a-5p in ibrutinib-resistant models, which would fuse L1 and L6 into one epigenetic hypothesis and substitute for azacitidine. That is now the highest-value cheap experiment on the desk.\n\nTwo new trials matter. NCT07673367 (nemtabrutinib + brexu-cel, R/R MCL) tests whether non-covalent BTKi given around CAR-T improves T-cell fitness and durability — directly probing open questions 4/5 and worth its own lead. NCT06980116 (EXS73565) and NCT06667687 (ABBV-291) are new-mechanism B-cell agents whose targets I will not assert from the registry text [SPECULATIVE]; flag for mechanism confirmation next visit rather than build on them.\n\nWindows: palbociclib neutropenia; APR-246 GSH depletion with neuro/cardiac liability; ATR inhibitors hit ATR-dependent HSCs. Escape routes: RB1 loss and cyclin E-CDK2 for palbociclib, NRF2/SLC7A11-restored glutathione for APR-246, true p53-null status blunting reactivation.","leadChanges":[{"id":"L1","title":"Restore miR-146a-5p / block MAPK-ERK+PI3K-AKT to reverse non-genetic ibrutinib resistance","level":"LEAD","status":"WEAKENED","confidence":0.45},{"id":"L6","title":"Eprenetapopt + palbociclib in TP53-altered, CCND1-driven MCL: redox/replication-stress synthetic lethality","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L7","title":"ATR/CHK1/WEE1 inhibition in ATM-altered, replication-stressed MCL — hypothesis without MCL data","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L8","title":"Non-covalent BTK inhibition around CD19 CAR-T: nemtabrutinib + brexu-cel in R/R MCL","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["Does UHRF1 depletion (by eprenetapopt+palbociclib or shRNA) demethylate the miR-146a promoter and restore miR-146a-5p and ibrutinib sensitivity, i.e. do L1 and L6 share one epigenetic node?","Is eprenetapopt+palbociclib synergy genuinely TP53-genotype-restricted (mut vs null vs wildtype), and is RB1 loss or cyclin E-CDK2 upregulation the dominant escape route?","Does any MCL-specific dataset exist for ATR/CHK1/WEE1 or PKMYT1 inhibition in ATM-altered disease — and if not by next visit, should the ATM anchor be retired as non-actionable in MCL?","What are the disclosed molecular targets of EXS73565 (NCT06980116) and ABBV-291 (NCT06667687), and do either overlap BTK degradation or ROR1/CD19 biology already on the board?","In post-CD19 CAR-T relapse, what fraction retain CD19 by biopsy, and does adding a non-covalent BTKi (NCT07673367) rescue T-cell-failure relapses specifically?","Can BCL2-inhibitor resistance (G101V vs MCL1/BCL-XL upregulation) be predicted before sonrotoclax exposure in the CELESTIAL-RRMCL population?"],"nextQueries":["\"mantle cell lymphoma\" AND (UHRF1 OR \"APR-246\" OR eprenetapopt OR palbociclib OR \"CDK4/6\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","\"mantle cell lymphoma\" AND (WEE1 OR PKMYT1 OR \"CHK1\" OR ceralasertib OR elimusertib OR \"CDK2\" OR \"cyclin E\") AND SRC:MED","\"mantle cell lymphoma\" AND (\"CAR T\" OR brexucabtagene) AND (relapse OR \"CD19 loss\" OR nemtabrutinib OR bridging) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"38279263","doi":"10.3390/ijms25021263","year":2024,"isNew":true,"title":"Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets"},{"pmid":"38539474","doi":"10.3390/cancers16061139","year":2024,"isNew":true,"title":"Triple-Negative Breast Cancer and Emerging Therapeutic Strategies: ATR and CHK1/2 as Promising Targets"},{"pmid":"39492835","doi":"10.1002/mco2.788","year":2024,"isNew":true,"title":"Targeting the DNA damage response in cancer"},{"pmid":"40422251","doi":"10.3390/cells14100748","year":2025,"isNew":true,"title":"Cancer Vulnerabilities Through Targeting the ATR/Chk1 and ATM/Chk2 Axes in the Context of DNA Damage"},{"pmid":"41402978","doi":"10.1186/s12957-025-04101-9","year":2025,"isNew":true,"title":"Research progress of DNA damage repair (DDR) and DDR inhibitors in tumor immunotherapy"},{"pmid":"42068675","doi":"10.1016/j.tranon.2026.102794","year":2026,"isNew":true,"title":"Eprenetapopt in combination with Palbociclib exerts synthetic lethality in mantle cell lymphoma"},{"pmid":"42142763","doi":"10.1016/j.bcp.2026.118058","year":2026,"isNew":true,"title":"Nanoparticle-Based delivery of proteasome inhibitors for glioblastoma Therapy: Strategies to overcome Blood-Brain barrier and therapeutic resistance"},{"pmid":"42303626","doi":"10.1038/s41392-026-02729-x","year":2026,"isNew":true,"title":"Non-receptor tyrosine kinase signaling pathways and therapeutic implications"},{"pmid":"42226293","doi":"10.1186/s44342-026-00074-7","year":2026,"isNew":true,"title":"Precision Medicine Gene Network Analyser: part I-cancer driver gene identification through network topology and ensemble machine learning"},{"pmid":"41861100","doi":"10.1002/advs.202600027","year":2026,"isNew":true,"title":"Tumor-Induced Splenic Remodeling: Mechanisms of Systemic Immunosuppression and Emerging Therapeutic Opportunities"}],"trialsShown":[{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06742996","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study to Investigate the Efficacy and Safety of Sonrotoclax Plus Zanubrutinib Compared With Placebo Plus Zanubrutinib in Adults With Relap"},{"nct":"NCT07673367","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Nemtabrutinib With CAR T Therapy in Relapsed/Refractory Mantle Cell Lymphoma"},{"nct":"NCT06667687","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study to Evaluate Adverse Events, Change in Disease Activity, and How Intravenously Infused ABBV-291 Moves Through the Body in Adult Partici"},{"nct":"NCT05458297","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of Zilovertamab Vedotin (MK-2140) as Monotherapy and in Combination in Participants With Aggressive and Indolent B-cell Malignancies"},{"nct":"NCT06980116","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Dose Determining Study of EXS73565 in Participants With Relapsed or Refractory B-Cell Malignancies"},{"nct":"NCT05495464","phase":"EARLY_phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Pilot \"Window-3\" Study of Acalabrutinib Plus Rituximab Followed by Brexucabtagene Autoleucel Therapy in Patients With Previously Untreated"},{"nct":"NCT06564038","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study of AZD0486 Monotherapy or in Combination With Other Anti-Cancer Agents for Mature B-Cell Malignancies"}],"usage":{"input":11696,"output":7064},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"mantle cell lymphoma\" AND (\"miR-146a\" OR \"microRNA\" OR \"DNA methylation\" OR azacitidine OR decitabine) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"mantle cell lymphoma\" AND (ATM OR \"ATR inhibitor\" OR ceralasertib OR elimusertib OR \"synthetic lethality\") AND SRC:MED"],"evidenceIds":["PMID:38279263","PMID:38539474","PMID:39492835","PMID:40422251","PMID:41402978","PMID:42068675","PMID:42142763","PMID:42303626","PMID:42226293","PMID:41861100","NCT05006716","NCT06742996","NCT07673367","NCT06667687","NCT05458297","NCT06980116","NCT05495464","NCT06564038"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787169334748","cycle":100,"visit":2,"ts":"2026-08-19T19:55:34.748Z","cancer":{"key":"follicular lymphoma","name":"follicular lymphoma","mondo":{"id":"MONDO:0018906","name":"follicular lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Epcoritamab+R2 outperformed real-world R2/chemoimmunotherapy in R/R FL (ORR 96.9% vs 80.5%, DoR HR 0.29), promoting the CD3-engager-displaces-chemotherapy lead to CANDIDATE while the antigen-loss/exhaustion resistance question remains entirely unaddressed.","confidence":0.55,"notebook":"The pack delivers one genuinely clinical result and two useful biology anchors; the rest is off-target (P1, P5 melanoma, P7, P8, P10).\n\n**L1 promoted to CANDIDATE.** PMID:42415230 gives the first outcome data in this programme: epcoritamab + R² in R/R FL (EPCORE NHL-2 arm 2, NCT04663347) versus a COTA real-world R²/CIT cohort — ORR 96.9% vs 80.5%, DoR HR 0.29. Caveat stated plainly: this is an adjusted external-control comparison, not randomised, single-arm-vs-EHR confounding is unquantifiable from the abstract, and it tests an engager *plus* lenalidomide rather than engager displacement of chemotherapy. Still, it is the first evidence that CD3xCD20 redirection outperforms a chemoimmunotherapy standard in FL, which is exactly the premise the two phase 3s (NCT06337318, NCT06549595) test prospectively. No antigen-loss, trogocytosis or exhaustion data appeared in the pack despite the targeted query — open question 1 remains completely unanswered and is the main risk to L1.\n\n**L3 strengthened but deliberately not promoted.** PMID:41436233 supplies the missing mechanistic half: MHC-II-dependent CD4+ cytotoxic T cells are a real effector population, so class II loss removes an endogenous killing arm and plausibly the arm lenalidomide re-arms, while CD3 engagers crosslink CD4 and CD8 T cells irrespective of peptide-MHC [INFERRED]. PMID:41137062 is FL-specific and closer to the point: CREBBP/KMT2D/CARD11/STAT6 mutations co-occur with *downregulated immune-associated pathways* and with POD24 risk in 403 sequenced FL. That is correlative transcriptomics, not MHC-II protein, so I withhold CANDIDATE until HLA-DR IHC or class II gene-set data are in hand.\n\n**L2 weakened (0.40→0.32).** CARD11 mutation enrichment in high-risk/extranodal FL (PMID:41137062) is a structurally BTK-independent NF-κB route [KNOWN], i.e. an a priori resistance population in exactly the patients most in need; and P6 raises the bar the zanubrutinib arm of NCT05100862 must clear. No FL-specific BGB-16673 response data this visit.\n\n**New L4** on POD24/extranodal biology: STAT6 (IL-4/IL-13→JAK1-STAT6, TFH-derived ligand) and CARD11 as node-specific dependencies in the high-risk subset, testable as JAK1 inhibition or IL4R blockade layered on an MHC-independent engager (PMID:41137062, PMID:41337699).\n\n**Notebook, do-not-repropose:** PMID:42255257 — venetoclax added to R-GDP in R/R LBCL reached CR 12.5% with no EFS/OS gain versus contemporaneous R-GDP. Different disease, but it further discourages naive BCL2-inhibitor-plus-chemotherapy designs in t(14;18) FL absent an MCL1/BFL1 co-dependency read-out (open question 5 still unanswered).","leadChanges":[{"id":"L1","title":"CD3 bispecific engagers displace chemoimmunotherapy in t(14;18)/BCL2-driven FL","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.68},{"id":"L2","title":"BTK degradation vs occupancy: is chronic active BCR signalling a maintenance dependency in FL?","level":"LEAD","status":"WEAKENED","confidence":0.32},{"id":"L3","title":"MHC class II (HLA-DRB1 anchor) status as the stratifier splitting immunomodulatory from MHC-independent immunotherapy in FL","level":"LEAD","status":"STRENGTHENED","confidence":0.45},{"id":"L4","title":"POD24/multi-extranodal FL as a distinct dependency class: STAT6-IL-4/JAK and CARD11-NF-kB on an MHC-independent effector backbone","level":"LEAD","status":"NEW","confidence":0.34}],"unverifiedCitations":1,"openQuestions":["Still unanswered: what are the mechanisms of relapse after CD20xCD3 engagers in FL (CD20 truncating/splice mutations, surface density loss, trogocytosis, TOX/PD-1-hi exhaustion), and does prior engager exposure cross-resist to CD19 CAR-T or","In epcoritamab+R2, is lenalidomide additive or dispensable, and does MHC-II/HLA-DR-low status selectively erode the R2 contribution while sparing engager activity?","Is granzyme B+ MHC-II-restricted CD4 CTL frequency in the FL follicular niche an independent predictor of response to lenalidomide-based versus engager-based therapy?","Do STAT6 hotspot and CARD11 mutations define an IL-4/JAK-dependent, BCR-independent high-risk FL subset, and does JAK1 inhibition antagonise or cooperate with T-cell engager killing in autologous assays?","Which anti-apoptotic co-dependency (MCL1, BCL-XL, BFL1) explains venetoclax underperformance in t(14;18) FL, given that venetoclax added to R-GDP failed to improve EFS/OS in R/R LBCL?","Does BTK degradation (BGB-16673) produce FL-specific responses in CARD11-mutant or BCR-signalling-low tumours, i.e. is the FL BTK dependency real outside a molecular subset?"],"nextQueries":["(\"follicular lymphoma\" AND (mosunetuzumab OR epcoritamab OR glofitamab OR odronextamab) AND (relapse OR \"CD20 loss\" OR trogocytosis OR \"T-cell exhaustion\" OR \"paired biopsies\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"follicular lymphoma\" AND (STAT6 OR CARD11 OR \"IL-4\" OR JAK1) AND (mutation OR signaling OR microenvironment OR \"follicular helper\")) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]","(\"follicular lymphoma\" AND (venetoclax OR MCL1 OR BCL-XL OR BFL1 OR BCL2A1) AND (resistance OR combination OR \"BH3 profiling\")) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"papersShown":[{"pmid":"41560619","doi":"10.1080/19420862.2026.2614669","year":2026,"isNew":true,"title":"Antibodies to watch in 2026"},{"pmid":"41436233","doi":"10.1136/jitc-2025-013461","year":2025,"isNew":true,"title":"Cytotoxic CD4+ T cells in cancer: an emerging target for next-generation anticancer immunotherapy?"},{"pmid":"41137062","doi":"10.1186/s13073-025-01557-y","year":2025,"isNew":true,"title":"Clinical characteristics and molecular heterogeneity in Follicular lymphoma with extranodal involvement"},{"pmid":"41337699","doi":"10.1182/bloodadvances.2025018079","year":2026,"isNew":true,"title":"Consensus recommendations from the 2024 International Follicular Lymphoma Scientific Workshop"},{"pmid":"42220432","doi":"10.32604/or.2026.077913","year":2026,"isNew":true,"title":"EZH2 in Acral Lentiginous Melanoma: Molecular, Epigenetic, and Therapeutic Perspectives"},{"pmid":"42415230","doi":"10.1080/2162402x.2026.2691549","year":2026,"isNew":true,"title":"Comparison of epcoritamab, lenalidomide, and rituximab versus usual care in relapsed/refractory follicular lymphoma"},{"pmid":"42033215","doi":"10.1080/15384047.2026.2658896","year":2026,"isNew":true,"title":"Advances in natural killer cell immunotherapy for hematologic malignancies"},{"pmid":"41700001","doi":"10.1080/2162402x.2026.2632421","year":2026,"isNew":true,"title":"Trial Watch - bispecific T cell engagers and higher-order multispecific immunotherapeutics"},{"pmid":"42255257","doi":"10.1016/j.bneo.2026.100233","year":2026,"isNew":true,"title":"A phase 1 study of R-GDP-venetoclax before autologous transplant in relapsed/refractory large B-cell lymphoma (CCTG LY.18)"},{"pmid":"42318525","doi":"10.1002/mco2.70808","year":2026,"isNew":true,"title":"Chemical-Assembled Macrophage-Engaging Glypican-3 × Signal Regulatory Protein-α (SIRP-α) Bispecific Antibody for Immunotherapy Against Liver Cancer"}],"trialsShown":[{"nct":"NCT06724237","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Testing Whether High Dose Chemotherapy and Infusion of the Patients' Own Stem Cells Improves Survival in Patients With Peripheral T-cell Lym"},{"nct":"NCT07630545","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Phase I Study in Healthy Volunteers and Parkinson's Disease (PD) Patients."},{"nct":"NCT06549595","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study of Surovatamig (AZD0486) Plus Rituximab in Previously Untreated Follicular Lymphoma Patients"},{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06860594","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Testing the Addition of an Anti-Cancer Drug, Triapine, to the Usual Radiation Therapy for Recurrent Glioblastoma or Astrocytoma"},{"nct":"NCT02390869","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Rituximab and Lenalidomide vs Rituximab Alone as Maintenance After R-chemoterapy for Relapsed/Refractory FL Patients"},{"nct":"NCT05100862","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of Zanubrutinib Plus Anti-CD20 Versus Lenalidomide Plus Rituximab in Participants With Relapsed/Refractory Follicular or Marginal Zo"},{"nct":"NCT06337318","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Comparing Rituximab and Mosunetuzumab Drug Treatments for People With Low Tumor Burden Follicular Lymphoma"}],"usage":{"input":10730,"output":7429},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"follicular lymphoma\" AND (mosunetuzumab OR epcoritamab OR glofitamab OR \"bispecific antibody\") AND (resistance OR \"antigen loss\" OR \"CD20 mutation\" OR exhaustion)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"follicular lymphoma\" AND (CREBBP OR EZH2 OR \"MHC class II\" OR HLA-DR) AND (immune OR \"antigen presentation\" OR microenvironment)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41560619","PMID:41436233","PMID:41137062","PMID:41337699","PMID:42220432","PMID:42415230","PMID:42033215","PMID:41700001","PMID:42255257","PMID:42318525","NCT06724237","NCT07630545","NCT06549595","NCT05006716","NCT06860594","NCT02390869","NCT05100862","NCT06337318"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787169115325","cycle":99,"visit":2,"ts":"2026-08-19T19:51:55.325Z","cancer":{"key":"diffuse large b-cell lymphoma","name":"diffuse large B-cell lymphoma","mondo":{"id":"MONDO:0018905","name":"diffuse large B-cell lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"BTK degradation in ABC/MCD-DLBCL is promoted to CANDIDATE on class-level evidence that degraders survive C481S/T474/L528 kinase-domain mutations while covalent and non-covalent inhibitors are mutually cross-resistant, with MALT1 protease inhibition opened as the distal bypass for CARD11/PLCG2-mediat","confidence":0.45,"notebook":"This visit's pack answered open question 3 largely in the negative-by-absence. The BTK-degrader query returned four reviews (PMID:39941922, PMID:38578606, PMID:39456530, PMID:40719810) plus three CLL landscape reviews (PMID:41303291, PMID:40723181, PMID:39941798) and no DLBCL-specific degrader efficacy or resistance dataset. What the pack does deliver is class-level mechanistic corroboration that was previously carried as [KNOWN]/[INFERRED] on L3: covalent BTKi resistance runs through C481S and PLCG2 (PMID:39456530); non-covalent pirtobrutinib overcomes C481 but is defeated by kinase-domain mutations at T474 and L528, and — decisively — zanubrutinib and acalabrutinib are cross-resistant to those same non-covalent-selected mutations, so covalent-after-non-covalent sequencing is not a rescue strategy (PMID:38578606). BTK L528W is described as kinase-inactivating (PMID:38578606), which mechanistically implies BCR signalling can proceed through kinase-independent BTK scaffold function [INFERRED]; that is the strongest argument yet for degradation over occupancy, and preclinically degraders overcome common BTK mutations (PMID:39941922). I therefore move L3 to CANDIDATE, but with an explicit caveat: all of this corroboration is CLL/SLL-derived review-level evidence, and no DLBCL response rate, MCD-genotype breakdown, or emergent-mutation catalogue exists in this pack. Confidence rises only modestly.\n\nRecorded as a design constraint for the desk: do not propose covalent-BTKi salvage after non-covalent BTKi failure (cross-resistance, PMID:38578606); and do not assume kinase-inhibitor-refractory equals BTK-pathway-independent, since L528W-type kinase-dead alleles retain scaffold signalling.\n\nNew lead L6: MALT1 protease inhibition as a distal bypass of proximal BCR resistance. PMID:40723181 lists MALT1 inhibitors among agents advancing for double-refractory B-cell disease. In ABC/MCD-DLBCL the CARD11–BCL10–MALT1 complex sits downstream of BTK, so CARD11 gain-of-function and PLCG2 mutations — the exact escape routes named for L3 — should remain MALT1-dependent [KNOWN/INFERRED]. Normal-tissue caveat: MALT1 protease loss impairs Treg fitness and can precipitate autoimmunity in mice [KNOWN], so the window argument is immune, not haematopoietic. Pack evidence is CLL-review-level only; confidence 0.35.\n\nL1 (METTL3/CTNNB1/YTHDF2) is weakened. A dedicated Europe PMC query for DLBCL m6A/METTL3/STM2457 across 2023–2026 returned nothing new, so PMID:42242087 remains a single-line, single-xenograft result whose YTHDF2-mediated stabilisation still contradicts canonical YTHDF2 decay function. No replication, no independent axis support: 0.45 → 0.35. L2, L4, L5 saw no relevant evidence (the pack's NK-engager, FDX1-cuproptosis and palladium-chemistry reviews are off-target noise and are not cited).\n\nNext I need DLBCL-restricted degrader data and any lymphoma MALT1 preclinical/clinical readout.","leadChanges":[{"id":"L3","title":"BTK degradation plus BCL2/NF-κB co-targeting in ABC/MCD-like DLBCL","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55},{"id":"L6","title":"MALT1 protease inhibition to bypass proximal BCR-resistance mutations in ABC/MCD-DLBCL","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L1","title":"METTL3 inhibition to reverse rituximab resistance in double-expressor DLBCL","level":"LEAD","status":"WEAKENED","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["What is the DLBCL-specific ORR/CR of BGB-16673 and NX-5948 in the dose-expansion cohorts, broken down by LymphGen genotype and by prior covalent/non-covalent BTKi exposure?","Which mutations emerge on BTK degraders in DLBCL specifically — cereblon/CRBN neosubstrate-interface changes, E3 machinery loss, or distal CARD11/PLCG2 — and do they preserve sensitivity to MALT1 inhibition?","Does MALT1 protease inhibition kill CARD11-mutant and BTK-degrader-resistant ABC-DLBCL models, and at what cost to Treg-dependent immune tolerance?","Is there any DLBCL-selective therapeutic window for OGT inhibition, i.e. does O-GlcNAc loss spare normal B and myeloid progenitors at active doses?","Which selector — interim PET versus ctDNA MRD — identifies frontline patients who benefit from engager intensification (NCT04980222), and do TGF-β-driven M2 macrophages predict engager failure?","In EZB/GCB genotypes, does dual PI3K/HDAC inhibition (BEBT-908, NCT06792253) show genotype-restricted benefit and phenocopy EZH2 inhibition?"],"nextQueries":["(\"diffuse large B-cell lymphoma\" OR \"DLBCL\") AND (BGB-16673 OR NX-5948 OR NX-2127 OR \"BTK degrader\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(MALT1 AND (inhibitor OR protease)) AND (lymphoma OR \"activated B-cell\" OR CARD11) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"diffuse large B-cell lymphoma\" AND (OGT OR \"O-GlcNAc\" OR OGA) AND (venetoclax OR apoptosis OR toxicity)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"39941922","doi":"10.3390/cancers17030557","year":2025,"isNew":true,"title":"BTK Is the Target That Keeps on Giving: A Review of BTK-Degrader Drug Development, Clinical Data, and Future Directions in CLL"},{"pmid":"38578606","doi":"10.1158/1078-0432.ccr-23-0409","year":2024,"isNew":true,"title":"New Means and Challenges in the Targeting of BTK"},{"pmid":"39456530","doi":"10.3390/cancers16203434","year":2024,"isNew":true,"title":"Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B-Cell Lymphoid Malignancies"},{"pmid":"40719810","doi":"10.1007/s00277-025-06515-7","year":2025,"isNew":true,"title":"Next-generation Bruton tyrosine kinase inhibitors and degraders in the treatment of B-cell malignancies: advances and challenges"},{"pmid":"41303291","doi":"10.3390/jcm14228247","year":2025,"isNew":true,"title":"The Development of Novel Therapies for Chronic Lymphocytic Leukaemia in the Era of Targeted Drugs"},{"pmid":"40723181","doi":"10.3390/cancers17142298","year":2025,"isNew":true,"title":"Chronic Lymphocytic Leukemia: Novel Therapeutic Targets Under Investigation"},{"pmid":"39941798","doi":"10.3390/cancers17030430","year":2025,"isNew":true,"title":"Improving Treatment Options for Patients with Double Refractory CLL"},{"pmid":"42033215","doi":"10.1080/15384047.2026.2658896","year":2026,"isNew":true,"title":"Advances in natural killer cell immunotherapy for hematologic malignancies"},{"pmid":"41693699","doi":"10.1080/14756366.2026.2621477","year":2026,"isNew":true,"title":"Palladium-catalysed synthesis of small-molecule epigenetic inhibitors as anticancer therapeutics"},{"pmid":"41853121","doi":"10.1016/j.cpt.2025.11.002","year":2026,"isNew":true,"title":"Role of Ferredoxin 1 &lt;i&gt;(FDX1)&lt;/i&gt; in cancer and its therapeutic potential"}],"trialsShown":[{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06792253","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Study Comparing BEBT-908 Combined With R to SOC for the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma"},{"nct":"NCT04104776","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas"},{"nct":"NCT06781359","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Study on Plasmablastic Lymphoma Patients"},{"nct":"NCT03226704","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Leukapheresis for CAR or Adoptive Cell Therapy Manufacturing"},{"nct":"NCT03223610","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (ViPOR) in Relapsed/Refractory B-cell Lymphoma"},{"nct":"NCT04980222","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate the Safety and Efficacy of Glofitamab in Combination With Rituximab (R) Plus Cyclophosphamide, Doxorubicin, Vincristine,"},{"nct":"NCT02203526","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (TEDDI-R) in Pri"}],"usage":{"input":10841,"output":5535},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"diffuse large B-cell lymphoma\" AND (METTL3 OR m6A OR STM2457) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"diffuse large B-cell lymphoma\" AND (\"BTK degrader\" OR BGB-16673 OR NX-5948 OR \"pirtobrutinib\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:39941922","PMID:38578606","PMID:39456530","PMID:40719810","PMID:41303291","PMID:40723181","PMID:39941798","PMID:42033215","PMID:41693699","PMID:41853121","NCT05006716","NCT06792253","NCT04104776","NCT06781359","NCT03226704","NCT03223610","NCT04980222","NCT02203526"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787168922247","cycle":98,"visit":2,"ts":"2026-08-19T19:48:42.247Z","cancer":{"key":"waldenstrom macroglobulinemia","name":"Waldenstrom macroglobulinemia","mondo":{"id":"MONDO:0100280","name":"Waldenstrom macroglobulinemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Multiple independent 2024–2026 reviews establish that non-C481 BTK mutations (T474I, L528W) cross-resist both covalent and non-covalent BTKi while BTK retains a kinase-independent scaffolding function (TLR9/HCK/ILK), making BTK degradation — not occupancy — the mechanistically correct strategy for M","confidence":0.56,"notebook":"This visit's pack is CLL-weighted — query drift toward the larger disease — but it is mechanistically load-bearing for L2 and largely silent on imaging.\n\nFour independent 2024–2026 reviews (PMID:38478390, PMID:38578606, PMID:39062757, PMID:39456530) converge on the same resistance architecture: C481 mutations defeat covalent BTKi; pirtobrutinib is C481-agnostic but selects T474I and L528W; and those non-C481 kinase-domain alleles are cross-resistant back to zanubrutinib and acalabrutinib (PMID:38578606). PMID:39062757 supplies the mechanistic reason my lead needed: BTK acts as a non-catalytic scaffold assembling TLR9, HCK, VCAM-1 and ILK, so kinase-dead alleles (L528W, C481F/Y/R) still support survival signalling. In MYD88 L265P WM, where HCK is the documented myddosome-to-BTK bridge, loss of catalysis with retained scaffolding predicts that occupancy-based inhibition is intrinsically insufficient and that degradation is the mechanistically correct modality [INFERRED]. All four reviews name BTK degraders (PROTACs) as active against C481 and non-C481 variants in vitro. This is new, independent, multi-source corroboration of L2's core mechanism, so L2 moves to CANDIDATE — with the explicit caveat that every allele frequency cited is CLL-derived; no WM-specific L528W/T474I incidence appears in this pack, which keeps open question 2 alive.\n\nL1 gains tooling, not biology. PMID:42102951 describes a single-tube multiplex allele-specific qPCR detecting MYD88 L265P and CXCR4 S338* (C>G and C>A) simultaneously — a cheap stratification and potential MRD readout for the pentixafor-guided trial design, and it restates that BTKi are less effective in MYD88/CXCR4 double-mutant disease. Two cautions: a corrigendum exists (PMID:42493305), so I will not lean on the quoted sensitivity figures, and PMID:42544657 reports CXCR4 mutations in only 3/17 tested patients (17.6%) versus MYD88 82.4% (28/34), with incomplete testing — the addressable CXCR4 population may be smaller than the canonical 30–40%. Net: modest strengthening of feasibility, no confidence promotion, and no new pentixafor imaging data at all.\n\nL3 gains only a passing mention of MALT1 inhibitors within a CLL novel-target survey (PMID:40723181); EXS73565's target remains undisclosed in the pack, so my MALT1 attribution stays unverified and confidence stays low.\n\nNew at low confidence: PMID:41303291 and PMID:41741806 describe venetoclax escape running through AKT-dependent stabilisation of alternative BCL2-family members and BAK/BAX pore disruption, plus next-generation sonrotoclax/lisaftoclax and MRD-guided fixed duration. This is a testable but wholly CLL-extrapolated frame for post-BTKi WM; it must be validated with WM-specific BCL2 dependency data before it earns anything.\n\nNotebook: do not re-derive CLL BTKi resistance taxonomy next visit; the open gap is WM-specific allele spectra and WM BCL2 data.","leadChanges":[{"id":"L2","title":"BTK degradation and non-covalent BTK occupancy for BTKi-resistant MYD88-mutant WM","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.62},{"id":"L1","title":"Pentixafor-guided CXCR4 antagonism to eradicate BTKi-persistent WM clones","level":"LEAD","status":"STRENGTHENED","confidence":0.56},{"id":"L3","title":"Bypassing BTK entirely: MALT1/IRAK4 blockade downstream of the L265P myddosome","level":"LEAD","status":"STRENGTHENED","confidence":0.33},{"id":"L5","title":"BCL2-axis dependence and MRD-guided fixed duration in post-BTKi WM","level":"LEAD","status":"NEW","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["What is the actual spectrum and frequency of BTK C481S/T474I/L528W and PLCG2 alleles at progression in WM specifically (not CLL), and does BGB-16673 clear L528W-bearing WM clones?","Does 68Ga-pentixafor uptake in BTKi-treated WM track CXCR4 S338* genotype and MYD88 L265P marrow MRD, or merely tumour bulk?","What is the true CXCR4-mutation prevalence in systematically tested WM cohorts, given only 3/17 tested patients in PMID:42544657 — does this shrink the mavorixafor/ulocuplumab-eligible population?","What is EXS73565's disclosed molecular target, and is MALT1 or IRAK4 the superior MYD88-L265P-downstream node in WM models including BTK-L528W isogenics?","Is there any WM-specific BH3-profiling or venetoclax/sonrotoclax response data to justify a BCL2-axis lead, or should it be retired as CLL extrapolation?","Why does anti-MAG neuropathy disability persist after clone-directed therapy, and is complement blockade or IgM clearance needed rather than deeper clone suppression?"],"nextQueries":["(\"Waldenstrom\" OR \"lymphoplasmacytic lymphoma\") AND (venetoclax OR sonrotoclax OR \"BH3 profiling\" OR BCL2 OR MCL1) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"Waldenstrom\" OR \"MYD88 L265P\") AND (\"BTK mutation\" OR PLCG2 OR \"acquired resistance\") AND (zanubrutinib OR ibrutinib OR pirtobrutinib) AND SRC:MED","(\"anti-MAG\" OR \"IgM neuropathy\" OR \"Bing-Neel\") AND (rituximab OR ibrutinib OR complement OR \"efgartigimod\" OR plasmapheresis) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"38478390","doi":"10.1182/bloodadvances.2023012221","year":2024,"isNew":true,"title":"BTK inhibitors in CLL: second-generation drugs and beyond"},{"pmid":"38578606","doi":"10.1158/1078-0432.ccr-23-0409","year":2024,"isNew":true,"title":"New Means and Challenges in the Targeting of BTK"},{"pmid":"39062757","doi":"10.3390/ijms25147516","year":2024,"isNew":true,"title":"The Evolving Role of Bruton's Tyrosine Kinase Inhibitors in B Cell Lymphomas"},{"pmid":"39456530","doi":"10.3390/cancers16203434","year":2024,"isNew":true,"title":"Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B-Cell Lymphoid Malignancies"},{"pmid":"41303291","doi":"10.3390/jcm14228247","year":2025,"isNew":true,"title":"The Development of Novel Therapies for Chronic Lymphocytic Leukaemia in the Era of Targeted Drugs"},{"pmid":"40723181","doi":"10.3390/cancers17142298","year":2025,"isNew":true,"title":"Chronic Lymphocytic Leukemia: Novel Therapeutic Targets Under Investigation"},{"pmid":"41741806","doi":"10.1007/s11899-026-00776-3","year":2026,"isNew":true,"title":"When Targeted Therapy Falls Short: Unraveling Resistance Mechanisms in Chronic Lymphocytic Leukemia"},{"pmid":"42102951","doi":"10.1016/j.clinbiochem.2026.111141","year":2026,"isNew":true,"title":"Rapid and highly sensitive detection of MYD88/CXCR4 mutations in Waldenström macroglobulinemia by MAS-qPCR: A pilot study"},{"pmid":"42493305","doi":"10.1016/j.clinbiochem.2026.111173","year":2026,"isNew":true,"title":"Corrigendum to \"Rapid and highly sensitive detection of MYD88/CXCR4 mutations in Waldenström macroglobulinemia by MAS-qPCR: A pilot study\" [Clin. Biochem. 144 (2026) 111141]"},{"pmid":"42544657","doi":"10.19746/j.cnki.issn1009-2137.2026.03.012","year":2026,"isNew":true,"title":"[Clinical Characteristics and Prognosis of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia]"}],"trialsShown":[{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT00923507","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphopla"},{"nct":"NCT04728893","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)"},{"nct":"NCT06980116","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Dose Determining Study of EXS73565 in Participants With Relapsed or Refractory B-Cell Malignancies"},{"nct":"NCT00039676","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Clinical, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Hematologic Cancer"},{"nct":"NCT06340737","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"AutologousCD22 Chimeric Antigen Receptor (CAR)T Cells in w/Recurrent/Refractory B Cell Lymphomas"},{"nct":"NCT07426484","phase":"phase 4","status":"RECRUITING","isNew":false,"title":"Cosibelimab for CSCC in Patients With Kidney Transplant or Hematologic Malignancy"},{"nct":"NCT07169331","phase":"phase 4","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate the Efficacy and Safety of Zanubrutinib in Chinese Adults With Treatment-Naive Waldenström Macroglobulinemia"}],"usage":{"input":10341,"output":6422},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"Waldenstrom\" OR \"lymphoplasmacytic lymphoma\") AND (CXCR4 OR pentixafor OR mavorixafor OR ulocuplumab) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"Waldenstrom\" OR \"MYD88 L265P\") AND (\"BTK degrader\" OR BGB-16673 OR NX-5948 OR pirtobrutinib OR \"L528W\" OR \"C481S\") AND SRC:MED"],"evidenceIds":["PMID:38478390","PMID:38578606","PMID:39062757","PMID:39456530","PMID:41303291","PMID:40723181","PMID:41741806","PMID:42102951","PMID:42493305","PMID:42544657","NCT05006716","NCT00923507","NCT04728893","NCT06980116","NCT00039676","NCT06340737","NCT07426484","NCT07169331"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787168718883","cycle":97,"visit":2,"ts":"2026-08-19T19:45:18.883Z","cancer":{"key":"multiple myeloma","name":"multiple myeloma","mondo":{"id":"MONDO:0009693","name":"plasma cell myeloma"}},"control":false,"modelLabel":"SCIENCE","summary":"Antigen switching after bispecific failure is now supported by three independent datasets (GPRC5D→BCMA, BCMA→GPRC5D, and FcRH5/cevostamab in BCMA-pretreated patients), so the actionable next step is a biomarker-triggered switch trial that measures surface BCMA density/TNFRSF17 status at progression ","confidence":0.6,"notebook":"This visit's pack is dominated by antigen-switch data, and it lands squarely on L1. Three independent [NEW] sources now populate the escape ladder I proposed as a design variable: talquetamab's 3-year MonumenTAL-1 update shows durable GPRC5D-directed activity including in a prior-T-cell-redirection cohort (ORR 67–74%, CR+ 33–42%, 36-month OS 44.6–60.8%) (PMID:42561120); a real-world multicentre series shows the reverse order also works — BCMA bispecific after prior GPRC5D bispecific, ORR 58%, mPFS 6.8 months, n=26 (PMID:42401497); and cevostamab establishes a third, lineage-independent antigen (FcRH5) with activity in a cohort 47.5% BCMA-pretreated (PMID:42487061). Mechanistically this argues that antigen escape, not global T-cell exhaustion, is the dominant recoverable failure mode after first bispecific relapse, since a fresh antigen restores response in the same T-cell pool [INFERRED]. L1 therefore moves to CANDIDATE. Caveats: PMID:42401497 is n=26 retrospective; cevostamab carried treatment-related grade 5 HLH and DIC (PMID:42487061); none of these studies measured surface BCMA density or TNFRSF17 copy number, so the biomarker-triggered switch remains untested — that is now the sharpest gap.\n\nNew lead: simultaneous rather than sequential dual targeting. The RedirecTT-1 commentary reports unexpectedly high response in true extramedullary disease with teclistamab+talquetamab, attributed to targeting breadth, stronger synapse formation and distributed exhaustion signalling — all explicitly speculative and single-arm, with substantial serious infection (PMID:42419103). This reframes EMD/PCL, and I correspondingly weaken L4: XVRd's 16.7% MRD negativity in an EMD-enriched cohort now looks like a poor bar next to dual-TCE response rates.\n\nL2 is sharpened, not confirmed. The Italian +1q review documents that +1q associates with CD38 downregulation, impaired complement-dependent cytotoxicity and immunosuppression, and that R2-ISS now calls +1q high-risk, while noting no agreed iFISH cut-off (PMID:39945832). That undercuts the naive \"isatuximab is better in 1q\" claim via a Fc/complement route but supports the Fc-independent arm of the hypothesis (ectoenzyme inhibition, ROS, FOXM1). The falsification test is now cleaner: if +1q kills CDC, an isatuximab advantage must be complement-independent, and any stratified reanalysis must pre-specify a copy-number threshold.\n\nNotebook floor for comparator arms: melflufen+dexamethasone in penta-refractory, post-BCMA/GPRC5D disease gives ORR 28% (33% in immunotherapy-exposed), mPFS 4.8 months with ≥grade 3 thrombocytopenia/neutropenia in 68% (PMID:42270486). Any post-immunotherapy salvage claiming benefit must beat that. AZD0305's mechanism remains unstated in the trial record — still unverified after two visits.","leadChanges":[{"id":"L1","title":"Antigen-escape-adapted BCMA immunotherapy: pre-specify BCMA density/shedding and switch antigen rather than re-treat","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.72},{"id":"L2","title":"Genotype-directed choice of anti-CD38 antibody: isatuximab for 1q21-amplified myeloma, daratumumab as immune primer before T-cell redirection","level":"LEAD","status":"STRENGTHENED","confidence":0.52},{"id":"L6","title":"Simultaneous dual-antigen T-cell engagement (BCMA+GPRC5D) for extramedullary and antigen-heterogeneous myeloma, with infection prophylaxis as the co-primary des","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"XPO1 inhibition (selinexor) added to VRd for high-risk NDMM with extramedullary/plasma-cell-leukaemia biology — depth of response is the limiting problem","level":"LEAD","status":"WEAKENED","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does surface BCMA density / TNFRSF17 copy number at progression actually predict which patients need antigen switch versus gamma-secretase-inhibitor-augmented BCMA re-treatment, and is there any prospective dataset measuring it?","What is the optimal antigen order and interval (BCMA->GPRC5D->FcRH5 vs GPRC5D->BCMA), and does an intervening treatment-free interval restore T-cell fitness?","What is the mechanism/target of AZD0305 (NCT06106945), still unstated in the trial record after two visits?","Is there any +1q-stratified randomised or registry comparison of isatuximab versus daratumumab, and does +1q-associated CD38 downregulation/CDC impairment abolish benefit from either?","Do inobrodib phase 3 or mechanistic data confirm IRF4/MYC collapse as the on-target PD readout, and does t(11;14)/CCND1 [SOMATIC] status predict response to inobrodib or venetoclax?","Can serious infection with dual or sequential T-cell engagers be mitigated by fixed-duration/response-adapted dosing plus IVIG, without losing depth of response?","Is LIG4 [SOMATIC-likely] alteration in myeloma an exploitable NHEJ-deficiency state (PARP/POLQ/ATR) or only a genomic-instability correlate?"],"nextQueries":["(\"multiple myeloma\") AND (\"talquetamab\" OR \"teclistamab\" OR \"cevostamab\") AND (\"antigen density\" OR \"TNFRSF17\" OR \"GPRC5D loss\" OR \"single-cell\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"multiple myeloma\") AND (\"inobrodib\" OR \"CCS1477\" OR \"p300\" OR \"CBP\") AND (\"IRF4\" OR \"MYC\") AND SRC:MED","(\"multiple myeloma\") AND (\"t(11;14)\" OR \"CCND1\") AND (venetoclax OR \"BCL2\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41542910","doi":"10.1080/19420862.2026.2613548","year":2026,"isNew":true,"title":"The making of multispecific immunoglobulins - a clinical perspective"},{"pmid":"41348019","doi":"10.1182/hematology.2025000732","year":2025,"isNew":true,"title":"Choosing the optimal maintenance strategy in multiple myeloma"},{"pmid":"39945832","doi":"10.1007/s00277-025-06212-5","year":2025,"isNew":true,"title":"Overview of 1q abnormalities in multiple myeloma: scientific opinions from Italian experts"},{"pmid":"42070121","doi":"10.1080/2162402x.2026.2667160","year":2026,"isNew":true,"title":"Trial watch: antibody-drug conjugates in cancer therapy"},{"pmid":"41700001","doi":"10.1080/2162402x.2026.2632421","year":2026,"isNew":true,"title":"Trial Watch - bispecific T cell engagers and higher-order multispecific immunotherapeutics"},{"pmid":"42419103","doi":"10.1016/j.tranon.2026.102907","year":2026,"isNew":true,"title":"Dual-targeting bispecific antibodies against extramedullary myeloma: A hypothesis-driven commentary"},{"pmid":"42561120","doi":"10.1182/blood.2025031994","year":2026,"isNew":true,"title":"Talquetamab in patients with relapsed/refractory multiple myeloma: 3-year follow-up of the phase 1/2 MonumenTAL-1 study"},{"pmid":"42487061","doi":"10.1038/s41591-026-04522-3","year":2026,"isNew":true,"title":"FcRH5×CD3 bispecific antibody cevostamab in relapsed or refractory multiple myeloma: a phase 1 trial"},{"pmid":"42401497","doi":"10.1016/j.clml.2026.06.005","year":2026,"isNew":true,"title":"Real-World Evidence of Immunotherapy Sequencing in Multiple Myeloma: Durable Responses With BCMA-Targeting Bispecific Antibodies Following Prior GPRC5D-Targeting Therapy"},{"pmid":"42270486","doi":"10.1016/j.clml.2026.05.002","year":2026,"isNew":true,"title":"Real-World Outcomes of Melflufen Plus Dexamethasone in Heavily Pretreated Relapsed/Refractory Multiple Myeloma After Exposure to Immunotherapies"}],"trialsShown":[{"nct":"NCT06106945","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"AZD0305 as Monotherapy or in Combination With Anticancer Agents in Participants With Multiple Myeloma"},{"nct":"NCT05714839","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Investigate the Safety and Efficacy of Belantamab for the Treatment of Multiple Myeloma When Used as Monotherapy and in Combinati"},{"nct":"NCT03937635","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Lenalidomide, and Dexamethasone With or Without Daratumumab in Treating Patients With High-Risk Smoldering Myeloma"},{"nct":"NCT04566328","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Testing the Use of Combination Therapy in Adult Patients With Newly Diagnosed Multiple Myeloma, the EQUATE Trial"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT07772024","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Inobrodib, Pomalidomide and Dexamethasone Versus Standard Available Therapy in Relapsed or Refractory Multiple Myeloma"},{"nct":"NCT04898790","phase":"NA","status":"RECRUITING","isNew":false,"title":"Improving Cognitive Function in Older Adults Undergoing Stem Cell Transplant"},{"nct":"NCT07485647","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Identifying Effective and Cost-Conscious Maintenance Daratumumab Dosing"}],"usage":{"input":11463,"output":6698},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"multiple myeloma\") AND (\"BCMA\" OR \"TNFRSF17\") AND (\"antigen loss\" OR \"gamma-secretase\" OR \"GPRC5D\" OR \"FcRH5\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"multiple myeloma\") AND (\"1q21\" OR \"CKS1B\" OR \"gain(1q)\") AND (isatuximab OR daratumumab OR CD38) AND SRC:MED"],"evidenceIds":["PMID:41542910","PMID:41348019","PMID:39945832","PMID:42070121","PMID:41700001","PMID:42419103","PMID:42561120","PMID:42487061","PMID:42401497","PMID:42270486","NCT06106945","NCT05714839","NCT03937635","NCT04566328","NCT06904066","NCT07772024","NCT04898790","NCT07485647"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787168505377","cycle":96,"visit":10,"ts":"2026-08-19T19:41:45.377Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Asciminib exposure-response (PMID:40848059) and nilotinib TDM (PMID:40978483) together establish measurable concentration floors (and, for nilotinib, a toxicity ceiling) for molecular response, so CML dose individualisation should be anchored to Cmin thresholds rather than label-dose fractions, with","confidence":0.52,"notebook":"The BH3-profiling query returned nothing CML-specific (only the previously-seen mitochondrial review, PMID:41899586), so open question 3 stays open and L11 does not move; record the absence — two consecutive targeted queries have failed to produce MCL1/BCL-xL priming data in CD34+CD38− CML.\n\nThe exposure query paid off and closes open question 4. PMID:40848059 gives the ASC4FIRST/ASCEMBL/phase-1 exposure–response: week-48 MMR probability is 70–80% across the second-to-fourth quartiles of daily AUC and Cmin but drops to 45% in the lowest exposure quartile, while the only exposure-related safety signal was grade ≥3 lipase rise (5.8–11.2%). That is precisely the floor-plus-plateau geometry L9 predicted: depth is lost below a Cmin threshold, not gained above it. Caveat stated plainly — quartile exposure confounds PK with adherence (the authors' own conclusion is about compliance), so a \"floor\" derived this way may partly be a dose-intensity artefact [INFERRED]. Independently, retrospective nilotinib TDM (PMID:40978483) supplies both bounds in one agent: an efficacy Cmin threshold discriminating MMR (AUC 0.693) and a hyperbilirubinaemia toxicity threshold at ~1290 ng/mL, with adverse events otherwise concentration-independent. Three agents (flumatinib, asciminib, nilotinib) now show measurable floors; nilotinib adds a ceiling. L9 promotes to CANDIDATE — TDM-anchored dosing is the operational form of the therapeutic-window argument, and it constrains L7: de-escalation should target a measured concentration floor, not a label fraction.\n\nL7 also gains a better stratifier and loses its old one. In 598 patients, deep cytomorphology (erythroid enrichment, monocyte nuclear lobulation, low WBC) predicted MMR at AUROC 0.76 while ELTS scored 0.53 — essentially chance (PMID:41694735). The desk should stop specifying ELTS as the gate for de-escalation/TFR protocols and test the Morphoclinical model instead.\n\nPMID:40550748 reiterates that TFR failure is LSC persistence and that microenvironment-directed and rotation strategies have underperformed; this weakens L12 (ILK/niche) further toward retirement absent CML-specific same-donor data. PMID:40568725 restates asciminib's potency-without-toxicity break, consistent with L8, but adds no mutation-level data.\n\nTwo new leads, both deliberately low: STAT5A CRISPR knockout restored apoptosis and TKI sensitivity in imatinib- and ponatinib-resistant K562 (PMID:42033509) — one line, one lab, and STAT5 is required for normal HSC/erythroid and GH/prolactin signalling [KNOWN]; and MDM2 PROTAC MD-265, which killed 105 primary leukaemic stem-cell samples at median 16 nM with a 100-fold normal-HSC window and TP53-mutant-restricted resistance (PMID:41986621) — AML data, but chronic-phase CML is near-uniformly TP53-wild-type [KNOWN], making p53 restoration plus asciminib a testable LSC-directed pairing.","leadChanges":[{"id":"L9","title":"Concentration-floor (TDM-anchored) de-escalation: reduce exposure to a measured pharmacokinetic threshold, not to a fraction of label dose","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.58},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.65},{"id":"L12","title":"ILK as a microenvironment-coupled, kinase-independent resistance node in CML LSCs","level":"LEAD","status":"WEAKENED","confidence":0.12},{"id":"L13","title":"STAT5A as a druggable transcriptional node of BCR-ABL1-kinase-independent TKI resistance","level":"LEAD","status":"NEW","confidence":0.2},{"id":"L14","title":"MDM2 degradation (PROTAC) to restore wild-type p53 in TP53-intact CML LSCs alongside BCR-ABL1 blockade","level":"LEAD","status":"NEW","confidence":0.24}],"unverifiedCitations":0,"openQuestions":["Does BH3 profiling of asciminib- or ponatinib-resistant CML CD34+CD38- cells show MCL1/BCL-xL rather than BCL2 priming, and is any MCL1-class or platelet-sparing BCL-xL agent usable? (two targeted queries have now returned nothing)","Can a DMR-specific asciminib Cmin floor be derived from ASC4FIRST/ASC4OPT PK once adherence/relative dose intensity is deconfounded from true pharmacokinetic exposure?","Does clinical-grade HDAC6 inhibition (ricolinostat/citarinostat) plus asciminib deplete primary CD34+CD38- chronic-phase LSCs in LTC-IC while sparing same-donor normal HSPCs, and is the Beclin 1 acetyl/phospho double hit reproducible in pri","Does MDM2 degradation restore p53 output and deplete TP53-wild-type chronic-phase CML LSCs, and does it select TP53-mutant subclones?","What is the published spectrum and frequency of kinase-domain mutations at asciminib failure beyond A337V, and which ATP-site agent rescues each?","Does the Morphoclinical cytomorphology model (or any image-derived marker) predict TFR success and safe de-escalation, not just MMR attainment?"],"nextQueries":["(\"chronic myeloid leukemia\" OR CML) AND (MDM2 OR \"p53 restoration\" OR nutlin OR idasanutlin OR PROTAC) AND (\"CD34\" OR \"leukemic stem cell\" OR \"stem cell\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"chronic myeloid leukemia\") AND (ricolinostat OR citarinostat OR \"HDAC6 inhibitor\") AND (autophagy OR \"Beclin 1\" OR MCL1 OR \"BCL-xL\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(asciminib) AND (\"kinase domain mutation\" OR \"resistance mutation\" OR A337V OR P465S OR \"myristoyl pocket\") AND (sequencing OR NGS) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"40550748","doi":"10.1111/ejh.70000","year":2025,"isNew":true,"title":"Treatment-Free Remission in Chronic Myeloid Leukemia: Revisiting the \"W\" Questions"},{"pmid":"41986621","doi":"10.1038/s41375-026-02957-8","year":2026,"isNew":true,"title":"Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models"},{"pmid":"40848059","doi":"10.1007/s00280-025-04806-4","year":2025,"isNew":true,"title":"Exposure-response analysis of asciminib efficacy and safety in patients with chronic myelogenous leukemia in chronic phase"},{"pmid":"42132094","doi":"10.1042/bcj20260185","year":2026,"isNew":true,"title":"Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia"},{"pmid":"42033509","doi":"10.1007/s12032-026-03295-6","year":2026,"isNew":true,"title":"Targeting STAT5A via CRISPR/Cas9 restores TKI sensitivity in resistant chronic myeloid leukemia cells"},{"pmid":"41694735","doi":"10.1002/hem3.70319","year":2026,"isNew":true,"title":"Deep cytomorphology identifies erythroid skewing and monocytic morphology to predict TKI sensitivity in CML patients"},{"pmid":"41960165","doi":"10.34172/bi.32564","year":2026,"isNew":true,"title":"The interplay between non-coding RNAs and Wnt signaling pathway in leukemia: A narrative review"},{"pmid":"40568725","doi":"10.3324/haematol.2024.286798","year":2025,"isNew":true,"title":"Asciminib for Philadelphia chromosome-positive leukemias"},{"pmid":"40978483","doi":"10.3389/fphar.2025.1676800","year":2025,"isNew":true,"title":"Correlation analysis between plasma concentration of nilotinib and clinical efficacy and safety in patients with chronic myeloid leukemia: a single-center retrospective cohort stud"},{"pmid":"41899586","doi":"10.3390/cancers18060982","year":2026,"isNew":false,"title":"Targeting Mitochondrial Vulnerabilities in Chronic Myeloid Leukemia: From Pathobiology to Novel Therapeutic Opportunities"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":16403,"output":7941},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic myeloid leukemia\" AND (\"BH3 profiling\" OR \"dynamic BH3\" OR MCL1 OR \"BCL-xL\") AND (\"CD34+CD38-\" OR \"leukemic stem cell\" OR \"primary patient\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(asciminib) AND (pharmacokinetic* OR trough OR \"exposure-response\" OR Cmin) AND (\"major molecular response\" OR MR4 OR MMR) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:40550748","PMID:41986621","PMID:40848059","PMID:42132094","PMID:42033509","PMID:41694735","PMID:41960165","PMID:40568725","PMID:40978483","PMID:41899586","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787168281654","cycle":95,"visit":2,"ts":"2026-08-19T19:38:01.654Z","cancer":{"key":"myelodysplastic syndrome","name":"myelodysplastic syndrome","mondo":{"id":"MONDO:0018881","name":"myelodysplastic syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"OncoSplice (PMID:40333990) supplies the first cited genetic validation of IRAK4 dependency and PRMT5-corrected U2AF1-like missplicing, promoting the innate-immune-kinase lead to CANDIDATE and opening a PRMT5 lead, while confirming that direct spliceosome modulators are a dead end in SF3B1-mutant MDS","confidence":0.5,"notebook":"This visit's pack is mostly noise (FOXO/neurodegeneration P3, NSCLC SRC P5, glioblastoma mifepristone P6 — \"MDS\" here means molecular dynamics simulation, not the disease), but one paper is high-value and one review kills a strategy.\n\nP1 (PMID:40333990) is the first cited support for the IRAK4 arm of L3. OncoSplice defines a \"U2AF1-like\" splicing subtype present *without* splicing-factor mutations, stable through relapse, imposing an LSC program and poor prognosis; PRMT5 inhibition reverses the missplicing, and genetic IRAK4 deletion blocks leukaemia engraftment in xenografts. That converts my previously [KNOWN]-only TRAF6/IRAK axis into cited mechanism and, importantly, widens the biomarker from *SF3B1/U2AF1* genotype to a splicing-signature phenotype [INFERRED] — a mutation-agnostic enrichment strategy for NCT06303193. Caveats I will not paper over: the work is AML (adult+paediatric), not MDS; the validated node is IRAK4, whereas pacritinib's declared kinase set is IRAK1/CSF1R/JAK2/FLT3 (NCT06303193), so an IRAK4-selective agent [KNOWN: emavusertib] may be the truer test of P1's genetics. L3 → CANDIDATE, confidence 0.52, with the isoform/signature PD assay now the critical path.\n\nNew lead from the same paper: PRMT5 inhibition as the upstream corrector of U2AF1-like missplicing, with IRAK4 as the convergent downstream effector (PMID:40333990). This is mechanistically distinct from direct spliceosome modulators — which P8 (PMID:40124717) states plainly \"have failed to deliver\" in SF3B1-mutant MDS. Logged as a dead end: the desk will not re-propose H3B-8800-class SF3B1 modulators. P8 also flags TLR/NF-κB inhibitors as still unvalidated, which caps L3's ceiling honestly.\n\nP10 (PMID:42294112) gives real-world stratification for the venetoclax leads: HMA-VEN beats HMA monotherapy (median OS 11.2 vs 6.5 mo) but adverse-risk OS is 7.7 mo and ELN 2024 discriminates poorly in secondary AML arising from a prior myeloid neoplasm — the exact MDS-progressed population L1/L2 target. Indirect, AML-based, no XPO1 or BH3 data, so L1 gains only a small increment and stays a LEAD; it does argue that any MDS salvage trial must pre-specify adverse-risk/sM-AML strata rather than pool them.\n\nQ5 (surface antigens/NK) is answered negatively this visit: P2 and P9 are generic NK reviews with no MDS antigen data — no lead created. LR-MDS reviews P4/P7 anchor a new low-risk lead: luspatercept and imetelstat as the platform on which disease-modifying combinations must be built, with SF3B1-clone VAF reduction as the endpoint that separates cytoreduction from symptom control.","leadChanges":[{"id":"L3","title":"Innate-immune kinase blockade (pacritinib: IRAK1/CSF1R/JAK2/FLT3) in MDS and MDS/MPN overlap","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.52},{"id":"L5","title":"PRMT5 inhibition to reverse U2AF1-like missplicing in MDS and MDS-derived secondary AML","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L1","title":"XPO1 inhibition (selinexor/eltanexor) plus venetoclax in HMA-refractory MDS, restricted to TP53-wild-type disease","level":"LEAD","status":"STRENGTHENED","confidence":0.52},{"id":"L6","title":"Disease-modifying combinations on the luspatercept/imetelstat backbone in lower-risk MDS, with clonal VAF reduction as the endpoint","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["Does the U2AF1-like splicing signature (PMID:40333990) exist in MDS marrow cohorts specifically, and does it track IPSS-M risk or predict HMA failure independently of splicing-factor genotype?","Is IRAK4 or IRAK1 the operative kinase in MDS: does pacritinib reduce IRAK4-L signalling in patient marrow, and are there clinical data for an IRAK4-selective inhibitor (emavusertib) in MDS?","What is the haematopoietic therapeutic window for PRMT5 inhibition, and is any PRMT5 inhibitor being tested in myeloid neoplasms rather than MTAP-deleted solid tumours?","Is there any published response (not synergy) data for XPO1 inhibitor plus venetoclax in TP53-mutant versus wild-type MDS, and does venetoclax add benefit at all in MDS-derived secondary AML given PMID:42294112?","Do luspatercept or imetelstat reduce SF3B1 clone VAF in LR-MDS, and does iron chelation at ferritin >=500 change outcomes rather than merely marking risk?","Are there platelet-sparing BCL-xL modalities (lineage-directed degraders, intermittent dosing) with any myeloid data, and does a BCL2:BCL2L1 ratio prospectively select responders?"],"nextQueries":["(PRMT5 AND (inhibitor OR GSK3326595 OR PF-06939999 OR JNJ-64619178) AND (leukemia OR myelodysplastic OR myeloid)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","((IRAK4 OR emavusertib OR CA-4948) AND (myelodysplastic OR \"lower-risk MDS\" OR AML)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","((imetelstat OR luspatercept) AND (\"variant allele frequency\" OR clonal OR SF3B1 OR \"disease modifying\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"40333990","doi":"10.1126/scitranslmed.adr1471","year":2025,"isNew":true,"title":"Splicing regulatory dynamics for precision analysis and treatment of heterogeneous leukemias"},{"pmid":"41799416","doi":"10.1016/j.pscia.2026.100109","year":2026,"isNew":true,"title":"Mechanisms of tumor cell evasion from NK cell-mediated killing and advances in NK cell-based cancer immunotherapy"},{"pmid":"42202637","doi":"10.1016/j.redox.2026.104218","year":2026,"isNew":true,"title":"FOXO family and neurodegenerative diseases: Mechanisms of action and therapeutic potential"},{"pmid":"41348013","doi":"10.1182/hematology.2025000768","year":2025,"isNew":true,"title":"Updates in low/intermediate-risk MDS"},{"pmid":"41858068","doi":"10.1080/13880209.2026.2641262","year":2026,"isNew":true,"title":"Rabdosin B suppresses proliferation of nonsmall cell lung cancer by regulating the SRC/PI3K/AKT signaling pathway"},{"pmid":"41439468","doi":"10.1080/15384047.2025.2603095","year":2026,"isNew":true,"title":"Assessing progesterone receptor modulation in glioblastoma: from &lt;i&gt;in vitro&lt;/i&gt; and animal model to a human pilot protocol"},{"pmid":"41300977","doi":"10.3390/cancers17223610","year":2025,"isNew":true,"title":"Molecular Insights and Therapeutic Advances in Low-Risk Myelodysplastic Neoplasms: A Clinical Review"},{"pmid":"40124717","doi":"10.1002/hem3.70103","year":2025,"isNew":true,"title":"Low-risk MDS-A spotlight on precision medicine for &lt;i&gt;SF3B1-&lt;/i&gt;mutated patients"},{"pmid":"41622937","doi":"10.1080/07853890.2025.2601404","year":2026,"isNew":true,"title":"Synergistic immune interactions between T cells and natural killer cells in allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: current status and futu"},{"pmid":"42294112","doi":"10.1016/j.bneo.2026.100238","year":2026,"isNew":true,"title":"Validation of ELN 2024 genetic classification in patients with AML treated with HMA-based regimens: PETHEMA registry study"}],"trialsShown":[{"nct":"NCT07228624","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Ruxolitinib Before, During and After Hematopoietic Cell Transplant in Older Patients With Myelofibrosis and Myelodysplastic Syndrome/Myelopr"},{"nct":"NCT06399640","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Eltanexor and Venetoclax in Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT06782373","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Assess the Effectiveness and Safety of Pacritinib in Patients With VEXAS Syndrome (PAXIS)"},{"nct":"NCT06303193","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysp"},{"nct":"NCT04898790","phase":"NA","status":"RECRUITING","isNew":false,"title":"Improving Cognitive Function in Older Adults Undergoing Stem Cell Transplant"},{"nct":"NCT02521493","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syn"}],"usage":{"input":11459,"output":7242},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"myelodysplastic syndrome\" OR \"MDS\") AND (venetoclax OR \"BCL-2\" OR \"BCL-xL\" OR MCL1) AND (resistance OR \"BH3 profiling\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"myelodysplastic\" AND (SF3B1 OR U2AF1 OR SRSF2) AND (IRAK4 OR TRAF6 OR \"splicing modulator\" OR \"synthetic lethal\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:40333990","PMID:41799416","PMID:42202637","PMID:41348013","PMID:41858068","PMID:41439468","PMID:41300977","PMID:40124717","PMID:41622937","PMID:42294112","NCT07228624","NCT06399640","NCT06904066","NCT06566742","NCT06782373","NCT06303193","NCT04898790","NCT02521493"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787168067875","cycle":94,"visit":2,"ts":"2026-08-19T19:34:27.875Z","cancer":{"key":"chronic lymphocytic leukemia","name":"chronic lymphocytic leukemia","mondo":{"id":"MONDO:0004948","name":"B-cell chronic lymphocytic leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"BTK A428D pre-exists and expands as a pan-resistance mutation to both BTK inhibitors and degraders because it blocks the shared adenine-mimetic binding mode, so degrader programmes need pretreatment A428D screening, venetoclax co-targeting, and non-adenine-mimetic BTK binders.","confidence":0.6,"notebook":"PMID:42484277 (Cancer Discovery, peer-reviewed, serial patient sequencing from the zelebrudomide and bexobrutideg phase I trials) is the highest-value item in this pack and it partially falsifies my own L1 mechanism. I had asserted that A428D [SOMATIC], as a kinase-impaired/scaffold-retaining mutant, should be covered by degradation. It is not: A428D recurrently expands from *preexisting* subclones at degrader relapse and confers pan-resistance to both inhibitors and degraders. The crystal structure explains why — the mutant aspartate clashes with the ATP adenine ring *and* with the adenine-mimetic moiety shared by current inhibitors and by the BTK-binding warhead of current PROTACs. So this is a ligand-binding failure, not a degradation-machinery failure: no CRBN/DDB1 loss was needed. Question 1 is therefore answered in part (the dominant clinical escape reported is target-binding, not E3 loss) and CRBN/neddylation escape remains unobserved rather than excluded.\n\nTwo actionable consequences. First, L1 is narrowed but genuinely corroborated by independent peer-reviewed literature (degrader efficacy in BTKi-resistant disease confirmed), so it moves to CANDIDATE with the A428D exclusion written into the mechanism; pretreatment ddPCR/ctDNA screening for A428D at low VAF becomes a required eligibility assay, not an optional biomarker. Second, two orthogonal strategies fall out of the same paper: venetoclax co-administration mitigated A428D expansion in their models, and A428D cells are *less fit* than wild-type without BTK-directed pressure — which argues for time-limited or intermittent degrader dosing to let the mutant clone contract [INFERRED]. I open L5 for this, and flag the medicinal-chemistry ask: BTK degraders whose binder is not adenine-mimetic (allosteric/non-ATP-site or molecular-glue) should retain A428D activity [SPECULATIVE]. This also indirectly strengthens L3 — BCL2 co-targeting suppresses selection of BTK mutants, not only BCL2 G101V/D103Y.\n\nQuestion 4 is only weakly served: the pack returned four generic DDR/synthetic-lethality reviews (PMID:40422251, PMID:40240755, PMID:40759474, PMID:41614897) with no CLL-specific ATR/WEE1 data. I open L6 at low confidence and record the killer caveat now: circulating CLL cells are largely quiescent, so replication-stress-directed agents may lack a substrate outside proliferation centres [KNOWN/INFERRED], and germline ATM heterozygosity [GERMLINE] complicates tolerability. Mutant-p53 reactivation (APR-246; PMID:41917811, PMID:42306789) is noted but not nominated — no CLL data, and prior MDS/AML results were modest [KNOWN]. Pack items T5 (neoantigen TCR; CLL is mutationally quiet), T7, T8 and the JAK review P4 are off-programme noise. L2 and L4 unchanged, no new evidence either way.","leadChanges":[{"id":"L1","title":"BTK protein degradation for BTKi-resistant CLL/SLL with scaffold or kinase-impaired BTK mutants","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.68},{"id":"L5","title":"Anti-A428D strategies: BCL2 co-targeting, intermittent dosing to exploit the mutant's fitness cost, and non-adenine-mimetic BTK binders","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L3","title":"Preemptive dual BCL2/BTK blockade with next-generation agents to suppress BCL2 resistance mutations","level":"LEAD","status":"STRENGTHENED","confidence":0.58},{"id":"L6","title":"ATR/CHK1/WEE1 synthetic lethality in ATM-deleted (11q) and TP53-disrupted CLL","level":"LEAD","status":"NEW","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["What is the pretreatment prevalence of BTK A428D subclones in BTKi-exposed CLL, and what assay sensitivity (ddPCR/ctDNA VAF floor) is needed to exclude patients from degrader monotherapy?","Can a non-adenine-mimetic or allosteric BTK ligand form a productive ternary complex with CRBN on A428D-BTK, and do any next-generation degraders in development already do so?","Does intermittent or MRD-guided fixed-duration degrader dosing actually contract A428D clones in vivo, as the reported fitness disadvantage predicts?","Are CRBN/DDB1/neddylation-pathway losses or BTK loss-of-expression observed at all as degrader-specific escape, or is target-binding failure the sole clinical route?","Do quiescent circulating CLL cells respond to ATR/CHK1/WEE1 inhibition, or is activity confined to proliferation-centre-mimicking stimulated cells, and does ATM biallelic status predict it?","Is Richter transformation enriched on BTK degraders, and does it co-occur with A428D or with TP53 disruption?"],"nextQueries":["\"chronic lymphocytic leukemia\" AND (\"A428D\" OR CRBN OR cereblon) AND (degrader OR PROTAC OR bexobrutideg OR \"NX-5948\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic lymphocytic leukemia\" AND (ATR inhibitor OR ceralasertib OR WEE1 OR adavosertib OR CHK1) AND (ATM OR \"11q deletion\" OR TP53) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"Richter transformation\" OR \"Richter syndrome\") AND (\"BTK degrader\" OR bexobrutideg OR \"BGB-16673\" OR zelebrudomide OR pirtobrutinib) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"40422251","doi":"10.3390/cells14100748","year":2025,"isNew":true,"title":"Cancer Vulnerabilities Through Targeting the ATR/Chk1 and ATM/Chk2 Axes in the Context of DNA Damage"},{"pmid":"40240755","doi":"10.1038/s41420-025-02418-8","year":2025,"isNew":true,"title":"Perspectives on cancer therapy-synthetic lethal precision medicine strategies, molecular mechanisms, therapeutic targets and current technical challenges"},{"pmid":"41614897","doi":"10.3390/cimb48010067","year":2026,"isNew":true,"title":"Replication Stress in Cancer: Mechanistic Insights and Therapeutic Opportunities for Radiosensitization"},{"pmid":"41907306","doi":"10.1016/j.pscia.2026.100116","year":2026,"isNew":true,"title":"Next-generation Janus kinase inhibitors: Integrating synthetic innovation, structural biology, and computational design for precision drug discovery"},{"pmid":"40759474","doi":"10.14791/btrt.2025.0017","year":2025,"isNew":true,"title":"Therapeutic Targeting of DNA Damage Response Pathways in &lt;i&gt;TP53&lt;/i&gt;- and &lt;i&gt;ATM&lt;/i&gt;-Mutated Tumors"},{"pmid":"41917811","doi":"10.1186/s11658-026-00907-x","year":2026,"isNew":true,"title":"Targeting mutant p53 in cancer: from mechanistic insights to therapeutic strategies"},{"pmid":"42484277","doi":"10.1158/2159-8290.cd-26-0251","year":2026,"isNew":true,"title":"Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors"},{"pmid":"42306789","doi":"10.1016/j.bbrep.2026.102661","year":2026,"isNew":true,"title":"Fundamentals and emerging frontiers in p53-targeted drug development"},{"pmid":"42303626","doi":"10.1038/s41392-026-02729-x","year":2026,"isNew":true,"title":"Non-receptor tyrosine kinase signaling pathways and therapeutic implications"},{"pmid":"42278639","doi":"10.3390/ijms27115117","year":2026,"isNew":true,"title":"Chronic Lymphocytic Leukemia: Molecular Pathologies and Therapeutic Strategies"}],"trialsShown":[{"nct":"NCT02966756","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of Venetoclax in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma"},{"nct":"NCT07221500","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Study of NX-5948 in Adults With CLL/SLL Previously Treated With a Bruton's Tyrosine Kinase Inhibitor and a B-cell Lymphoma-2 Inhibitor (DA"},{"nct":"NCT07774390","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Ibrutinib Plus Venetoclax Long-Term Outcomes in CLL"},{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT07277231","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Sonrotoclax (BGB-11417) Plus Zanubrutinib (BGB-3111) Compared With Venetoclax Plus Acalabrutinib in Adults With Previ"},{"nct":"NCT05082519","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Caloric Restriction and Activity to Reduce Chemoresistance in B-ALL"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"}],"usage":{"input":10581,"output":7356},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic lymphocytic leukemia\" AND (\"BTK degrader\" OR PROTAC OR bexobrutideg OR \"BGB-16673\" OR \"NX-5948\") AND resistance AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic lymphocytic leukemia\" AND (ATM OR TP53 OR POT1 OR RPS15) AND (\"synthetic lethality\" OR ATR OR WEE1 OR PARP) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:40422251","PMID:40240755","PMID:41614897","PMID:41907306","PMID:40759474","PMID:41917811","PMID:42484277","PMID:42306789","PMID:42303626","PMID:42278639","NCT02966756","NCT07221500","NCT07774390","NCT05006716","NCT06904066","NCT07277231","NCT05082519","NCT03147612"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787167849232","cycle":93,"visit":2,"ts":"2026-08-19T19:30:49.232Z","cancer":{"key":"acute lymphoblastic leukemia","name":"acute lymphoblastic leukemia","mondo":{"id":"MONDO:0004967","name":"acute lymphoblastic leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Glucocorticoid resistance in ALL converges on failure to shift the BIM:BCL2 ratio — reachable from ETV6/CDKN1B loss (B-lineage) or ZFP36L2 loss (T-lineage) — making biomarker-selected venetoclax or dexamethasone+GSI/MEK combinations the programme's lead axis, while post-CD19 relapse must be split pr","confidence":0.58,"notebook":"This visit's pack was rich on the apoptotic/GC axis and on CD19 escape, silent on the T-lineage fusion question and silent on L4.\n\nMechanistically the most useful item is P3 (PMID:42287749): ZFP36L2-low T-ALL is glucocorticoid-resistant because GR fails to autoupregulate, BIM induction is blunted and BCL2 fails to be downregulated — the same effector node L1 posited downstream of ETV6-SE/CDKN1B loss, reached by a completely different lesion [SOMATIC]. That partially answers open question 6: GC resistance converges on \"failure to shift the BIM:BCL2 ratio\", not on one genotype. It also delivers the first pharmacological dependency in this pack for T-ALL — GSI (DAPT) or trametinib restored GC sensitivity in vitro — so NOTCH/MEK are the reported bypasses, and I open that as a separate lead rather than diluting L1. P5 (PMID:42309255) independently corroborates druggable BCL2 dependency in B-ALL: venetoclax + decitabine synergised, but explicitly *not* via BCL2 protein or global methylation change — the synergy is metabolic (VEN collapses both OXPHOS and glycolysis; DEC deepens it). That reframes venetoclax combinations as metabolic co-targeting and warns that BCL2 protein level alone is a poor pharmacodynamic readout. P6 (PMID:42294111) is the high-value negative: venetoclax/ponatinib/trametinib doublets were synergistic in cell lines, reproduced in PDX, yet none prevented KMT2A-r infant ALL outgrowth, and primary-sample in vitro validation failed. Recorded so the desk never proposes a venetoclax doublet as sufficient therapy in KMT2A-r; ≥3 drugs required.\n\nOn L2: P2 (PMID:41720609) shows CD19 remains exploitable after both blinatumomab and autologous CD19 CAR-T failure — donor CAR-NK achieved CR (grade 3 ICANS, bridged to HSCT), i.e. effector failure, not antigen loss, in that case. P8 (PMID:42382092) is the mirror image: CD19-negative relapse post-blinatumomab with retained cytoplasmic CD22 salvaged (non-durably) by inotuzumab, plus an apparent karyotype shift — supporting mandatory paired antigen/cytogenetic profiling and a CD22 fallback arm. P9 (PMID:42541895) complicates my trigger design: blinatumomab improved DFS (RR 0.63) and OS (RR 0.62) in paediatric B-ALL without significant MRD-clearance benefit, so MRD conversion may under-read engager benefit. L2 → CANDIDATE. L1 → CANDIDATE on the node, with the ETV6/CDKN1B biomarker still single-source.\n\nP4 (Zataria extract + cytarabine, NALM-6, docking) is not actionable — noted and set aside. P1 (JAK review) has no ALL data but flags Ph-like/CRLF2 JAK-STAT as an untouched arm of this programme [KNOWN]. P7 (MAL/lineage plasticity) is the framework for lineage-switch escape and ETP-ALL; parked for next visit. L4 unaddressed — queries must target it or I retire it next visit.","leadChanges":[{"id":"L1","title":"ETV6-SE/CDKN1B loss as a biomarker for BCL-2 dependency: venetoclax + dexamethasone in ETV6-rearranged ALL","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.6},{"id":"L2","title":"CD19 re-engagement sequencing: T-cell engager AZD0486 after CAR-T failure, triggered by NGS-MRD/B-cell recovery","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.6},{"id":"L5","title":"ZFP36L2-low T-ALL: restoring glucocorticoid sensitivity with a gamma-secretase inhibitor or trametinib","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L6","title":"KMT2A-rearranged infant ALL requires triplets, not venetoclax doublets — negative-result guardrail plus a triplet design","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does ZFP36L2-low status prospectively predict benefit from dexamethasone + trametinib or dexamethasone + GSI in primary T-ALL/PDX, and does ZFP36L2 loss also raise BCL2 enough to confer venetoclax sensitivity (linking the new T-lineage lead","If venetoclax's effect in ALL is metabolic (OXPHOS + glycolysis collapse) rather than BCL-2-expression-dependent, what is the correct predictive assay — dynamic BH3 profiling, mitochondrial priming, or metabolic flux — and does BH3 profilin","In post-blinatumomab/post-CAR CD19-negative relapse, what fraction retains surface versus cytoplasmic CD22, and what are the reported durabilities of inotuzumab versus CD22 CAR in that specific setting?","Given that blinatumomab improved DFS/OS without significant MRD-clearance benefit in pooled paediatric RCTs, is NGS-MRD a valid trigger endpoint for engager sequencing after CAR-T, or must the trigger be B-cell recovery kinetics plus antige","Can the MALAT1/METTL14/HMGB1 NK-suppression axis (L4) be replicated by an independent group with primary NK cells and patient blasts — retire L4 next visit if the literature is still silent?","Is there ALL-specific clinical or PDX evidence for JAK inhibition in Ph-like/CRLF2-rearranged disease, which this programme has not yet covered?"],"nextQueries":["(\"acute lymphoblastic leukemia\" AND (ZFP36L2 OR \"gamma-secretase\" OR NOTCH1 OR trametinib OR MEK) AND (glucocorticoid OR dexamethasone OR prednisolone)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"B-cell acute lymphoblastic leukemia\" AND (CD22 OR inotuzumab OR \"CAR-NK\") AND (\"antigen loss\" OR \"CD19-negative\" OR \"after CAR\" OR \"lineage switch\")) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"acute lymphoblastic leukemia\" AND (\"Ph-like\" OR CRLF2 OR JAK2 OR ruxolitinib) AND (trial OR xenograft OR resistance)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41907306","doi":"10.1016/j.pscia.2026.100116","year":2026,"isNew":true,"title":"Next-generation Janus kinase inhibitors: Integrating synthetic innovation, structural biology, and computational design for precision drug discovery"},{"pmid":"41720609","doi":"10.1136/jitc-2025-013714","year":2026,"isNew":true,"title":"Donor-derived CD19-targeted CAR-NK cells induce complete remission in a child with relapsed B-ALL after failure of blinatumomab and autologous CD19-targeted CAR-T"},{"pmid":"42287749","doi":"10.1097/fpc.0000000000000607","year":2026,"isNew":true,"title":"Low expression of ZFP36L2 causes glucocorticoid resistance in childhood T-cell acute lymphoblastic leukemia"},{"pmid":"42599368","doi":"10.1007/s12032-026-03353-z","year":2026,"isNew":true,"title":"In vitro and in silico evaluation of the synergistic effect of Cytarabine and Zataria multiflora Boiss extract on pre-B acute lymphoblastic leukemia cells (NALM-6 cell line)"},{"pmid":"42309255","doi":"10.1016/j.molmet.2026.102402","year":2026,"isNew":true,"title":"Venetoclax and hypomethylating agents synergize to increase cell death and metabolic remodeling in acute B-lymphoblastic leukemia cells"},{"pmid":"42294111","doi":"10.1016/j.bneo.2026.100230","year":2026,"isNew":true,"title":"From cell lines to PDXs: in vivo confirmation of synergistic drug responses identified in leukemia cell line models"},{"pmid":"42255260","doi":"10.1016/j.bneo.2026.100231","year":2026,"isNew":true,"title":"Co-option of lineage plasticity as a hallmark of multipotent acute leukemias"},{"pmid":"42382092","doi":"10.1016/j.lrr.2026.100600","year":2026,"isNew":true,"title":"CD19-negative relapse with an apparent cytogenetic shift after blinatumomab-induced measurable residual disease clearance in Philadelphia chromosome-negative B-cell acute lymphobla"},{"pmid":"42541895","doi":"10.1016/j.currproblcancer.2026.101328","year":2026,"isNew":true,"title":"Blinatumomab versus chemotherapy in pediatric B-ALL: A meta-analysis of randomized trials in relapsed and high-risk frontline disease"},{"pmid":"41685195","doi":"10.3389/fphar.2026.1654783","year":2026,"isNew":true,"title":"Targeted therapies in pediatric B-Cell acute lymphoblastic leukemia: mechanisms, efficacy, and future directions"}],"trialsShown":[{"nct":"NCT05480904","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Characterizing Sleep Among Long-term Survivors of Childhood Cancer"},{"nct":"NCT07070219","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study of CTD402 in T-ALL/LBL Patients"},{"nct":"NCT03876769","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06137118","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"AZD0486 as Monotherapy in B-cell Acute Lymphoblastic Leukaemia"},{"nct":"NCT06710418","phase":"NA","status":"RECRUITING","isNew":false,"title":"Evaluating the Effects of Hemoglobin Threshold-specific Packed Red Blood Cell Transfusions on Quality of Life and Functional Outcomes in Pat"},{"nct":"NCT03007147","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblasti"},{"nct":"NCT05621291","phase":"NA","status":"RECRUITING","isNew":false,"title":"A Multicenter Study to Evaluate Next-Generation Sequencing (NGS) Testing and Monitoring of B-Cell Recovery to Guide Management Following Chi"}],"usage":{"input":11839,"output":8668},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"acute lymphoblastic leukemia\" AND (venetoclax OR navitoclax OR \"BCL-2\" OR MCL1 OR \"BH3 profiling\") AND (dexamethasone OR glucocorticoid OR resistance)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"B-cell acute lymphoblastic leukemia\" AND (\"CD19\" OR \"CD22\") AND (\"bispecific\" OR \"T-cell engager\" OR blinatumomab OR \"antigen loss\") AND (\"after CAR\" OR relapse OR resistance)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:41907306","PMID:41720609","PMID:42287749","PMID:42599368","PMID:42309255","PMID:42294111","PMID:42255260","PMID:42382092","PMID:42541895","PMID:41685195","NCT05480904","NCT07070219","NCT03876769","NCT06904066","NCT06137118","NCT06710418","NCT03007147","NCT05621291"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787167616690","cycle":92,"visit":9,"ts":"2026-08-19T19:26:56.690Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"HDAC6-inhibitor-plus-asciminib autophagy blockade gains independent mechanistic corroboration via dual Beclin 1 post-translational reprogramming (PMID:42480967) and is promoted to CANDIDATE, while a targeted search still yields no CML-specific BH3 profiling to name MCL1 versus BCL-xL as the primed d","confidence":0.45,"notebook":"This visit's pack is dominated by generic reviews, but one item is substantive. PMID:42480967 (title-only, Cancer Letters) reports that dual post-translational reprogramming of Beclin 1 by BCR-ABL and by HDAC6 inhibition disables autophagic flux and overcomes CML resistance. That is an independent, mechanistically distinct corroboration of L11's core claim — HDAC6 inhibition as an autophagy-directed, kinase-independent co-dependency in CML — and it names the convergence node the visit-8 abstract (PMID:42284888) left unspecified: Beclin 1 itself, plausibly acetylation-dependent (HDAC6 substrate) layered on BCR-ABL-driven phosphorylation [INFERRED, abstract unavailable]. L11 accordingly moves to CANDIDATE at 0.45: two evidence-bearing visits, two independent primary reports, but still zero primary CD34+CD38- LSC data, no clinical-grade HDAC6 agent tested, and no full text for the new paper. Open question 1 remains open on the LSC/normal-HSPC window, which is the whole argument for this class.\n\nOpen question 2 was targeted directly and returned nothing usable: PMID:41596764 is a pan-cancer BCL-2/BCL-xL review with no CML BH3 profiling, and PMID:41899586 is a narrative CML mitochondrial review that frames redox, metabolic rewiring and apoptotic evasion without supplying primed-dependency measurements in TKI-resistant CD34+ cells. Recorded as a targeted absence: the desk still has no CML-specific evidence that MCL1 or BCL-xL, rather than BCL2, is the primed dependency, so no BH3-mimetic partner can be nominated. The platelet-lifespan liability of BCL-xL inhibition remains the binding window constraint [KNOWN]; both reviews are attached to L11 as mechanistic context only, not as support for a combination.\n\nNCT03906292 is unreported for a ninth consecutive visit and NCT02689440 remains ACTIVE_NOT_RECRUITING with no readout, reconfirming the retirement of both venetoclax leads. L1 is weakened again (0.45) purely for silence; PMID:41376545 is still title-only, so true concurrent dual-site exposure remains a single unpublished case.\n\nOne new low-confidence lead: PMID:42282109 claims ILK is 5–20-fold overexpressed in malignant haematopoietic cells, mediates microenvironment-dependent therapy resistance, and that ILK inhibition selectively kills therapy-resistant LSCs while sparing normal progenitors. Review-only, no CML-specific data in the abstract, and ILK is required for integrin–actin coupling in cardiomyocytes and skeletal muscle [KNOWN], so the window claim is unverified. Admitted at 0.18 as a stroma-adhesion complement to L6's chromatin-state framing.\n\nThe LLPS, ceRNA, lactylation, proteostasis and heterocycle reviews contributed nothing CML-specific; queries will be narrowed to primary-cell and clinical PK sources.","leadChanges":[{"id":"L11","title":"HDAC6-selective inhibition plus asciminib: autophagy blockade to maladaptive ISR, MCL-1 loss and BCL-xL-dependent apoptosis in CML","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.45},{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"WEAKENED","confidence":0.45},{"id":"L12","title":"ILK as a microenvironment-coupled, kinase-independent resistance node in CML LSCs","level":"LEAD","status":"NEW","confidence":0.18}],"unverifiedCitations":0,"openQuestions":["Does HDAC6 inhibition (clinical-grade ricolinostat/citarinostat, not tool compound 7b) plus asciminib deplete primary CD34+CD38- chronic-phase CML LSCs in LTC-IC and serial replating while sparing same-donor normal HSPCs?","Is the Beclin 1 acetyl/phospho double-hit of PMID:42480967 reproducible in primary CML cells, and is autophagic-flux collapse necessary for the asciminib synergy or a parallel event?","Does BH3 profiling of asciminib- or ponatinib-resistant CML CD34+CD38- cells show MCL1/BCL-xL rather than BCL2 priming, and is there any MCL1-class or platelet-sparing BCL-xL agent with a usable window?","Is there any asciminib exposure-response dataset (trough vs Cmax) linked to MMR/MR4.5 from ASC4FIRST or ASC4OPT from which a DMR trough floor can be derived?","What is the published spectrum and frequency of kinase-domain mutations at asciminib failure beyond A337V, and which ATP-site agent rescues each?","Is ILK overexpression and stroma-dependent survival signalling documented in CML specifically, with any same-donor normal-progenitor comparison?"],"nextQueries":["\"chronic myeloid leukemia\" AND (\"BH3 profiling\" OR \"dynamic BH3\" OR MCL1 OR \"BCL-xL\") AND (\"CD34+CD38-\" OR \"leukemic stem cell\" OR \"primary patient\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(asciminib) AND (pharmacokinetic* OR trough OR \"exposure-response\" OR Cmin) AND (\"major molecular response\" OR MR4 OR MMR) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"chronic myeloid leukemia\" OR BCR-ABL) AND (BECN1 OR \"Beclin 1\" OR HDAC6) AND (acetylation OR \"autophagic flux\") AND SRC:MED AND PUB_YEAR:[2025 TO 2026]"],"papersShown":[{"pmid":"41596764","doi":"10.3390/ijms27021123","year":2026,"isNew":true,"title":"BCL-2 and BCL-xL in Cancer: Regulation, Function, and Therapeutic Targeting"},{"pmid":"42006285","doi":"10.1016/j.isci.2026.115420","year":2026,"isNew":true,"title":"Liquid-liquid phase separation in cancer therapy resistance"},{"pmid":"42192969","doi":"10.3390/cancers18101610","year":2026,"isNew":true,"title":"miRNA-lncRNA Cross-Regulation Landscape in Cancer: From Molecular Mechanisms to Therapeutic and Diagnostic Applications"},{"pmid":"42002813","doi":"10.1186/s13578-026-01572-5","year":2026,"isNew":true,"title":"Lactate metabolic reprogramming and lactylation modification: molecular mechanisms reshaping the tumor immunosuppressive microenvironment"},{"pmid":"41899586","doi":"10.3390/cancers18060982","year":2026,"isNew":true,"title":"Targeting Mitochondrial Vulnerabilities in Chronic Myeloid Leukemia: From Pathobiology to Novel Therapeutic Opportunities"},{"pmid":"42480967","doi":"10.1016/j.canlet.2026.218755","year":2026,"isNew":true,"title":"Dual Beclin 1 post-translational reprogramming by BCR-ABL and HDAC6 inhibition disables autophagic flux and overcomes CML resistance"},{"pmid":"42259777","doi":"10.1038/s41392-026-02714-4","year":2026,"isNew":true,"title":"Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases"},{"pmid":"42221857","doi":"10.1093/pcmedi/pbag014","year":2026,"isNew":true,"title":"Protein modification systems as cancer biomarkers and therapeutic targets"},{"pmid":"42196157","doi":"10.3390/ijms27104172","year":2026,"isNew":true,"title":"Diversity and Multi-Target Potential of Pyrazole, Imidazole or Triazole Derivatives in Modern Anticancer Therapy"},{"pmid":"42282109","doi":"10.34172/bi.32638","year":2026,"isNew":true,"title":"Integrin-linked kinase (ILK) in hematologic malignancies: Bridging molecular mechanisms to therapeutic innovation"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":14336,"output":5698},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic myeloid leukemia\" AND (HDAC6 OR ricolinostat OR citarinostat OR \"tubulin acetylation\") AND (autophagy OR \"integrated stress response\" OR apoptosis) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic myeloid leukemia\" AND (\"BH3 profiling\" OR MCL1 OR MCL-1 OR \"BCL-xL\" OR navitoclax) AND (\"leukemic stem cell\" OR CD34 OR resistance) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:41596764","PMID:42006285","PMID:42192969","PMID:42002813","PMID:41899586","PMID:42480967","PMID:42259777","PMID:42221857","PMID:42196157","PMID:42282109","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787167423991","cycle":91,"visit":2,"ts":"2026-08-19T19:23:43.991Z","cancer":{"key":"acute myeloid leukemia","name":"acute myeloid leukemia","mondo":{"id":"MONDO:0018874","name":"acute myeloid leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Independent mechanistic consolidation of MCL-1/BCL-xL lineage switching as the dominant venetoclax-escape route promotes the gilteritinib+AZA+VEN triplet to CANDIDATE, while two new leads open — TIM3-targeted nanoformulated venetoclax with NK engagement (VINCENT) and randomised ATRA add-on to decita","confidence":0.55,"notebook":"This visit's pack is venetoclax-resistance-centric and it moves the programme's centre of gravity from \"new targets\" to \"how venetoclax is delivered and combined.\"\n\nP8 (PMID:42575085, Cancer Cell) independently codifies the exact mechanism L1 and L2 were built on: compensatory lineage-associated switching to MCL-1/BCL-xL dependence, oncogenic signalling activation, blast differentiation stage, plus less-validated BAX mutations, integrated stress response, amino-acid uptake and FAO-sustained OXPHOS. It is a review, not primary data, so I treat it as mechanistic corroboration only — but it is independent of the originating groups and it is precisely the rationale for collapsing MCL1 pharmacologically (gilteritinib/STAT5-PIM in FLT3-ITD; XPO1 blockade for MCL1 protein output). L1 advances to CANDIDATE on that basis, with the caveat printed here: no NCT06317649 readout exists yet, so the promotion rests on mechanism, not outcome. L2 strengthens modestly; its kill criterion (no responses in TP53-WT/MCL1-high) is unchanged, and BAX mutation now joins the resistance list as a route that would defeat both drugs.\n\nGenuinely new: P7 (PMID:42587178) reports VINCENT — anti-CD16 × anti-TIM3 engager carrying nanoformulated venetoclax — active in VEN-resistant lines, PDX and primary samples, with efficacy tracking the NK:TIM3+ blast ratio. The abstract's own framing is that naked TIM3 blockade underperformed clinically [KNOWN: sabatolimab STIMULUS-MDS2 missed], so the claimed value is delivery plus NK re-arming, not checkpoint biology. P10 (PMID:42529898) independently shows a plain venetoclax-lipid formulation outperforms free drug, which is a confound: some of VINCENT's gain may be pharmacokinetic rather than TIM3-directed [INFERRED]. New lead L6 with that falsification built in. Window risk: TIM3 is expressed on normal HSPC subsets, monocytes and activated T/NK cells, so on-target myelosuppression and NK fratricide must be measured.\n\nSecond new lead L7: DECIDER-2 (PMID:42563153) is a randomised phase III of ATRA versus placebo added to decitabine+venetoclax, built on a positive phase II (OS 8.2 vs 5.1 months, HR 0.65) in non-fit AML. Non-APL ATRA repurposing on the approved HMA/VEN backbone is the cheapest translational bet in this dossier and RARA is a KG anchor.\n\nL4 (raloxifene/ANP32B) is retired as pre-declared: no independent target-engagement or epistasis data surfaced. L3 stays put — P2 and P3 (ferroptosis PTM/ubiquitination; NRF2's dual role) only reinforce that NRF2/KEAP1 activation is the predictable escape and give no primary-AML or HSPC-sparing data. QTX-2101 remains uncharacterised in the pack; question carried forward. P4/P6 noted, not lead-worthy (CAR-T review; lncRNA screen hits AC009299.3 unreplicated).","leadChanges":[{"id":"L1","title":"FLT3 inhibition plus BCL2/HMA triplet in FLT3-mutant AML unfit for intensive therapy","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.66},{"id":"L2","title":"XPO1 inhibition (eltanexor) to resensitise R/R AML/MDS to venetoclax","level":"LEAD","status":"STRENGTHENED","confidence":0.5},{"id":"L4","title":"Raloxifene repurposing against the ANP32B-MYC super-enhancer axis in pediatric AML","level":"LEAD","status":"RETIRED","confidence":0.08},{"id":"L6","title":"TIM3-directed nanoformulated venetoclax with NK engagement (VINCENT) for venetoclax-resistant AML","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L7","title":"ATRA add-on to decitabine plus venetoclax in non-fit AML (DECIDER-2)","level":"LEAD","status":"NEW","confidence":0.5}],"unverifiedCitations":0,"openQuestions":["Does the TIM3 targeting arm of VINCENT add anything over an untargeted venetoclax-lipid nanoparticle, and what is its effect on normal CD34+ HSPC colony formation and NK CD16 integrity?","In DECIDER-2, which biomarker segregates ATRA benefit on a DAC+VEN backbone, and does ATRA-induced monocytic differentiation antagonise venetoclax in any subset?","Are BAX loss-of-function mutations and integrated stress response activation clinically prevalent venetoclax-resistance mechanisms, and do they defeat MCL1-directed strategies (L1/L2) as well?","Is venetoclax-refractory monocytic AML GSH/GPX4/SLC7A11-dependent in primary patient samples with normal-HSPC sparing, and does NRF2/KEAP1 status predict escape?","What is the composition and mechanism of QTX-2101 (NCT07504458), and can it displace IV arsenic trioxide in APL?","Do reported correlatives from NCT06317649 show MCL1-shifted or RAS/MAPK-driven relapse, and is the gilteritinib triplet tolerable enough to beat FLT3i+HMA doublet?"],"nextQueries":["(\"acute myeloid leukemia\") AND (TIM3 OR HAVCR2) AND (NK OR engager OR sabatolimab) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"acute myeloid leukemia\") AND (BAX AND mutation) AND (venetoclax OR apoptosis) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"acute myeloid leukemia\") AND (\"all-trans retinoic acid\" OR tretinoin) AND (decitabine OR azacitidine OR venetoclax) AND NOT (promyelocytic) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"41560619","doi":"10.1080/19420862.2026.2614669","year":2026,"isNew":true,"title":"Antibodies to watch in 2026"},{"pmid":"41588554","doi":"10.1186/s40164-025-00737-1","year":2026,"isNew":true,"title":"Epigenetic and post-translational regulatory networks of ferroptosis in the tumor immune microenvironment"},{"pmid":"42218132","doi":"10.1038/s41389-026-00630-4","year":2026,"isNew":true,"title":"Tipping the balance: NRF2's dual role in ferroptotic fate"},{"pmid":"41800605","doi":"10.1080/07853890.2026.2640457","year":2026,"isNew":true,"title":"Preclinical advances and mechanistic insights of CAR-T therapy for acute myeloid leukemia: from target iteration to microenvironment regulation"},{"pmid":"41639774","doi":"10.1080/2162402x.2026.2624244","year":2026,"isNew":true,"title":"Enhancing immunogenic cell death by targeting the GPX4-ZP3 immune checkpoint"},{"pmid":"42388349","doi":"10.1016/j.ncrna.2026.05.002","year":2026,"isNew":true,"title":"Identification of long non-coding RNAs involved in leukemogenesis and venetoclax response in acute myeloid leukemia through functional CRISPR-dCas9 interference screens"},{"pmid":"42587178","doi":"10.1038/s43018-026-01217-z","year":2026,"isNew":true,"title":"TIM3-targeted delivery of venetoclax overcomes drug resistance and reinvigorates NK cell activity in acute myeloid leukemia"},{"pmid":"42575085","doi":"10.1016/j.ccell.2026.07.004","year":2026,"isNew":true,"title":"Beyond BCL-2: What drives venetoclax resistance in acute myeloid leukemia?"},{"pmid":"42563153","doi":"10.1186/s12885-026-16617-8","year":2026,"isNew":true,"title":"DECIDER-2: Prospective randomized multicenter phase III trial of decitabine and venetoclax administered in combination with all-trans retinoic acid or placebo in patients with acut"},{"pmid":"42529898","doi":"10.1039/d6tb01032f","year":2026,"isNew":true,"title":"Bioactive venetoclax-lipid nanomedicine enhances therapeutic efficacy in acute myeloid leukemia"}],"trialsShown":[{"nct":"NCT07504458","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Pivotal Open-label Phase 3 Clinical Study of QTX-2101 in Adult Patients With Acute Promyelocytic Leukemia"},{"nct":"NCT06399640","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Eltanexor and Venetoclax in Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT05554393","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Comparing Cytarabine + Daunorubicin Therapy Versus Cytarabine + Daunorubicin + Venetoclax Versus Venetoclax + Azacitidine in Younger Patient"},{"nct":"NCT06710418","phase":"NA","status":"RECRUITING","isNew":false,"title":"Evaluating the Effects of Hemoglobin Threshold-specific Packed Red Blood Cell Transfusions on Quality of Life and Functional Outcomes in Pat"},{"nct":"NCT06317649","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Venetoclax and HMA Treatment of Older and Unfit Adults With FLT3 Mutated Acute Myeloid Leukemia (AML) (A MyeloMATCH Treatment Trial)"},{"nct":"NCT06917911","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing the Addition of Venetoclax or Gemtuzumab Ozogamicin (GO) to Usual Treatment Regimen (Cytarabine and Daunorubicin, \"7+3\") for Core Bi"},{"nct":"NCT02521493","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syn"}],"usage":{"input":10973,"output":6884},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"acute myeloid leukemia\") AND (venetoclax) AND (resistance OR \"MCL1\" OR monocytic) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"acute myeloid leukemia\") AND (ferroptosis OR SLC7A11 OR GPX4 OR cystine) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41560619","PMID:41588554","PMID:42218132","PMID:41800605","PMID:41639774","PMID:42388349","PMID:42587178","PMID:42575085","PMID:42563153","PMID:42529898","NCT07504458","NCT06399640","NCT06904066","NCT05554393","NCT06710418","NCT06317649","NCT06917911","NCT02521493"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787167215153","cycle":90,"visit":2,"ts":"2026-08-19T19:20:15.153Z","cancer":{"key":"renal cell carcinoma","name":"renal cell carcinoma","mondo":{"id":"MONDO:0005086","name":"renal cell carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"ALOX5 is the actionable RCC lipid node this visit — it drives sunitinib resistance via p38/ERK/PPARα/CPT1A (PMID:42287957), making zileuton+sunitinib re-sensitisation testable, while new chelation literature (PMID:42122232) offers an iron-depletion/anti-metastatic alternative to the deferasirox-ferr","confidence":0.44,"notebook":"This visit's pack is lipid/iron-heavy and it cuts both ways for L1.\n\nThe sharpest new item is P7 (PMID:42287957): ALOX5 is upregulated in TKI-resistant RCC tissue and cells, tracks with poor prognosis, and drives sunitinib resistance through p38/ERK→PPARα→CPT1A — i.e. shunting fatty acids into β-oxidation. That answers Open Question 5 in an unexpected direction: ALOX5 in RCC is not acting as a pro-ferroptotic lipoxygenase but as the switch into FAO, which [INFERRED] drains peroxidisable PUFA-phospholipid pools and would raise the ferroptosis threshold — consistent with, and mechanistically better specified than, my visit-1 guess. It also promotes ALOX5 from \"escape node\" to a standalone repurposing lead: zileuton is an approved 5-LOX inhibitor [KNOWN], and P7 reports in vivo tumour and lung-metastasis suppression on ALOX5 inhibition. New L5.\n\nAgainst L1: P8 (PMID:42122232) frames clinical chelators (deferoxamine, deferasirox, deferiprone) as iron-*removing* agents — explicitly noting deferiprone can strip iron from iron-loaded renal cancer cells and from iron-laden TAMs, with anti-metastatic rather than ferroptotic intent. Bulk labile-iron depletion antagonises ferroptosis [KNOWN], so the pack does not corroborate the deferasirox-as-DANGER-inhibitor→ferroptosis reading; it offers a competing explanation for any chelator effect in ccRCC. L1 weakened (0.45→0.38) and its critical experiment is now sharper: only genetic ITPRIP knockdown with ferrostatin rescue, and FerroOrange showing *redistribution* not depletion, can separate the two models. The chelation/anti-metastatic mechanism is split out as its own testable lead (L6) rather than being allowed to prop up L1, using P8 plus P10 (PMID:41513613) on TME/immune-cell iron dependence.\n\nP6 (PMID:41958067) adds an orthogonal ccRCC lipogenic node: ACLY upregulated via HIF-2α/LPCAT1/FBXW7 and VHL/PPARγ. LPCAT1 controls lysophospholipid re-acylation, so ACLY/LPCAT1 sits directly upstream of the same peroxidisable-membrane pool that ALOX5/CPT1A drains — new L7, low confidence, window concern because ACLY is required for nephrogenesis and renal lipid handling (P6).\n\nP1, P2, P3, P4, P5, P9 are non-RCC or generic reviews; recorded as non-informative here. Trials: T1/T4 unchanged and still recruiting, so L3 is unmoved (no subtype-resolved readout yet); no trial in this pack touches the axitinib-priming schedule (L2) or ferroptosis. L4 (Wnt/sFRP-4) has now gone two evidence-bearing visits without independent corroboration and is marked for retirement next visit absent new data.","leadChanges":[{"id":"L1","title":"Deferasirox-mediated disruption of the ITPRIP(DANGER)/NRF2/FTH1 axis to force ferroptosis in VHL-null ccRCC","level":"LEAD","status":"WEAKENED","confidence":0.38},{"id":"L5","title":"ALOX5 inhibition (zileuton) to reverse VEGFR-TKI resistance in RCC by blocking p38/ERK/PPARα/CPT1A fatty-acid oxidation","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L6","title":"Iron efflux/chelation (deferiprone) as an anti-metastatic, TAM-reprogramming strategy in RCC — distinct from ferroptosis induction","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L7","title":"ACLY/LPCAT1 lipogenic axis downstream of HIF-2alpha and VHL/PPARgamma as a ccRCC metabolic vulnerability","level":"LEAD","status":"NEW","confidence":0.28},{"id":"L4","title":"Wnt/β-catenin reactivation as a targetable node in sunitinib-resistant RCC (ZC3H13/m6A–sFRP-4 axis)","level":"LEAD","status":"WEAKENED","confidence":0.18}],"unverifiedCitations":0,"openQuestions":["Does genetic ITPRIP knockdown phenocopy deferasirox in VHL-null ccRCC with ferrostatin rescue, and does chelation raise or lower labile iron in the peroxidation-competent pool — the direct test separating L1 from the iron-depletion model?","Does zileuton (or FLAP inhibition) restore sunitinib/axitinib sensitivity in ALOX5-high resistant RCC in vivo, and is the effect epistatic with etomoxir/CPT1A loss rather than with lipoxygenase-derived peroxidation?","Are ALOX5-high, TKI-resistant RCC tumours ferroptosis-sensitised or ferroptosis-protected — i.e. is FAO diversion the dominant determinant of peroxidisable phospholipid supply?","Is ACLY or LPCAT1 dependence demonstrable in VHL-null ccRCC lines/PDX, is ACSVL1/SLC27A2 expressed sufficiently for bempedoic acid activation, and what is adult renal ACLY dependence?","Do OPTIC RCC (NCT05361720) or NCT03866382 yet report subtype-resolved responses for MET-altered papillary vs FH-deficient vs TFE3-fusion nccRCC?","Is there any human RCC dataset showing the post-axitinib myeloid/hypoxia shift, and does the pembrolizumab+aldesleukin trial (NCT05155033) offer a schedule-informative comparator for L2?"],"nextQueries":["(\"renal cell carcinoma\" OR ccRCC) AND (ALOX5 OR zileuton OR \"5-lipoxygenase\" OR CPT1A OR \"fatty acid oxidation\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"renal cell carcinoma\" OR ccRCC) AND (ACLY OR \"ATP citrate lyase\" OR LPCAT1 OR bempedoic OR SCD1) AND SRC:MED","(\"renal cell carcinoma\") AND (deferiprone OR \"tumor-associated macrophage\" AND iron OR ITPRIP OR DANGER) AND SRC:MED"],"papersShown":[{"pmid":"42210736","doi":"10.1080/07853890.2026.2673182","year":2026,"isNew":true,"title":"The role of protein palmitoylation in disease pathogenesis and therapeutic innovation"},{"pmid":"42186342","doi":"10.1080/07853890.2026.2677931","year":2026,"isNew":true,"title":"Overexpression of SLC44A4 suppresses ferroptosis and reduces lipid peroxidation &lt;i&gt;via&lt;/i&gt; noncanonical NF-κB signaling in a NIK-dependent manner"},{"pmid":"42157383","doi":"10.1080/15384101.2026.2668450","year":2026,"isNew":true,"title":"UBE2C promotes pancreatic cancer progression through PI3K/Akt/mTOR signaling pathway"},{"pmid":"42135894","doi":"10.1080/0886022x.2026.2667561","year":2026,"isNew":true,"title":"A review of the sirtuins family: pivotal regulators and emerging therapeutic targets in renal fibrosis"},{"pmid":"41963781","doi":"10.1080/19490976.2026.2651930","year":2026,"isNew":true,"title":"Microbiota as a modulator of drug response: targeting microbial-drug crosstalk in cancer therapy"},{"pmid":"41958067","doi":"10.1080/0886022x.2026.2652826","year":2026,"isNew":true,"title":"Emerging roles of ATP citrate lyase in kidney diseases: from pathogenic driver to therapeutic target"},{"pmid":"42287957","doi":"10.1016/j.intimp.2026.117006","year":2026,"isNew":true,"title":"ALOX5 mediates sunitinib resistance in renal cell carcinoma by reprogramming lipid metabolism through the p38/ERK/PPARα axis"},{"pmid":"42122232","doi":"10.3390/cancers18091436","year":2026,"isNew":true,"title":"Linking Iron Metabolism, Ferroptosis, and Cancer: New Targets and Prospects for Effective Anticancer Therapeutic Interventions"},{"pmid":"41670852","doi":"10.1007/s10565-026-10145-8","year":2026,"isNew":true,"title":"Lipocalin 2: a double-edged sword in cellular ferroptosis"},{"pmid":"41513613","doi":"10.1038/s41389-025-00595-w","year":2026,"isNew":true,"title":"Iron and metabolic rewiring in cancer"}],"trialsShown":[{"nct":"NCT03866382","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare G"},{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT05361720","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Genetic Testing to Select Therapy for the Treatment of Advanced or Metastatic Kidney Cancer, OPTIC RCC Study"},{"nct":"NCT05155033","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Phase II Trial of Combination Anti-PD-1 and Aldesleukin for Metastatic Melanoma and Renal Cell Carcinoma"},{"nct":"NCT04788095","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"App-Based Mindfulness Intervention for the Improvement of Quality of Life in Patients With Metastatic Renal Cell Cancer"},{"nct":"NCT06966024","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Study of DCC-2812 in Participants With Advanced Genitourinary Cancers"},{"nct":"NCT07160335","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Phase I Clinical Study to Evaluate the PK Profile, Efficacy, Safety and Immunogenicity of HLX17 vs. Keytruda® in Multiple Resected Solid T"}],"usage":{"input":11327,"output":7654},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"renal cell carcinoma\" OR ccRCC) AND (ferroptosis OR GPX4 OR NRF2 OR FTH1 OR \"labile iron\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"renal cell carcinoma\") AND (deferasirox OR \"iron chelation\" OR ITPRIP OR ALOX5) AND SRC:MED"],"evidenceIds":["PMID:42210736","PMID:42186342","PMID:42157383","PMID:42135894","PMID:41963781","PMID:41958067","PMID:42287957","PMID:42122232","PMID:41670852","PMID:41513613","NCT03866382","NCT07115043","NCT07636785","NCT05361720","NCT05155033","NCT04788095","NCT06966024","NCT07160335"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787166995327","cycle":89,"visit":2,"ts":"2026-08-19T19:16:35.327Z","cancer":{"key":"papillary renal cell carcinoma","name":"papillary renal cell carcinoma","mondo":{"id":"MONDO:0017884","name":"papillary renal cell carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Open a VEGF+EGFR+PD-L1 lead (bevacizumab/erlotinib/atezolizumab, NCT04981509) for FH-deficient and type 2 papillary RCC — which also pre-positions an EGFR-bypass salvage arm for MET-inhibitor failure — and treat the ENPP3xCD3 bispecific trial in ccRCC as the safety bellwether for KIM-1-directed prox","confidence":0.5,"notebook":"No new literature returned this visit — both queries (MET-inhibitor resistance in pRCC 2022–2026; HAVCR1/KIM-1 immunoconjugates 2020–2026) came back empty. That is itself a finding worth banking: there is apparently no indexed clinical or preclinical report of acquired MET-inhibitor resistance specifically in papillary RCC, so open question 5 cannot be answered from literature and must be reframed as a specimen/ctDNA question (PAPMET2 and CALYPSO banked samples) rather than a search question. The desk should not re-run that exact query string; broaden to crizotinib/savolitinib resistance in MET-driven tumours generally and back-infer.\n\nThe trial pack does move two things. NCT04981509 (bevacizumab + erlotinib + atezolizumab, recruiting) is new to the dossier and creates a lead the programme was missing: dual VEGF/EGFR blockade in FH-deficient/HLRCC-associated and sporadic type 2 pRCC. Mechanistically [KNOWN], FH loss drives fumarate accumulation, HIF stabilisation and glycolytic rewiring with EGFR-pathway dependence; bevacizumab+erlotinib has prior reported activity in HLRCC-related and sporadic papillary tumours, and adding atezolizumab tests whether the fumarate/succination-driven inflamed phenotype is checkpoint-tractable. This lead also directly hedges L1: EGFR/ERBB bypass is a predicted MET-inhibitor escape route, so erlotinib-containing regimens are the pre-positioned salvage arm rather than an unrelated programme. Resistance routes to anticipate: NRF2/KEAP1 axis activation downstream of fumarate, ERBB2/3 switching, VEGF-independent angiogenesis.\n\nL3 strengthens modestly. NCT05433142 (XmAb819, ENPP3×CD3 bispecific) is restricted to clear-cell RCC, but ENPP3 is a proximal-tubule brush-border antigen [KNOWN], so this trial is the closest available empirical test of whether a tubule-lineage surface antigen can be engaged with T cells without dose-limiting nephrotoxicity. If XmAb819 clears safety, the same window argument transfers to KIM-1/HAVCR1 in pRCC, where antigen load is reportedly higher (PMID:41934036); if it fails on renal toxicity, L3's entire premise weakens. This is an explicit falsification hook, not confirmation — confidence 0.4→0.45 only.\n\nNoted but not promoted to leads: NCT06792552 (SIM0505, first-in-human, undisclosed target in the pack — cannot be reasoned about without a target) and NCT04071223 (radium-223 + cabozantinib for bone-metastatic RCC), which is a cabozantinib-backbone permutation relevant to L1's osteotropic pRCC subset but histology-agnostic. L1 and L2 unchanged: no new efficacy data, and SUNNIFORECAST's pRCC signal remains exploratory and non-significant.\n\nNext visit priorities: FH/HLRCC biology and bev-erlotinib response data; ENPP3/CDH6/KIM-1 renal-antigen toxicity reports; and any PAPMET2 readout.","leadChanges":[{"id":"L6","title":"Dual VEGF/EGFR blockade plus PD-L1 inhibition in FH-deficient/HLRCC-associated and type 2 papillary RCC","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"Proximal-tubule lineage as the therapeutic window: KIM-1/HAVCR1-directed agents and tubule-selective toxins","level":"LEAD","status":"STRENGTHENED","confidence":0.45}],"unverifiedCitations":0,"openQuestions":["Does bevacizumab+erlotinib+atezolizumab (NCT04981509) show activity segregating by FH deficiency (2SC/FH IHC) versus FH-intact type 2 versus type 1 pRCC, and does PD-L1 or NRF2 status modify it?","Does XmAb819 (ENPP3xCD3) clear phase 1 without dose-limiting AKI — i.e. is the proximal-tubule antigen window real enough to justify KIM-1/HAVCR1 ADC or CAR development in pRCC?","Does PAPMET2 (NCT05411081) show PFS benefit from adding atezolizumab to cabozantinib, and does benefit track with MET alteration or inflamed/PD-L1 signature?","Since no pRCC-specific MET-resistance literature exists, what does MET-inhibitor resistance in other MET-driven cancers predict for pRCC (second-site kinase-domain mutation vs EGFR/ERBB3 vs NF2/RAS bypass), and can banked PAPMET2/CALYPSO ct","Is the SUNNIFORECAST pRCC ipi/nivo signal reproducible in any independent centrally-reviewed cohort, and does any biomarker-defined subset support a confirmatory randomised trial?","What is SIM0505's target (NCT06792552), and is it a renal-lineage or MET/HGF-axis agent worth tracking for pRCC?"],"nextQueries":["(\"hereditary leiomyomatosis\" OR HLRCC OR \"FH-deficient\") AND (\"renal cell\") AND (bevacizumab OR erlotinib OR atezolizumab OR NRF2) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(ENPP3 OR CDH6 OR HAVCR1 OR \"KIM-1\") AND (\"bispecific\" OR \"antibody-drug conjugate\" OR nephrotoxicity OR \"proximal tubule\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(MET AND (savolitinib OR crizotinib OR capmatinib) AND (\"acquired resistance\" OR \"secondary mutation\" OR ctDNA)) AND SRC:MED AND PUB_YEAR:[2019 TO 2026]"],"papersShown":[],"trialsShown":[{"nct":"NCT03866382","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare G"},{"nct":"NCT06792552","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Phase I Study of SIM0505 in Participants With Advanced Solid Tumors"},{"nct":"NCT05287945","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Study of Orellanine in Metastatic Clear-Cell or Papillary Renal Cell Carcinoma"},{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT05411081","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing Cabozantinib With or Without Atezolizumab in Patients With Advanced Papillary Kidney Cancer, PAPMET2 Trial"},{"nct":"NCT05433142","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Study of XmAb®819 in Subjects With Advanced Clear Cell Renal Cell Carcinoma"},{"nct":"NCT04981509","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing of Bevacizumab, Erlotinib, and Atezolizumab in Combination for Advanced-Stage Kidney Cancer"},{"nct":"NCT04071223","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer "}],"usage":{"input":5629,"output":4900},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"papillary renal cell carcinoma\" OR \"KIRP\") AND (MET AND (savolitinib OR cabozantinib OR crizotinib) AND resistance) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(HAVCR1 OR \"KIM-1\" OR \"kidney injury molecule\") AND (\"antibody-drug conjugate\" OR CAR-T OR immunoconjugate OR \"renal cell\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"evidenceIds":["NCT03866382","NCT06792552","NCT05287945","NCT00001238","NCT05411081","NCT05433142","NCT04981509","NCT04071223"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787166767701","cycle":88,"visit":2,"ts":"2026-08-19T19:12:47.701Z","cancer":{"key":"medullary thyroid carcinoma","name":"medullary thyroid carcinoma","mondo":{"id":"MONDO:0015277","name":"medullary thyroid gland carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"At selpercatinib progression in MTC, bypass alterations outnumber secondary RET mutations (MET amplification 15%, KRAS 7.1%, secondary RET only 22.7% of thyroid biopsies; PMID:41537704), so pivot resistance strategy to ctDNA-gated MET inhibition (cabozantinib repurposing) and pursue DLL3-directed ta","confidence":0.58,"notebook":"The RETgistry consortium (PMID:41537704) is the first clinical-scale answer to open question 1 and it reorders the resistance programme. Across 143 post-progression biopsies (tissue 91, plasma 52) in RET-altered solid tumours, secondary RET kinase mutations appeared in only 14% overall and 22.7% of thyroid biopsies; the dominant acquired off-target events were MET alterations (18.2%, amplification 15%), then TP53 8.2%, APC 7.6%, KRAS 7.1%, KEAP1 5.9%, CDKN2A/B 5.3%. Caveat: only 15 of 109 patients had thyroid primaries and the abstract states MET enrichment for the pooled post-SRI set, so MTC-specific frequency is not resolvable from the abstract [INFERRED]. Two consequences. First, L2 weakens: allele-specific next-generation RET inhibitors address at most ~1 in 5 progressing thyroid tumours, so genotype-gated enrolment is mandatory or trials will fail on dilution (PMID:41977363 corroborates secondary mutation plus MET/EGFR bypass as the two classes). Second, L1 weakens as written — NF1 loss did not surface in the clinical landscape, and the only MAPK-node event reported was KRAS at 7.1%; the MEK-combination hypothesis survives but must be gated on a MAPK-output readout (pERK/DUSP6) or KRAS/NF1 event rather than assumed.\n\nNew L4 replaces the vacated space with the most actionable clinical inference: MET amplification is the leading bypass, and cabozantinib — already approved in MTC — is a potent MET inhibitor alongside RET and VEGFR2 [KNOWN]. Sequencing cabozantinib (or a selective MET TKI plus continued selpercatinib, to preserve RET suppression) by ctDNA-detected MET copy gain at selpercatinib progression is a repurposing-first, near-term testable hypothesis; expected escape is MET kinase-domain mutation, HGF autocrine loop, or RET/MET compound events.\n\nOpen question 3 is answered for DLL3 and generates L5, the strongest new lead. Multicentre IHC in 119 resected MTC found DLL3 positivity in 89.1%, high (≥50%) in 35.3%, with DLL3-high tracking high-grade histology, desmoplasia, nodal spread and markedly worse DFS/OS (HR 7.96/11.x) (PMID:41345358) — i.e. the target enriches in exactly the population that fails RET inhibition. A post-selpercatinib RET-altered MTC patient treated with tarlatamab under a modified three-step step-up with intensified CRS/ICANS management had only grade 2 CRS and grade 2 ICANS and an ongoing biochemical and radiographic complete response at 8 weeks (PMID:42117355), tempering the prior safety signal. WHO-grade integration (PMID:42134278) gives the stratification variable. n=1; calcitonin/CEA kinetics as engager endpoints need prospective definition.\n\nNext: MTC-only MET/NF1 prevalence, DLL3 IHC threshold-to-response, whether MTC is eligible in tarlatamab NEC baskets (NCT07016230), and still-unaddressed RET-wildtype/RAS-mutant MTC biology.","leadChanges":[{"id":"L1","title":"RET + MEK dual blockade for MAPK-bypass resistance in RET-mutant MTC","level":"LEAD","status":"WEAKENED","confidence":0.45},{"id":"L2","title":"Next-generation RET inhibitors for on-target gatekeeper/solvent-front resistance","level":"LEAD","status":"WEAKENED","confidence":0.4},{"id":"L4","title":"MET-directed rescue at selective RET inhibitor progression: cabozantinib re-sequencing or selpercatinib + selective MET TKI, gated on MET amplification","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L5","title":"DLL3-directed T-cell engagement (tarlatamab) in DLL3-high MTC after RET inhibitor failure","level":"LEAD","status":"NEW","confidence":0.55}],"unverifiedCitations":1,"openQuestions":["In MTC-only post-selpercatinib cohorts, what are the true frequencies of MET amplification, KRAS/NF1 loss and secondary RET mutation, and are they mutually exclusive within a single biopsy?","Which DLL3 IHC threshold predicts tarlatamab benefit in MTC, and do calcitonin/CEA kinetics track radiographic response under T-cell engagement well enough to serve as trial endpoints?","Is there human dosing precedent for selpercatinib plus a selective MET inhibitor, or for cabozantinib immediately after selpercatinib, and what were the hepatic/hypertensive AEs?","Does DLL3-high status anti-correlate with SSTR2 and FAP positivity, i.e. can one biopsy triage patients between engager, radioligand and MET/MEK arms?","What drives RET-wildtype MTC (RAS-mutant and quadruple-negative), and do the KG anchors NTRK1 [SOMATIC] or ESR2 [SOMATIC] have any supported role there?","Is ERK hyperactivation-induced toxicity (PMID:41865130) exploitable in RET-driven MTC as an alternative to MAPK suppression?"],"nextQueries":["(\"medullary thyroid\" AND (\"MET amplification\" OR capmatinib OR tepotinib OR crizotinib OR cabozantinib) AND (resistance OR selpercatinib)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"medullary thyroid\" AND (DLL3 OR tarlatamab OR \"T-cell engager\") AND (calcitonin OR response OR \"cytokine release\")) AND SRC:MED","((\"medullary thyroid\" AND (\"RET wild-type\" OR \"RAS mutant\" OR HRAS OR KRAS OR NTRK1 OR ESR2)) AND (targeted OR trial)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"41345358","doi":"10.1007/s12022-025-09894-9","year":2025,"isNew":true,"title":"Multi-center Assessment of DLL3 Expression by Immunohistochemistry in Medullary Thyroid Carcinoma"},{"pmid":"41977363","doi":"10.3390/ijms27073180","year":2026,"isNew":true,"title":"RET Signaling Pathway in Human Cancer: Oncogenic Mechanisms, Selective Inhibitors, and Emerging Resistance Strategies"},{"pmid":"41992056","doi":"10.1002/cam4.71742","year":2026,"isNew":true,"title":"Immunotherapy in Thyroid Cancer: Current Strategies and Challenges"},{"pmid":"41994561","doi":"10.1016/j.omton.2026.201146","year":2026,"isNew":true,"title":"Targeted therapies in pediatric oncology: A start"},{"pmid":"41913261","doi":"10.1186/s13098-026-02095-2","year":2026,"isNew":true,"title":"Abstracts from The XXV Brazilian Diabetes Society Meeting"},{"pmid":"41865130","doi":"10.1007/s00018-026-06084-6","year":2026,"isNew":true,"title":"ERKed by too much signaling: from oncogenic driver to therapeutic vulnerability"},{"pmid":"41537704","doi":"10.1158/1078-0432.ccr-25-4382","year":2026,"isNew":true,"title":"Landscape of Genomic Mechanisms of Resistance to Selective RET Inhibitors in RET-Altered Solid Tumors: Analysis of the RETgistry Global Consortium"},{"pmid":"41751352","doi":"10.3390/biomedicines14020453","year":2026,"isNew":true,"title":"Cancer Stemness and Dedifferentiation in Anaplastic Thyroid Carcinoma: Insights into a Multigenic, Microenvironmental Network and the Role of CD44"},{"pmid":"42117355","doi":"10.1177/10507256261448706","year":2026,"isNew":true,"title":"A Novel Approach to Targeting DLL3 with Tarlatamab in a Patient with Medullary Thyroid Carcinoma after Progression on Selpercatinib"},{"pmid":"42134278","doi":"10.1016/j.clon.2026.104171","year":2026,"isNew":true,"title":"Management of Medullary Thyroid Carcinoma: Integrating World Health Organization Grading and Molecular Targets for Precision Therapy"}],"trialsShown":[{"nct":"NCT03866382","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare G"},{"nct":"NCT06161532","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Sacituzumab Govitecan With or Without Atezolizumab Immunotherapy in Rare Genitourinary Tumors (SMART) Such as High Grade Neuroendocrine Carc"},{"nct":"NCT04280081","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of Selpercatinib (LY3527723) in Participants With Advanced Solid Tumors Including RET Fusion-positive Solid Tumors, Medullary Thyroi"},{"nct":"NCT06444880","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Phase II Trial of Ubamatamab Alone or in Combination With Cemiplimab in MUC16-Expressing SMARCB1-Deficient Malignancies"},{"nct":"NCT07713901","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Database Linkage Study to Evaluate the Risk of Medullary Thyroid Carcinoma"},{"nct":"NCT07016230","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study Investigating Tarlatamab (AMG 757) in Patients With Metastatic/Locally Advanced Small-Cell Lung Cancer (SCLC) and Other Poorly Differe"},{"nct":"NCT07259304","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Social Health, Activity Behaviors, and Quality of Life Among Young Adult Cancer Survivors"},{"nct":"NCT04071223","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer "}],"usage":{"input":9770,"output":6344},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"medullary thyroid\" AND (\"NF1\" OR \"MAPK reactivation\" OR \"RET G810\") AND resistance) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"medullary thyroid carcinoma\" AND (\"DLL3\" OR \"CEACAM5\" OR \"SSTR2\" OR \"GLP-1 receptor\" OR \"bispecific\" OR \"antibody-drug conjugate\")) AND SRC:MED"],"evidenceIds":["PMID:41345358","PMID:41977363","PMID:41992056","PMID:41994561","PMID:41913261","PMID:41865130","PMID:41537704","PMID:41751352","PMID:42117355","PMID:42134278","NCT03866382","NCT06161532","NCT04280081","NCT06444880","NCT07713901","NCT07016230","NCT07259304","NCT04071223"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787166563823","cycle":87,"visit":2,"ts":"2026-08-19T19:09:23.823Z","cancer":{"key":"paraganglioma","name":"paraganglioma","mondo":{"id":"MONDO:0000448","name":"paraganglioma"}},"control":false,"modelLabel":"SCIENCE","summary":"Belzutifan is now approved in advanced PPGL with ORR 26%/DCR 85% but no published genotype correlates, so the actionable next step is genotype- and succinate-resolved correlative analysis plus testing belzutifan+VEGFR-TKI, while the new SDHB-selective neddylation/UBE2F vulnerability (pevonedistat) n","confidence":0.62,"notebook":"Visit 2 delivered one genuine mechanistic advance and one clean kill.\n\n**L1 → CANDIDATE.** P9 (PMID:42573142) supplies the numbers I asked for last visit: LITESPARK-015 belzutifan in locally advanced/metastatic PPGL gave ORR 26%, DCR 85%, with blood-pressure and QoL benefit and grade 1–3 anaemia as the dominant mechanism-based toxicity; belzutifan is now FDA-approved in this indication. P10 (PMID:42481355) is the decisive negative: a multistakeholder call explicitly stating that genomic correlates and genotype-resolved outcome data are *not* available. So Q1 is answered for efficacy and unanswered for stratification — no published SDHB vs SDHD vs EPAS1 vs VHL breakdown, no on-treatment biopsies, no PAS-B mutation or HIF1α-switch data. Practical consequence: an ORR of 26% against 85% DCR means most benefit is cytostatic, so the combination question (belzutifan + cabozantinib/sunitinib to close VEGF escape) and the succinate:fumarate ratio as pharmacodynamic biomarker remain the highest-value untested moves. Registry-linked correlative science, not a new trial, is the bottleneck.\n\n**New L5 — neddylation/UBE2F.** P3 (PMID:42181244) is the first unbiased CRISPR synthetic-lethal screen in an isogenic Sdhb-null immortalised mouse chromaffin cell system: Ube2f loss suppresses growth of Sdhb-deficient cells selectively, and pevonedistat and HA-9104 reproduce this pharmacologically. Note the internal control that the screen also found Mediator subunits acting as suppressors (loss *promotes* Sdhb-null growth) and that Ube2m loss goes the opposite way to Ube2f — genuine E2 specificity, not generic NEDD8 addiction. [KNOWN] UBE2F charges SAG/RBX2-CRL5, whose substrates include NOXA; selective NOXA stabilisation in an apoptosis-primed, OXPHOS-crippled cell is a plausible window [INFERRED]. Liabilities: mouse imCC monoculture, no in vivo, no human PPGL line or PDX, and pevonedistat's clinical record elsewhere is unimpressive [KNOWN]. Confidence 0.45.\n\n**L4 retired.** No paraganglioma-model MBTA data appeared; as pre-committed, it goes. Recorded so the desk does not re-propose it.\n\nAlso logged: P4 (PMID:41637165) extends succinate-driven global hypermethylation to SDH-deficient gliomas, keeping Q5 (hypomethylating/EZH2 agents) alive but still with zero PPGL-specific pharmacology; P2 (PMID:42150423) frames ETC-limitation as an NAD(P)H/reductive-stress state remodelling dioxygenase-dependent PTMs — mechanistically adjacent, not actionable. P6 (PMID:42164133) gives a Saudi SDHB founder allele c.268T>C p.R90* with 56.5% locally invasive/metastatic disease and 21.7% mortality — a defined high-risk enrichment population for L1/L2 trials. P5 (PMID:42316325) is a single SDHB brain-metastatic case with no CNS recurrence post-temozolomide; anecdote only, so I open the alkylator/MGMT axis at low confidence rather than ignore it. P1, P7, P8 irrelevant.","leadChanges":[{"id":"L1","title":"HIF2α antagonism in pseudohypoxic (cluster 1) paraganglioma","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.78},{"id":"L5","title":"Neddylation / UBE2F-CRL5 as a synthetic-lethal vulnerability of SDHB-deficient paraganglioma","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L6","title":"Alkylator/MGMT axis in metastatic SDHx paraganglioma (low-confidence placeholder)","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L4","title":"MBTA intratumoral innate-immune agonist cocktail for locally accessible or recurrent paraganglioma","level":"LEAD","status":"RETIRED","confidence":0.08}],"unverifiedCitations":0,"openQuestions":["Do LITESPARK-015 genomic correlates (once released) show differential belzutifan ORR/PFS across SDHB, SDHD, EPAS1 and VHL genotypes, and does baseline plasma succinate:fumarate ratio or 18F-FDG avidity predict response?","Is the UBE2F/neddylation dependency reproducible in human SDH-deficient PPGL models in vivo, is it rescued by exogenous succinate, and is the effector NOXA-dependent apoptosis?","Are there any published on-treatment PPGL biopsies after belzutifan progression showing HIF2α PAS-B mutation, HIF1α switching or VEGF-independent escape, and any belzutifan+VEGFR-TKI PPGL data?","Does MGMT promoter methylation segregate with SDHx genotype in PPGL and predict temozolomide benefit, and is there any PARP+temozolomide in vivo data in SDH-deficient chromaffin models?","Is post-177Lu-DOTATATE progression in SDHB-mutant PGL driven by SSTR2 loss or uptake heterogeneity, and has NCT06427798 reported any 212Pb-VMT-alpha-NET PPGL responses or dosimetry?","Does succinate-driven hypermethylation create a tractable epigenetic dependency in PPGL (hypomethylating agents, EZH2, LSD1) and does it explain the immune-cold, low-TMB phenotype?"],"nextQueries":["(pheochromocytoma OR paraganglioma) AND (belzutifan OR \"LITESPARK\") AND (SDHB OR genotype OR biomarker OR resistance) AND SRC:MED AND PUB_YEAR:[2024 TO 2027]","(neddylation OR pevonedistat OR NAE1 OR UBE2F OR \"cullin-RING\") AND (pheochromocytoma OR paraganglioma OR \"succinate dehydrogenase\" OR SDHB) AND SRC:MED","(pheochromocytoma OR paraganglioma) AND (MGMT OR temozolomide OR olaparib OR \"DOTATATE\" OR SSTR2) AND (response OR resistance OR methylation) AND SRC:MED AND PUB_YEAR:[2023 TO 2027]"],"papersShown":[{"pmid":"41427517","doi":"10.1080/10717544.2025.2577137","year":2026,"isNew":true,"title":"Polymersome-based nanomedicine for combined cancer therapy"},{"pmid":"42150423","doi":"10.1016/j.redox.2026.104224","year":2026,"isNew":true,"title":"Impact of mitochondrial reductive stress due to respiratory chain limitation on cancer via posttranslational modifications"},{"pmid":"42181244","doi":"10.1016/j.isci.2026.115885","year":2026,"isNew":true,"title":"Unbiased CRISPR synthetic lethal screening for genetic vulnerabilities in a succinate dehydrogenase-loss model of paraganglioma"},{"pmid":"41637165","doi":"10.1093/jnen/nlag004","year":2026,"isNew":true,"title":"Gliomas with succinate dehydrogenase deficiency: A case series and brief review of the literature of oncometabolite-driven gliomagenesis"},{"pmid":"42316325","doi":"10.1186/s13256-026-06213-6","year":2026,"isNew":true,"title":"Brain metastatic paraganglioma from liver: a case report and review of the literature"},{"pmid":"42164133","doi":"10.1210/jendso/bvag070","year":2026,"isNew":true,"title":"&lt;i&gt;SDHB&lt;/i&gt;-associated paraganglioma in Saudi Arabia: High metastatic risk linked to a likely founder mutation"},{"pmid":"41965096","doi":"10.1210/clinem/dgag151","year":2026,"isNew":true,"title":"Genetics of familial acromegaly and pituitary gigantism"},{"pmid":"41882478","doi":"10.1007/s12013-026-02050-y","year":2026,"isNew":true,"title":"Amino Acids as Targets for Immunotherapy against Solid Tumors"},{"pmid":"42573142","doi":"10.1210/clinem/dgag324","year":2026,"isNew":true,"title":"Belzutifan, A Hypoxia-Inducible Factor 2-Alpha Inhibitor, for Patients with Advanced Pheochromocytoma and Paraganglioma"},{"pmid":"42481355","doi":"10.1016/j.tem.2026.06.007","year":2026,"isNew":true,"title":"A multistakeholder call for belzutifan biomarker data in advanced pheochromocytoma and paraganglioma"}],"trialsShown":[{"nct":"NCT06427798","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Somatostatin-Receptors (SSTR)-Agonist [212Pb]VMT-alpha-NET in Metastatic or Inoperable SSTR+ Gastrointestinal Neuroendocrine Tumor and Pheoc"},{"nct":"NCT06479811","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"[212Pb]VMT-Alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive Gastrointestinal Neuroendocrine Tumors, Pheochromocytoma/Par"},{"nct":"NCT03206060","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma"},{"nct":"NCT00004847","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Diagnosis of Pheochromocytoma"},{"nct":"NCT06377033","phase":"NA","status":"RECRUITING","isNew":false,"title":"Using the EHR to Advance Genomic Medicine Across a Diverse Health System"},{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT01660984","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Natural History Study of Children and Adults With Medullary Thyroid Cancer"}],"usage":{"input":10870,"output":6180},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"pheochromocytoma\" OR \"paraganglioma\") AND (\"succinate\" OR \"SDHB\") AND (\"synthetic lethality\" OR PARP OR temozolomide OR NAD OR glutamine) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","belzutifan AND (pheochromocytoma OR paraganglioma OR \"HIF2\" ) AND (resistance OR \"response rate\" OR biomarker) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41427517","PMID:42150423","PMID:42181244","PMID:41637165","PMID:42316325","PMID:42164133","PMID:41965096","PMID:41882478","PMID:42573142","PMID:42481355","NCT06427798","NCT06479811","NCT03206060","NCT00004847","NCT06377033","NCT00001238","NCT04924075","NCT01660984"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787166361706","cycle":86,"visit":2,"ts":"2026-08-19T19:06:01.706Z","cancer":{"key":"pheochromocytoma","name":"pheochromocytoma","mondo":{"id":"MONDO:0008233","name":"pheochromocytoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Belzutifan now has real-world efficacy data in EPAS1/HIF2A-driven PPGL (4/5 PR, EPO −97% as PD marker), promoting it to CANDIDATE, while an unbiased CRISPR screen nominates UBE2F-dependent neddylation (pevonedistat) as the first credible SDHB synthetic-lethal target.","confidence":0.62,"notebook":"Belzutifan moves off the trial-only footing. P1 (PMID:41043588) is the first real-world outcome series in EPAS1/HIF2A-driven PPGL: 4/5 partial responses, 1 stable, mean 36.8% reduction in summed diameters, with chromogranin A −69%, EPO −97% and abolition of phlebotomy need — an on-target pharmacodynamic signature (EPO collapse, Hb −13%) that doubles as a response biomarker. P10 (PMID:41569310) independently records regulatory approval for advanced PPGL including ≥12 years and frames the on-target anaemia/hypoxia management problem. Two caveats I will not paper over: n=5, retrospective, and the responders are *EPAS1*-lesion patients — most PPGL EPAS1 gain-of-function is somatic/mosaic (Pacak–Zhuang), not germline [KNOWN], so this does **not** yet demonstrate that VHL [GERMLINE, Monarch anchor] or SDHx cluster-1 tumours respond equally. L1 is promoted to CANDIDATE but its stratification question sharpens rather than dissolves: the desk still needs SDHx- and VHL-stratified response rates from NCT04924075 and acquired-resistance genotypes (EPAS1 gatekeeper, HIF-1α switch, MYC/mTOR bypass remain [SPECULATIVE]).\n\nOpen question 3 gets its first real answer. P2 (PMID:42181244) is an unbiased CRISPR screen in Sdhb-null immortalised mouse chromaffin cells: UBE2F loss selectively suppresses Sdhb-deficient growth while UBE2M loss does the opposite, and pevonedistat/HA-9104 reduce UBE2F activity with selective toxicity to Sdhb-null cells. Mechanistically this points at CUL5-type neddylation rather than global CRL inhibition [INFERRED] — a genuinely new, druggable node (pevonedistat is clinically characterised, so repurposing-first applies). New lead. Notably the screen did *not* nominate PARP or glutamine dependency, so I am not carrying those forward without fresh evidence.\n\nTwo further new leads with honest ceilings: BUB1 as non-oncogene addiction in metastatic PPGL (P8, PMID:42014906 — TCGA/COMETE overexpression, hPheo1 dependency, BAY1816032 activity, pH2A-T120 as target engagement readout; single cell line, so LEAD only); and an oncometabolite-hypermethylation → MGMT-silencing rationale for temozolomide in SDHx disease, supported indirectly by P4 (PMID:41637165, succinate-driven global hypermethylation in SDH-deficient glioma) and a single SDHB brain-metastatic case with durable intracranial control on TMZ (P5, PMID:42316325); P6 (PMID:42164133) supplies the enrichment population — a Saudi SDHB p.R90* [GERMLINE] founder cohort with 56.5% metastasis and 21.7% mortality. P7 (PMID:42122265) shows SRS/SBRT gives 95.3% 5-year local control in non-head-and-neck PGL/PCC with 78% symptomatic control — I record this as a local-control backbone for oligoprogression rather than a new hypothesis, and as the comparator any systemic lead must beat for a solitary lesion.\n\nRLT (L2), MBTA (L3) and β-blockade (L4) received no new evidence; they persist unchanged. Next visit: RET-inhibitor evidence in MEN2 pheo, and human-model validation of UBE2F/BUB1.","leadChanges":[{"id":"L1","title":"HIF-2α inhibition (belzutifan) in cluster-1 pseudohypoxic PPGL","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.78},{"id":"L5","title":"UBE2F-dependent neddylation as a synthetic-lethal vulnerability in SDHB-deficient PPGL (pevonedistat repurposing)","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L6","title":"BUB1 kinase inhibition (BAY1816032) as non-oncogene addiction in metastatic PPGL","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L7","title":"Succinate-driven hypermethylation as a temozolomide-sensitivity rationale in SDHx PPGL (MGMT-guided)","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L8","title":"SRS/SBRT as local-control backbone for oligometastatic/oligoprogressive non-head-and-neck PGL and pheochromocytoma","level":"LEAD","status":"NEW","confidence":0.5}],"unverifiedCitations":0,"openQuestions":["Does belzutifan activity extend beyond EPAS1 gain-of-function to VHL [GERMLINE] and SDHx cluster-1 PPGL, and what are the response rates by cluster in NCT04924075?","What are the acquired-resistance genotypes on belzutifan in PPGL — EPAS1 gatekeeper variants, HIF-1α isoform switching, or MYC/mTOR bypass — and can EPO/CgA kinetics predict escape before RECIST progression?","Does UBE2F-dependent neddylation vulnerability replicate in human SDHB-deficient PPGL models, and is the UBE2F-vs-UBE2M asymmetry sufficient to give pevonedistat a therapeutic window over marrow?","Is BUB1 overexpression a metastasis-specific dependency in PPGL or merely a proliferation correlate, and does BAY1816032 radiosensitise to 177Lu/212Pb DOTATATE?","What is the MGMT promoter-methylation prevalence in SDHx versus cluster-2 PPGL, and does it predict temozolomide response in archival cohorts?","Does RET-mutant (MEN2) pheochromocytoma respond to selpercatinib/pralsetinib, or is the evidence still confined to medullary thyroid carcinoma?"],"nextQueries":["(\"pheochromocytoma\" OR \"paraganglioma\") AND (RET AND (selpercatinib OR pralsetinib OR \"RET inhibitor\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\") AND (MGMT OR \"promoter methylation\" OR \"epigenetic\" OR hypermethylation) AND (temozolomide OR alkylating) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(neddylation OR pevonedistat OR MLN4924 OR UBE2F OR CUL5) AND (\"neuroendocrine\" OR SDHB OR \"succinate dehydrogenase\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"papersShown":[{"pmid":"41043588","doi":"10.1016/j.eprac.2025.09.204","year":2026,"isNew":true,"title":"Belzutifan for HIF2A-Related Pheochromocytoma and Paraganglioma: A Retrospective Study of Real-World Data"},{"pmid":"42181244","doi":"10.1016/j.isci.2026.115885","year":2026,"isNew":true,"title":"Unbiased CRISPR synthetic lethal screening for genetic vulnerabilities in a succinate dehydrogenase-loss model of paraganglioma"},{"pmid":"41888104","doi":"10.1038/s41419-026-08583-7","year":2026,"isNew":true,"title":"AdipoR1-AMPK axis suppresses breast cancer across molecular subtypes via multimodal cell death pathways, including ferroptosis and apoptosis"},{"pmid":"41637165","doi":"10.1093/jnen/nlag004","year":2026,"isNew":true,"title":"Gliomas with succinate dehydrogenase deficiency: A case series and brief review of the literature of oncometabolite-driven gliomagenesis"},{"pmid":"42316325","doi":"10.1186/s13256-026-06213-6","year":2026,"isNew":true,"title":"Brain metastatic paraganglioma from liver: a case report and review of the literature"},{"pmid":"42164133","doi":"10.1210/jendso/bvag070","year":2026,"isNew":true,"title":"&lt;i&gt;SDHB&lt;/i&gt;-associated paraganglioma in Saudi Arabia: High metastatic risk linked to a likely founder mutation"},{"pmid":"42122265","doi":"10.3390/cancers18091470","year":2026,"isNew":true,"title":"External Beam Radiation Therapy for Pheochromocytoma and Non-Head and Neck Paraganglioma: A Single-Institution Experience and Systematic Review"},{"pmid":"42014906","doi":"10.1038/s41598-026-49408-z","year":2026,"isNew":true,"title":"BUB1 as a candidate non-oncogene addiction vulnerability in metastatic phaeochromocytoma/paraganglioma"},{"pmid":"41972240","doi":"10.1093/ehjcr/ytag240","year":2026,"isNew":true,"title":"Intracardiac paraganglioma in the left atrium in the context of a hereditary syndrome due to SDHD mutation: a case report"},{"pmid":"41569310","doi":"10.1007/s00280-025-04861-x","year":2026,"isNew":true,"title":"First-in-class HIF-2α therapy in genitourinary oncology: Belzutifan from von Hippel-Lindau disease to advanced renal cell carcinoma"}],"trialsShown":[{"nct":"NCT06427798","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Somatostatin-Receptors (SSTR)-Agonist [212Pb]VMT-alpha-NET in Metastatic or Inoperable SSTR+ Gastrointestinal Neuroendocrine Tumor and Pheoc"},{"nct":"NCT06479811","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"[212Pb]VMT-Alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive Gastrointestinal Neuroendocrine Tumors, Pheochromocytoma/Par"},{"nct":"NCT03206060","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma"},{"nct":"NCT00004847","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Diagnosis of Pheochromocytoma"},{"nct":"NCT06377033","phase":"NA","status":"RECRUITING","isNew":false,"title":"Using the EHR to Advance Genomic Medicine Across a Diverse Health System"},{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT01660984","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Natural History Study of Children and Adults With Medullary Thyroid Cancer"}],"usage":{"input":11937,"output":7070},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"pheochromocytoma\" OR \"paraganglioma\") AND (SDHB OR SDHx) AND (\"synthetic lethality\" OR PARP OR temozolomide OR MGMT) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\") AND (belzutifan OR \"HIF-2\" OR EPAS1) AND (response OR resistance) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41043588","PMID:42181244","PMID:41888104","PMID:41637165","PMID:42316325","PMID:42164133","PMID:42122265","PMID:42014906","PMID:41972240","PMID:41569310","NCT06427798","NCT06479811","NCT03206060","NCT00004847","NCT06377033","NCT00001238","NCT04924075","NCT01660984"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787166148216","cycle":85,"visit":2,"ts":"2026-08-19T19:02:28.216Z","cancer":{"key":"gastrointestinal stromal tumor","name":"gastrointestinal stromal tumor","mondo":{"id":"MONDO:0011719","name":"gastrointestinal stromal tumor"}},"control":false,"modelLabel":"SCIENCE","summary":"Rogaratinib's phase 2 SDH-deficient GIST cohort (ORR 41.7%, mPFS 31.0 mo) plus olverembatinib's phase 1b (ORR 23.1%, mPFS 25.7 mo) establish the methylation-driven FGF3/FGF4-FGFR1 autocrine loop as the validated actionable dependency in KIT/PDGFRA-wild-type SDH-deficient GIST, with a separate lipid-","confidence":0.62,"notebook":"This visit's pack is almost entirely SDH-axis, and it lands hard on L2. P5 (PMID:42191879) is the published readout of NCT04595747: 24 SDH-deficient GIST patients on rogaratinib, ORR 41.7%, median PFS 31.0 months, 1-year PFS 77.4%, toxicity limited to hyperphosphataemia/fatigue/diarrhoea. It also supplies the missing mechanistic chain — genome-wide hypermethylation disrupts genomic insulators, de-represses FGF3/FGF4, and creates an autocrine FGFR1 loop — so the FGFR dependency is now causal, not correlative. In a subtype with no standard option and imatinib insensitivity, a 31-month PFS is the largest single advance in this programme. L2 is promoted to CANDIDATE (independent new citation, second evidence-bearing visit) at 0.8, and OQ2 is partly answered: FGFR blockade is the demonstrated dominant dependency; belzutifan (NCT04924075) is still unreported, so HIF-2α remains a hypothesis rather than a competitor. Combination logic is now sequencing logic — test HIF-2α blockade at FGFR-inhibitor progression rather than upfront.\n\nP3 (PMID:41184234) independently supports the same subtype from a different angle: olverembatinib in 26 TKI-failed SDH-deficient GISTs, ORR 23.1%, clinical benefit rate 84.6%, median PFS 25.7 months — and the translational arm attributes activity to modulation of lipid metabolism, not to KIT/PDGFRA inhibition (abstract truncated at \"As a putat…\", so the effector lipid enzyme is unstated). [INFERRED] That decouples olverembatinib's benefit from its kinase label and, read with P1/P2 (succinate-dependent vs -independent oncogenic mechanisms) and P4 (respiratory-chain limitation → reductive stress, NAD(P)H backpressure, PTM rerouting), argues for a distinct metabolic-vulnerability lead in Complex II-null GIST. Opened as L6 at 0.4. Cross-trial ORR comparison is confounded by line of therapy (rogaratinib mixed-line vs olverembatinib post-TKI-failure) — not a head-to-head.\n\nNegative result worth recording: the dedicated Europe PMC query for GIST × HRD/PARP/olaparib (2020–2026) returned no GIST-specific paper. No second cohort, no biallelic HR-gene lesion, no functional HR assay. L1 weakened to 0.32; one more empty visit and it retires. P6–P10 are off-target noise (fertility preservation, chickpea flavonoids where \"SDH\" is sorbitol dehydrogenase, PKCγ, spaceflight) — logged so the desk does not re-query these strings.\n\nL3, L4, L5 unchanged: no velzatinib efficacy, no inlexisertib or KQB198 data in this pack.","leadChanges":[{"id":"L2","title":"Pseudohypoxia-axis blockade in SDH-deficient (KIT/PDGFRA wild-type) GIST","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.8},{"id":"L6","title":"Lipid-metabolic / reductive-stress vulnerability of Complex II-null GIST","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L1","title":"PARP inhibition in the HRD-signature G4 (metabolic) GIST subtype","level":"LEAD","status":"WEAKENED","confidence":0.32}],"unverifiedCitations":0,"openQuestions":["Which lipid-metabolic enzyme does olverembatinib modulate in SDH-deficient GIST (full text of PMID:41184234), and is that effect kinase-independent and reproducible in SDH-null models?","What resistance mechanisms emerge in the serial-biopsy WES from the rogaratinib SDH-deficient cohort - FGFR1 gatekeeper mutations, FGF ligand switching, or RAS/MAPK bypass - and do they predict a rational post-FGFR regimen?","Has the belzutifan GIST cohort of NCT04924075 reported, and does HIF-2alpha blockade have any activity in SDH-deficient GIST after or alongside FGFR inhibition?","Is there any second cohort with biallelic HR-gene loss or functional RAD51 deficiency in GIST, or should the PARP/G4 lead be retired?","What are the documented resistance mechanisms after ripretinib/avapritinib failure (new KIT mutations vs KIT-independent FGFR/AXL/MAPK/cell-cycle bypass), and does PDGFRA D842V resistance differ enough to justify a separate lead?","What is the evidence-based option set for KIT/PDGFRA wild-type, SDH-proficient GIST (NF1-associated [GERMLINE], BRAF V600E via plixorafenib NCT05503797, NTRK/FGFR fusions)?"],"nextQueries":["(GIST OR \"gastrointestinal stromal\") AND (rogaratinib OR \"FGFR1\" OR pemigatinib OR erdafitinib) AND (resistance OR \"gatekeeper\" OR V561 OR \"acquired mutation\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(GIST OR \"gastrointestinal stromal\") AND (ripretinib OR avapritinib OR sunitinib OR regorafenib) AND (resistance OR \"secondary mutation\" OR ctDNA OR bypass OR MAPK OR AXL) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"SDH-deficient\" OR SDHB OR succinate) AND (GIST OR paraganglioma) AND (\"fatty acid\" OR lipogenesis OR SCD1 OR FASN OR CPT1 OR NAD OR \"reductive stress\" OR belzutifan) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"40285898","doi":"10.1007/s10565-025-10022-w","year":2025,"isNew":true,"title":"SDH defective cancers: molecular mechanisms and treatment strategies"},{"pmid":"40685935","doi":"10.1002/jcp.70066","year":2025,"isNew":true,"title":"Metabolic Effects of Succinate Dehydrogenase Loss in Cancer"},{"pmid":"41184234","doi":"10.1038/s41392-025-02456-9","year":2025,"isNew":true,"title":"Olverembatinib, a multikinase inhibitor that modulates lipid metabolism, in advanced succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 1b study and transla"},{"pmid":"42150423","doi":"10.1016/j.redox.2026.104224","year":2026,"isNew":true,"title":"Impact of mitochondrial reductive stress due to respiratory chain limitation on cancer via posttranslational modifications"},{"pmid":"42191879","doi":"10.1038/s41591-026-04376-9","year":2026,"isNew":true,"title":"Fibroblast growth factor receptor inhibition for succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 2 trial"},{"pmid":"41985078","doi":"10.1080/07853890.2026.2650869","year":2026,"isNew":true,"title":"Advances in the application of assisted reproductive technology in fertility preservation for female patients with malignant tumours of the reproductive systems"},{"pmid":"42511318","doi":"10.3390/foods15142573","year":2026,"isNew":true,"title":"Inhibitory Effects on the Polyol Pathway in Type 2 Diabetic Rats by Chickpea Flavonoid Extract"},{"pmid":"42261381","doi":"10.1007/s13205-026-04776-1","year":2026,"isNew":true,"title":"Oligosaccharide prebiotics in functional foods and therapeutics: innovations and challenges"},{"pmid":"42217276","doi":"10.1016/j.redox.2026.104221","year":2026,"isNew":true,"title":"Inhibition of PKCγ phosphorylation protects against cerebral ischemia-reperfusion injury"},{"pmid":"42337079","doi":"10.1038/s43856-026-01728-x","year":2026,"isNew":true,"title":"Cardiovascular risks and hazards associated with deep space exploration"}],"trialsShown":[{"nct":"NCT07585266","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Velzatinib Compared With Imatinib in Adult Participants With Previously Untreated Metastatic and/or Unresectable Gast"},{"nct":"NCT04557969","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Surgery in Gastrointestinal Stromal Tumors (GISTs) for Treatment, Tumor Modeling, and Genomic Analysis"},{"nct":"NCT07406633","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"KQB198 in Combination With Imatinib in Participants With Advanced/Metastatic GIST in 1st Line Setting (SynerGIST-1st Line)"},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT04595747","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing the Anti-cancer Drug, Rogaratinib (BAY 1163877), for Treatment of Advanced Sarcoma With Alteration in Fibroblast Growth Factor Recep"},{"nct":"NCT05503797","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations"},{"nct":"NCT06640361","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"A Study of Olverembatinib in SDH-deficient GIST."},{"nct":"NCT05957367","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study of Inlexisertib (DCC-3116) in Combination With Anticancer Therapies in Participants With Advanced Malignancies"}],"usage":{"input":11537,"output":5704},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"gastrointestinal stromal tumor\" OR GIST) AND (\"homologous recombination\" OR \"HRD\" OR PARP OR olaparib) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"SDH-deficient\" OR SDHA OR SDHB OR succinate) AND (GIST OR \"gastrointestinal stromal\") AND (HIF2 OR belzutifan OR FGFR OR pseudohypoxia OR methylation) AND SRC:MED"],"evidenceIds":["PMID:40285898","PMID:40685935","PMID:41184234","PMID:42150423","PMID:42191879","PMID:41985078","PMID:42511318","PMID:42261381","PMID:42217276","PMID:42337079","NCT07585266","NCT04557969","NCT07406633","NCT04924075","NCT04595747","NCT05503797","NCT06640361","NCT05957367"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787165948083","cycle":84,"visit":8,"ts":"2026-08-19T18:59:08.083Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Selective HDAC6 inhibition plus asciminib kills primary CML cells via autophagy-block-driven ISR with MCL-1 suppression and BCL-xL-dependent apoptosis (PMID:42284888) — pursue this MCL1/BCL-xL-primed combination in CD34+CD38- LSCs and retire the BCL2/venetoclax salvage hypothesis.","confidence":0.62,"notebook":"Control visit; the desk again converges on the solved axis — direct BCR::ABL1 [SOMATIC; the Monarch \"ABL1 causal/germline\" annotation remains a KG artefact of fusion biology] inhibition, with the frontline hierarchy reaffirmed by ASC4FIRST East Asian subgroup data (PMID:42339511). Nothing this visit challenges that; the programme's value stays in the resistance/persistence and exposure margins.\n\nTwo fresh case reports sharpen the switch matrix (L8). PMID:40613032 documents concomitant T315I + E459K plus ASXL1 in a patient relapsing after imatinib cessation, dasatinib-intolerant, switched to olverembatinib with allo-HSCT recommended — cleft-mutation stacking on T315I still leaves a third-generation ATP-site option, and the ASXL1 co-mutation tracks blast transformation, reinforcing my ASXL1/RUNX1 exclusion in de-escalation and TFR selection (L7). PMID:41699336 is the first promyelocytic blast crisis salvaged with asciminib (multi-mutant, T315I, failing dasatinib then ponatinib) with pulsed ATRA directed at the separate PML-RARA clone; molecular response after ponatinib failure is exactly the sequential non-cross-resistance claim, in advanced phase. PMID:42042193 extends asciminib to three Ph+ acute leukaemias including T315I, CNS disease and post-CAR-T relapse with no major vascular toxicity, but always inside combinations — attribution is [INFERRED] at best, and the CNS clearance claim cannot be assigned to asciminib. L8 strengthened modestly; still no kinase-domain NGS at asciminib failure anywhere.\n\nThe important new mechanism is PMID:42284888: selective HDAC6 inhibition (compound 7b) blocks autophagosome maturation, triggers a maladaptive ISR (p-eIF2α/ATF4/CHOP), suppresses MCL-1, induces PUMA/NOXA, and kills through BCL-xL-dependent mitochondrial apoptosis, synergising with asciminib in viability and clonogenic assays while sparing healthy PBMCs. This is a kinase-independent co-dependency with a stated window (HDAC6-null mice are viable [KNOWN]) and a clinical-grade surrogate class (ricolinostat/citarinostat). It also decides my longest-running apoptotic question in the negative direction: the priming exposed here is MCL1/BCL-xL, not BCL2. Venetoclax-based CML salvage (L10) therefore loses its mechanistic rationale as well as its evidential base — PMID:40858806 remains title-only for a third visit and no CML BH3 profiling has ever appeared. L10 is retired and its assay burden transfers to the new HDAC6/ISR lead, which must show BH3 dependency in CD34+CD38− cells.\n\nL9 weakened by silence: a targeted PK/exposure-response query returned no new asciminib trough-versus-response data, so the BID>QD interpretation stays inference on one trial. L1 weakened: PMID:41376545 is still title-only, NCT03906292 unreported for an eighth visit, and no concurrent dual-site series exists; asciminib in P3/P4 is combined with non-TKI agents, not with a cleft inhibitor.","leadChanges":[{"id":"L11","title":"HDAC6-selective inhibition plus asciminib: autophagy blockade to maladaptive ISR, MCL-1 loss and BCL-xL-dependent apoptosis in CML","level":"LEAD","status":"NEW","confidence":0.32},{"id":"L10","title":"BCL2 co-dependence confined to multi-TKI/asciminib-resistant CML: venetoclax plus ponatinib as salvage","level":"LEAD","status":"RETIRED","confidence":0.1},{"id":"L8","title":"Sequential ATP-site to allosteric switch: asciminib as non-cross-resistant salvage after ponatinib and in T315I disease","level":"DOSSIER","status":"STRENGTHENED","confidence":0.78},{"id":"L9","title":"Concentration-floor (TDM-anchored) de-escalation: reduce exposure to a measured pharmacokinetic threshold, not to a fraction of label dose","level":"LEAD","status":"WEAKENED","confidence":0.4},{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"WEAKENED","confidence":0.5}],"unverifiedCitations":0,"openQuestions":["Does HDAC6-inhibitor plus asciminib synergy reproduce in primary CD34+CD38- chronic-phase CML LSCs (LTC-IC, serial replating) versus same-donor normal HSPCs, and does a clinical-grade HDAC6-selective agent (ricolinostat/citarinostat) reprod","Does BH3 profiling of asciminib- or ponatinib-resistant CML CD34+CD38- cells show MCL1/BCL-xL priming rather than BCL2, and which MCL1 or BCL-xL-class partner has a tolerable platelet/cardiac window?","Is there any asciminib exposure-response dataset (trough vs Cmax) linked to MMR/MR4.5 from ASC4FIRST or ASC4OPT, and what is the derived DMR trough floor?","What is the published spectrum and frequency of kinase-domain mutations at asciminib failure, including myristoyl-pocket variants beyond A337V, and which ATP-site agent rescues each?","For concomitant/compound T315I plus cleft mutations (e.g. T315I+E459K), what depth and duration does olverembatinib achieve, and does ASXL1 co-mutation abolish that benefit short of allografting?","Has NCT03906292 (frontline asciminib combination) or any prospective series reported concurrent dual-site exposure with molecular depth, cytopenia and arterial-event data?"],"nextQueries":["\"chronic myeloid leukemia\" AND (HDAC6 OR ricolinostat OR citarinostat OR \"tubulin acetylation\") AND (autophagy OR \"integrated stress response\" OR apoptosis) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic myeloid leukemia\" AND (\"BH3 profiling\" OR MCL1 OR MCL-1 OR \"BCL-xL\" OR navitoclax) AND (\"leukemic stem cell\" OR CD34 OR resistance) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","asciminib AND (\"kinase domain\" OR mutation OR \"next-generation sequencing\") AND (resistance OR failure OR \"myristoyl pocket\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"42284888","doi":"10.1016/j.biopha.2026.119652","year":2026,"isNew":true,"title":"Selective HDAC6 inhibition perturbs autophagy and enhances integrated stress response-mediated immunogenic apoptosis in chronic myeloid leukemia"},{"pmid":"40613032","doi":"10.3892/ol.2025.15156","year":2025,"isNew":true,"title":"Concomitant T315I and E459K mutations in chronic myeloid leukemia: A case report"},{"pmid":"41699336","doi":"10.1007/s00277-026-06793-9","year":2026,"isNew":true,"title":"Asciminib and pulsed ATRA as post-remission therapy in T315I mutated PML-RARA-positive blast crisis of chronic myeloid leukemia"},{"pmid":"42042193","doi":"10.3390/hematolrep18020028","year":2026,"isNew":true,"title":"Asciminib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Case Series and Review of Emerging Evidence"},{"pmid":"42584922","doi":"10.1080/17474086.2026.2715450","year":2026,"isNew":false,"title":"Nilotinib in chronic myeloid leukemia: clinical value, real-world challenges, and the potential of nilotinib tablets to improve therapeutic outcomes"},{"pmid":"42557142","doi":"10.1016/j.bulcan.2026.04.002","year":2026,"isNew":false,"title":"[Sexual and reproductive life of men and women with chronic myeloid leukemia: Opinion and practical considerations of the Fi-LMC group]"},{"pmid":"42463944","doi":"10.1038/s41375-026-02972-9","year":2026,"isNew":false,"title":"Asciminib monotherapy in patients with BCR::ABL1 T315I-mutated chronic-phase chronic myeloid leukemia: phase 1 trial final results"},{"pmid":"42412118","doi":"10.1007/s00280-026-04919-4","year":2026,"isNew":false,"title":"Pharmacokinetics of asciminib in a patient with chronic myeloid leukemia undergoing maintenance hemodialysis"},{"pmid":"42339511","doi":"10.1002/cam4.72019","year":2026,"isNew":false,"title":"Asciminib Provides Better Efficacy and Favorable Safety and Tolerability Against Investigator-Selected Tyrosine Kinase Inhibitors in East Asian Patients With Newly Diagnosed Chroni"},{"pmid":"42303626","doi":"10.1038/s41392-026-02729-x","year":2026,"isNew":false,"title":"Non-receptor tyrosine kinase signaling pathways and therapeutic implications"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":15635,"output":8692},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic myeloid leukemia\" AND asciminib AND (pharmacokinetic* OR trough OR Ctrough OR exposure-response OR \"therapeutic drug monitoring\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic myeloid leukemia\" AND (olverembatinib OR ponatinib) AND asciminib AND (combination OR concurrent OR \"blast phase\" OR T315I OR \"compound mutation\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:42284888","PMID:40613032","PMID:41699336","PMID:42042193","PMID:42584922","PMID:42557142","PMID:42463944","PMID:42412118","PMID:42339511","PMID:42303626","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787165715917","cycle":83,"visit":2,"ts":"2026-08-19T18:55:15.917Z","cancer":{"key":"synovial sarcoma","name":"synovial sarcoma","mondo":{"id":"MONDO:0010434","name":"synovial sarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"TAK-981 (SUMOylation inhibition) restores cBAF and dismantles the SS18::SSX transcriptome with chemo synergy in vivo, making it the desk's top fusion-directed lead and a rational partner/primer for MAGE-A4 TCR-T, whose ceiling is now quantified at ~39% ORR with ~11-month durability.","confidence":0.62,"notebook":"The pack is thin on the question I most wanted answered and unexpectedly rich on chromatin. Five of ten papers (P1, P4–P7) are generic solid-tumour immunotherapy reviews with no SS-specific content — recording that as a negative result: as of this pack there is **no published series** dissecting afami-cel/lete-cel relapse biopsies for MAGE-A4 downregulation vs HLA-A*02 LOH vs exhaustion, so Q1 stays open and the desk should not treat \"antigen loss dominates\" as established. P9 (PMID:41472526) does firm up the backbone: SPEARHEAD-1 ORR 39% in SS, 25% in MRCL, median duration >11 months, no treatment-related deaths, with HLA-A*02 restriction, TME resistance and manufacturing latency named as the limiting axes. That plus P4's cross-platform framing is new, independent corroboration of L1 → promoting to CANDIDATE (0.78). Note the honest ceiling: ~39% ORR with ~1-year durability means TCR-T is a backbone to be combined, not a cure.\n\nL3 dies as written. P10 (PMID:41797932) is a generic BRD9 review that explicitly makes BRD9 context-dependent and sometimes tumour-suppressive, and contains no SS-specific degrader data; my visit-1 condition (\"find SS-specific degrader data or retire\") is unmet, so L3 is RETIRED. Do not re-propose bare BRD9 degradation for SS without an SS18::SSX-model dataset.\n\nIts replacement is better. P2 (PMID:41193430) shows SS18::SSX itself activates a SUMOylation program; the clinical-stage SAE1/UBA2 inhibitor TAK-981 de-SUMOylates SMARCE1, restores cBAF on chromatin, collapses the SS18::SSX transcriptome, and produces DNA damage, cell death and tumour inhibition in human and mouse SS models, with synergy with cytotoxic chemotherapy and regressions. Mechanistically this inverts the ncBAF problem: rather than degrading the fusion complex, it rebuilds the competing cBAF assembly — a fusion-conditional dependency, which is the therapeutic-window argument [INFERRED]. Normal tissue: SUMOylation is essential broadly, but TAK-981 has completed dose-finding in humans [KNOWN]; expected resistance routes are SAE1/UBA2 mutation, SMARCE1/cBAF subunit loss, and DNA-damage-response upregulation. Because it converges with doxorubicin/ifosfamide backbone (T3) and with DNA-repair blockade (peposertib + liposomal doxorubicin, NCT05711615), the combination arms are pre-built. Two speculative hooks worth testing: SUMOylation inhibition induces type-I IFN, so it may raise MHC-I/CTA density and rescue antigen-low tumours (Q2), making TAK-981 → TCR-T sequencing testable [SPECULATIVE]. P3 (PMID:40849585) adds PRC1 and liquid–liquid phase separation as further fusion-proximal handles for later visits. L2 and L4 saw no new evidence; unchanged.","leadChanges":[{"id":"L1","title":"Cancer-testis antigen TCR-T (MAGE-A4, NY-ESO-1/LAGE-1a) as the backbone therapy in SS18::SSX-driven synovial sarcoma","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.78},{"id":"L5","title":"TAK-981-mediated SUMOylation blockade to restore cBAF and collapse the SS18::SSX transcriptome, plus chemotherapy","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L3","title":"Degrader-based attack on SS18::SSX chromatin dependencies (BRD9, PRC2)","level":"LEAD","status":"RETIRED","confidence":0.1}],"unverifiedCitations":0,"openQuestions":["In relapsed afami-cel/lete-cel synovial sarcoma, what do paired biopsies show — MAGE-A4/NY-ESO-1 downregulation, HLA-A*02 allelic LOH, TCR-T exhaustion/loss of persistence, or stromal exclusion — and is any mechanism dominant?","Does TAK-981 (or another SAE1/UBA2 inhibitor) raise MHC-I and cancer-testis antigen density in SS models, and can it be sequenced as a priming lead-in before CTA TCR-T?","What schedule, PD biomarker (SMARCE1-SUMO, cBAF chromatin occupancy) and normal-tissue toxicity define a workable TAK-981 + doxorubicin/ifosfamide combination in SS, and is there any sarcoma-inclusive TAK-981 trial?","Are SS18::SSX liquid-liquid phase separation and PRC1 recruitment druggable nodes with existing chemical matter, and do they phenocopy cBAF restoration?","Can SPP1/OPN or CD44/integrin blockade restore CD8 function in immunocompetent SS models in vivo, and does it add to PD-1 blockade or TCR-T?","Do any prospective randomised data (anlotinib, pazopanib maintenance) support antiangiogenic TKIs specifically in lung-metastatic SS, or does the retrospective OS gain collapse under era/selection adjustment?"],"nextQueries":["(TAK-981 OR subasumstat OR \"SUMOylation inhibitor\" OR SAE1 OR UBA2) AND (sarcoma OR \"SS18-SSX\" OR \"SS18::SSX\" OR \"MHC class I\" OR \"type I interferon\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"synovial sarcoma\" AND (\"HLA-A*02\" OR \"loss of heterozygosity\" OR \"antigen loss\" OR \"MAGE-A4 expression\" OR relapse) AND (afamitresgene OR letetresgene OR \"TCR T\" OR biopsy) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"SS18-SSX\" OR \"SS18::SSX\") AND (\"phase separation\" OR PRC1 OR RING1B OR \"condensate\" OR SMARCB1) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"41793185","doi":"10.1002/advs.202522864","year":2026,"isNew":true,"title":"Nanomedicine Meets Immunotherapy: Advancing Adoptive Cell Therapy with Nanoparticles in the Treatment of Cancer with Sustainability Perspectives"},{"pmid":"41193430","doi":"10.1038/s41467-025-64665-8","year":2025,"isNew":true,"title":"Targeting SUMOylation promotes cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial sarcoma"},{"pmid":"40849585","doi":"10.1038/s41388-025-03547-1","year":2025,"isNew":true,"title":"Molecular and epigenetic oncogenesis in synovial sarcoma: implications for cancer biology, diagnosis and treatment"},{"pmid":"42045541","doi":"10.1038/s41416-026-03450-w","year":2026,"isNew":true,"title":"Advances in cancer immunotherapy: adoptive cell therapy and immune cell engagers in solid tumours"},{"pmid":"42320989","doi":"10.1136/jitc-2025-014656","year":2026,"isNew":true,"title":"Advances in immunotherapies in ovarian cancer"},{"pmid":"42316257","doi":"10.1186/s13046-026-03762-y","year":2026,"isNew":true,"title":"Cellular immunotherapy in melanoma: the next frontier in cancer treatment"},{"pmid":"42261754","doi":"10.1002/advs.76020","year":2026,"isNew":true,"title":"Advances in Cancer Immunotherapy for Solid Tumors"},{"pmid":"42243856","doi":"10.1186/s13019-026-04296-2","year":2026,"isNew":true,"title":"A rare case of relapsed primary pulmonary synovial sarcoma (PPSS) following surgery with multidisciplinary team management: case report and systematic review of literature"},{"pmid":"41472526","doi":"10.1080/14737140.2025.2612043","year":2026,"isNew":true,"title":"An evaluation of afamitresgene autoleucel for the treatment of advanced synovial sarcoma and myxoid round cell liposarcoma"},{"pmid":"41797932","doi":"10.1016/j.isci.2026.115013","year":2026,"isNew":true,"title":"The dual role of BRD9 in cancer: Mechanistic insights and therapeutic prospects"}],"trialsShown":[{"nct":"NCT05642455","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"SPEARHEAD-3 Pediatric Study"},{"nct":"NCT03967223","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Master Protocol to Assess the Safety and Antitumor Activity of Genetically Engineered T Cells in NY-ESO-1 and/or LAGE-1a Positive Solid Tumo"},{"nct":"NCT06239272","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhab"},{"nct":"NCT05711615","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Testing Low-Dose Common Chemotherapy (Liposomal Doxorubicin) in Combination With an Anti-Cancer Drug, Peposertib, in Advanced Sarcoma"},{"nct":"NCT06083883","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Phase I/Ib Study of NK Expressing an Affinity-enhanced T-cell Receptor (TCR) Against the NY-ESO-1"},{"nct":"NCT05227326","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"AOH1996 for the Treatment of Refractory Solid Tumors"},{"nct":"NCT02650986","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Gene-Modified T Cells With or Without Decitabine in Treating Patients With Advanced Malignancies Expressing NY-ESO-1"},{"nct":"NCT06625190","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors"}],"usage":{"input":10374,"output":5400},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"synovial sarcoma\" AND (\"MAGE-A4\" OR \"NY-ESO-1\" OR afamitresgene OR letetresgene) AND (resistance OR relapse OR \"antigen loss\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"SS18-SSX\" OR \"SS18::SSX\") AND (BRD9 OR ncBAF OR PRC2 OR EZH2 OR degrader OR PROTAC) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41793185","PMID:41193430","PMID:40849585","PMID:42045541","PMID:42320989","PMID:42316257","PMID:42261754","PMID:42243856","PMID:41472526","PMID:41797932","NCT05642455","NCT03967223","NCT06239272","NCT05711615","NCT06083883","NCT05227326","NCT02650986","NCT06625190"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787165522015","cycle":82,"visit":2,"ts":"2026-08-19T18:52:02.015Z","cancer":{"key":"chondrosarcoma","name":"chondrosarcoma","mondo":{"id":"MONDO:0008977","name":"chondrosarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Reframe the IDH programme around D-2-HG/mutant-protein abundance rather than genotype (engineered-model synthetic lethalities do not hold in endogenous chondrosarcoma), retire ferroptosis induction on cartilage-toxicity grounds, and open an AXL/VEGFR-TKI plus checkpoint-blockade lead in dedifferenti","confidence":0.45,"notebook":"Visit 2 changed the shape of this programme. PMID:42508370 [NEW] is the most consequential item: vector-based IDH1-mutant chondrosarcoma models reproduce the published synthetic-lethal vulnerabilities (the PARP/NAD/glutaminase-type dependencies developed in engineered AML and glioma), but CRISPR-edited isogenic pairs and endogenous IDH-MUT chondrosarcoma lines do not, and sensitivity tracks with mutant protein expression and D-2-HG level — vulnerabilities could be *induced* by raising D-2-HG. Mechanistically this says the 2-HG-driven epigenetic block in chondrosarcoma is quantitatively shallower than in glioma/AML, so removing 2-HG may not release a differentiation programme. PMID:42575314 [NEW] converges: IDH-mutant methylome clusters span enchondroma/ACT through high-grade and dedifferentiated CS (plus a distinct skull-base group), i.e. the methylator state is a lineage/founder signature rather than a grade driver, while CNV burden including CDKN2A loss rises with grade. L1 is therefore WEAKENED (0.6→0.45) and its design must change: any LY3410738/HMA-HDACi arm needs tumour D-2-HG and mutant-IDH protein quantification as an eligibility/pharmacodynamic gate, not IDH genotype alone [INFERRED]. Correspondingly L4 is STRENGTHENED — CDKN2A/B loss is now shown to be grade-linked in a 214-tumour chondrogenic cohort, supporting RB1-intact, CDKN2A-deleted selection for NCT04040205.\n\nThe ferroptosis arm did not replicate. The pack returned only osteoarthritis literature (PMID:39624950, PMID:39529997, PMID:40951445, PMID:41287770); no independent group touched REGγ/PSME3/WDR6 in chondrosarcoma. Worse for the window argument, PMID:41287770 [NEW] shows p53→SLC7A11/GPX4-dependent ferroptosis in IL-1β-treated SW1353 with cartilage matrix loss in vivo, and the reviews frame chondrocyte ferroptosis as the effector of cartilage degradation — so systemic ferroptosis induction plus GPX4/SLC7A11 blockade risks articular cartilage and subchondral toxicity in exactly the tissue we are treating [INFERRED]. L2 drops to 0.28; notebook flag: do not re-propose GPX4/system-xc− inducers for chondrosarcoma without cartilage-toxicity readouts.\n\nTwo DDCS reviews (PMID:42525308, PMID:41895355 [NEW]) quantify the chemotherapy ceiling — ORR ~20%, PFS 4–5 months, 5-year OS 7–24% — and report durable responses in a minority on checkpoint blockade with higher response rates for ICI plus antiangiogenic TKI. PMID:42352463 [NEW] nominates AXL phosphorylation as a candidate node in conventional CS, tied to EMT and immune evasion. These fuse into one new lead: AXL/VEGFR multikinase inhibition (cabozantinib) with PD-(L)1 blockade in dedifferentiated/high-grade CS, anchored to NCT04458922. Vismodegib (NCT01267955) still has no published readout; EXT1 remains unaddressed as a maintenance question.","leadChanges":[{"id":"L1","title":"Mutant IDH1/IDH2 inhibition plus hypomethylating/HDAC therapy in conventional central chondrosarcoma","level":"LEAD","status":"WEAKENED","confidence":0.45},{"id":"L2","title":"REGγ (PSME3) inhibition to release WDR6/STK11-AMPK-dependent ferroptosis and resensitise chondrosarcoma to cisplatin","level":"LEAD","status":"WEAKENED","confidence":0.28},{"id":"L4","title":"CDK4/6 inhibition in CDKN2A/B-deleted or CDK4-amplified high-grade and dedifferentiated chondrosarcoma","level":"LEAD","status":"STRENGTHENED","confidence":0.5},{"id":"L5","title":"AXL/VEGFR multikinase inhibition combined with PD-(L)1 blockade in dedifferentiated and high-grade chondrosarcoma","level":"LEAD","status":"NEW","confidence":0.5}],"unverifiedCitations":0,"openQuestions":["Do CRISPR-edited or endogenous IDH-MUT chondrosarcoma models respond to mutant-IDH inhibitors themselves (not just to synthetic-lethal partners), and does tumour D-2-HG concentration predict response in NCT04521686/NCT04340843?","What are the actual response rates, durations and pAXL/PD-L1 correlates in published ICI-plus-antiangiogenic-TKI series in dedifferentiated and high-grade chondrosarcoma, and is cabozantinib activity AXL- or VEGFR-driven?","Is AXL phosphorylation demonstrated by primary tumour data (IHC/phosphoproteomics) in chondrosarcoma cohorts, and is AXL knockdown/inhibition cytotoxic in endogenous CS lines?","Does the IDH-WT-2 high-CNV/high-grade methylome cluster (PMID:42575314) correspond to CDKN2A-deleted, RB1-intact tumours suitable for abemaciclib selection, and is the skull-base IDH-MUT cluster biologically distinct enough to need separate","Any published readout for vismodegib (NCT01267955) in chondrosarcoma, and is EXT1/heparan-sulfate loss [GERMLINE] a maintenance dependency in secondary peripheral chondrosarcoma or purely predisposition?","Can the REGγ-WDR6 axis be salvaged as a chemosensitisation strategy without inducing chondrocyte/cartilage ferroptosis, i.e. is there any tumour-selective ferroptosis node in chondrosarcoma?"],"nextQueries":["(\"chondrosarcoma\" AND (AXL OR GAS6 OR cabozantinib OR bemcentinib OR \"multikinase\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026])","(\"chondrosarcoma\" AND (pembrolizumab OR nivolumab OR atezolizumab OR \"immune checkpoint\") AND (apatinib OR axitinib OR lenvatinib OR pazopanib OR regorafenib) AND SRC:MED)","((\"chondrosarcoma\" OR \"cartilage tumor\") AND (\"CDKN2A\" OR \"CDK4\" OR abemaciclib OR palbociclib OR \"copy number\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026])"],"papersShown":[{"pmid":"39624950","doi":"10.1111/cpr.13779","year":2025,"isNew":true,"title":"Ferroptosis in Osteoarthritis: Towards Novel Therapeutic Strategy"},{"pmid":"39529997","doi":"10.2147/jir.s493001","year":2024,"isNew":true,"title":"Ferroptosis in Osteoarthritis: Current Understanding"},{"pmid":"40951445","doi":"10.2147/jir.s514309","year":2025,"isNew":true,"title":"Programmed Cell Death of Chondrocytes, Synovial Cells, Osteoclasts, and Subchondral Bone Cells in Osteoarthritis"},{"pmid":"41287770","doi":"10.2147/jir.s572167","year":2025,"isNew":true,"title":"Astragaloside IV Alleviates Osteoarthritis by Inhibiting Chondrocyte Ferroptosis via the p53/SLC7A11/GPX4 Axis"},{"pmid":"42575314","doi":"10.1016/j.modpat.2026.101061","year":2026,"isNew":true,"title":"Methylome Profiling of Cartilage Tumors: A Promising New Diagnostic Tool?"},{"pmid":"42068107","doi":"10.1002/dc.70135","year":2026,"isNew":true,"title":"Cytological Diagnosis of Metastatic Dedifferentiated Chondrosarcoma in Pleural Effusion: A Rare Case Report"},{"pmid":"42525308","doi":"10.1007/s11864-026-01407-y","year":2026,"isNew":true,"title":"Dedifferentiated Chondrosarcoma: Current Advances and Future Perspectives"},{"pmid":"42508370","doi":"10.1016/j.neo.2026.101338","year":2026,"isNew":true,"title":"Targeting vulnerabilities in IDH mutant tumours: The model matters"},{"pmid":"41895355","doi":"10.1016/j.critrevonc.2026.105297","year":2026,"isNew":true,"title":"Chemotherapy in dedifferentiated chondrosarcoma: From neoadjuvant to palliative treatment options"},{"pmid":"42352463","doi":"10.3390/cancers18121929","year":2026,"isNew":true,"title":"The Role of AXL Signaling and Mutant &lt;i&gt;Isocitrate Dehydrogenase 1/2&lt;/i&gt; in Conventional Chondrosarcoma"}],"trialsShown":[{"nct":"NCT01267955","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Vismodegib in Treating Patients With Advanced Chondrosarcomas"},{"nct":"NCT06239272","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhab"},{"nct":"NCT04340843","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing the Combination of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional C"},{"nct":"NCT01659203","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Proton or Photon RT for Retroperitoneal Sarcomas"},{"nct":"NCT04458922","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing Atezolizumab in People 2-17 Years Old With Clear Cell Sarcoma or Advanced Chondrosarcoma"},{"nct":"NCT07734805","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Radiological Diagnosis of Pediatric Neck Swellings"},{"nct":"NCT04040205","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Abemaciclib for Bone and Soft Tissue Sarcoma With Cyclin-Dependent Kinase (CDK) Pathway Alteration"},{"nct":"NCT04521686","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations"}],"usage":{"input":11077,"output":7420},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"chondrosarcoma\" AND (IDH1 OR IDH2 OR \"2-hydroxyglutarate\" OR ivosidenib OR vorasidenib) AND SRC:MED AND PUB_YEAR:[2022 TO 2026])","(\"chondrosarcoma\" AND (ferroptosis OR GPX4 OR SLC7A11 OR \"lipid peroxidation\" OR PSME3 OR \"REG gamma\") AND SRC:MED)"],"evidenceIds":["PMID:39624950","PMID:39529997","PMID:40951445","PMID:41287770","PMID:42575314","PMID:42068107","PMID:42525308","PMID:42508370","PMID:41895355","PMID:42352463","NCT01267955","NCT06239272","NCT04340843","NCT01659203","NCT04458922","NCT07734805","NCT04040205","NCT04521686"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787165305920","cycle":81,"visit":2,"ts":"2026-08-19T18:48:25.920Z","cancer":{"key":"chordoma","name":"chordoma","mondo":{"id":"MONDO:0008978","name":"chordoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Reframe chordoma trials around CDKN2A/B-deleted, RB1-intact tumours (33% of 86 sequenced cases) for CDK4/6 inhibition, and prioritise halofuginone/EPRS inhibition as a TBXT-independent, PDX-validated ISR-apoptosis strategy.","confidence":0.55,"notebook":"This visit's pack shifts the programme's centre of gravity from TBXT toward two things: a prevalence-anchored cell-cycle target and a genuinely new, TBXT-independent in vivo vulnerability.\n\nThe largest primary dataset yet (86 tumours, three centres) makes CDKN2A/B alteration the single most common event in chordoma at 33%, spanning conventional, chondroid and dedifferentiated subtypes, with LRP1B 12%, PBRM1 11% and EGFR 9% (PMID:40802536). A 108-study/6349-patient classification synthesis independently names CDKN2A/B loss and SWI/SNF as the cross-cutting theranostic themes (PMID:42121852). This is new, independent corroboration of L2's cell-cycle arm, so L2 is promoted to CANDIDATE — but reframed: CDKN2A/B loss is population-wide, not cluster-restricted, so genotype (CDKN2A/B-deleted, RB1-intact) should be the enrolment criterion and the CN cluster only a secondary stratifier. [INFERRED] p16 loss → CDK4/6–cyclin D dependence [KNOWN]; resistance routes unchanged (RB1 loss, CCNE1, CDK2/6 amplification).\n\nL5 (new) is the strongest single new lead: focused screening identified EPRS (glutamyl-prolyl-tRNA synthetase) inhibitors, prototypically halofuginone, killing chordoma lines via ATF4/DDIT3 integrated-stress-response apoptosis explicitly *not* via TBXT, with tumour growth inhibition in PDX (PMID:41319040). Halofuginone is an existing clinical-stage agent [KNOWN], so this is repurposing-first with in vivo support. Window argument: ISR hyperactivation is tolerated in normal tissue at antifibrotic doses, but GI toxicity and thrombocytopenia bounded earlier halofuginone dosing [KNOWN]. Pre-specify ATF4/DDIT3 induction as pharmacodynamic readout; anticipated resistance = GCN2/ATF4 axis loss, DDIT3 silencing, GADD34-mediated eIF2α dephosphorylation, proline/glutamate supply changes [INFERRED].\n\nL1 is weakened, not retired: the same paper states TBXT-directed clinical outcomes are underexplored or modest, and the only new TBXT chemistry in the pack is a docking/MD-only phytochemical exercise with no cellular data (PMID:41419749). Oligonucleotide-based PROTACs are a plausible route to a DNA-binding TF like TBXT but remain generic (PMID:41713321). L1 stays LEAD at 0.50 pending real degrader in vivo data.\n\nL3 gains subset definition, not efficacy: paediatric poorly differentiated chordoma is clivus-predominant, SMARCB1-deficient, brachyury-positive, Ki-67-high, prognostically worse, and separable by methylation class (PMID:42293322). Notably SHH-pathway IHC is homogeneous in conventional but promiscuous in PDC — consistent with pathway expression without proof of ligand/SMO dependence, so Q2 remains open and SMO inhibitors stay unjustified. PBRM1 loss at 11% widens the SWI/SNF-deficient fraction beyond SMARCB1, and SMARCA4/SMARCA2-paralogue-directed agents are now catalogued (PMID:42293462), giving L3 a non-immunological second arm.\n\nL6 (new, modest): EGFR alterations in 9% plus repeated citation of EGFR/PDGFR inhibitors in sacral-chordoma practice (PMID:41971904) justify a genotype-selected receptor-TKI arm rather than unselected use.","leadChanges":[{"id":"L2","title":"Copy-number cluster-directed therapy: CDK4/6 inhibition in chr9/CDKN2A-loss (C9), GLI/SHH blockade in chr2+chr7-gain (C2)","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.62},{"id":"L5","title":"EPRS/tRNA-synthetase inhibition (halofuginone) driving ATF4-DDIT3 integrated stress response apoptosis — TBXT-independent","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L1","title":"TBXT (brachyury) lineage addiction: degraders, covalent binders, peptide-centric CAR-T","level":"LEAD","status":"WEAKENED","confidence":0.5},{"id":"L3","title":"SMARCB1/INI1-deficient (poorly differentiated) chordoma as a checkpoint-blockade subset","level":"LEAD","status":"STRENGTHENED","confidence":0.38},{"id":"L6","title":"Genotype-selected EGFR (and PDGFR) TKI arms in chordoma","level":"LEAD","status":"NEW","confidence":0.32}],"unverifiedCitations":0,"openQuestions":["In CDKN2A/B-deleted chordoma, what fraction is RB1-intact, and do cluster-annotated PDX/lines actually respond to palbociclib/abemaciclib?","What are the MSI and PD-L1 rates reported in the 86-tumour cohort (abstract truncated), and do they justify continuing the checkpoint arm of L3?","Is the chordoma ATF4-DDIT3 dependency reproducible with a second EPRS chemotype and orthogonal genetic knockdown, and what dose of halofuginone is tolerable alongside particle radiotherapy?","Given promiscuous versus homogeneous SHH-member staining in PDC versus conventional chordoma, is any chordoma SMO/ligand-dependent, or is GLI activation non-canonical (making SMO inhibitors futile)?","Is PBRM1 loss in conventional chordoma associated with SMARCA2 or EZH2 dependency, and does it share the PDC methylation class?","Are BRCA2/PALB2 alterations in chordoma germline or somatic, and is there functional HR deficiency (RAD51 foci/HRDetect) that could be exploited under LETd-escalated particle therapy?"],"nextQueries":["\"chordoma\" AND (halofuginone OR EPRS OR ATF4 OR DDIT3 OR \"integrated stress response\") AND SRC:MED","\"chordoma\" AND (CDKN2A OR RB1 OR palbociclib OR abemaciclib OR ribociclib) AND (xenograft OR \"cell line\" OR response) AND PUB_YEAR:[2022 TO 2026]","(chordoma OR \"poorly differentiated chordoma\") AND (SMARCB1 OR PBRM1 OR SMARCA2 OR EZH2 OR tazemetostat OR nivolumab OR pembrolizumab) AND (\"response rate\" OR outcome OR trial) AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"40802536","doi":"10.1002/cncr.70033","year":2025,"isNew":true,"title":"Mutational analysis of primary and advanced chordoma tissue using next-generation sequencing"},{"pmid":"41399767","doi":"10.1016/j.jbo.2025.100729","year":2025,"isNew":true,"title":"The regulatory networks and mechanisms of bone microenvironment in tumorigenesis and metastasis"},{"pmid":"42121852","doi":"10.3390/cells15090750","year":2026,"isNew":true,"title":"From Histology to Multi-Omics: Review of Chordoma Classification and Its Clinical Implications"},{"pmid":"41713321","doi":"10.1016/j.ejmech.2026.118688","year":2026,"isNew":true,"title":"Fulfilling multiple roles in PROTAC design: The emerging potential of oligonucleotides"},{"pmid":"41319040","doi":"10.1002/1878-0261.70176","year":2026,"isNew":true,"title":"ATF4-mediated stress response as a therapeutic vulnerability in chordoma"},{"pmid":"41496885","doi":null,"year":2025,"isNew":true,"title":"Abstracts of the Annual Meeting of the Iuliu HaţieganuUniversity of Medicine and Pharmacy: 8&lt;sup&gt;th&lt;/sup&gt; - 13&lt;sup&gt;th&lt;/sup&gt; December 2025, Cluj-Napoca"},{"pmid":"41419749","doi":"10.1038/s41598-025-27893-y","year":2025,"isNew":true,"title":"AI-assisted identification of innovative phytochemicals from Aizoon canariense aimed at brachyury protein in chordoma: a computational strategy"},{"pmid":"42293322","doi":"10.1093/braincomms/fcag207","year":2026,"isNew":true,"title":"Comprehensive profiling of paediatric chordoma: poorly differentiated and conventional subtypes"},{"pmid":"42293462","doi":"10.36401/jipo-25-35","year":2026,"isNew":true,"title":"SMARCA4-Directed Treatment in Oncology Clinical Trials: A Review"},{"pmid":"41971904","doi":"10.21037/jss-25-180","year":2026,"isNew":true,"title":"Sacral chordomas: surgical management, reconstruction, and translational advances: a systematic review"}],"trialsShown":[{"nct":"NCT03910465","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Children and Adults With Chordoma"},{"nct":"NCT01200680","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Genetic Clues to Chordoma Etiology: A Protocol to Identify Sporadic Chordoma Patients for Studies of Cancer-Susceptibility Genes"},{"nct":"NCT05286801","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors"},{"nct":"NCT04416568","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of Nivolumab and Ipilimumab in Children and Young Adults With INI1-Negative Cancers"},{"nct":"NCT06625190","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors"},{"nct":"NCT01346124","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"High Dose Intensity Modulated Proton Radiation Treatment +/- Surgical Resection of Sarcomas of the Spine, Sacrum and Base of Skull"},{"nct":"NCT02834013","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Nivolumab and Ipilimumab in Treating Patients With Rare Tumors"},{"nct":"NCT00496119","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Proton Beam Therapy for Chordoma Patients"}],"usage":{"input":10283,"output":7662},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chordoma\" AND (brachyury OR TBXT) AND (degrader OR PROTAC OR \"CAR-T\" OR covalent) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"chordoma\" AND (CDKN2A OR \"CDK4/6\" OR palbociclib OR hedgehog OR GLI OR SMARCB1 OR EZH2) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:40802536","PMID:41399767","PMID:42121852","PMID:41713321","PMID:41319040","PMID:41496885","PMID:41419749","PMID:42293322","PMID:42293462","PMID:41971904","NCT03910465","NCT01200680","NCT05286801","NCT04416568","NCT06625190","NCT01346124","NCT02834013","NCT00496119"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787165087685","cycle":80,"visit":2,"ts":"2026-08-19T18:44:47.685Z","cancer":{"key":"uveal melanoma","name":"uveal melanoma","mondo":{"id":"MONDO:0006486","name":"uveal melanoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Genomic HLA-haplotype loss is now a documented tebentafusp escape mechanism, so next-line ImmTAC selection (PRAME/brenetefusp) must be matched to the retained haplotype and paired with antigen-agnostic options (DYP688 PMEL17-ADC, darovasertib combinations), while pegargiminase+melphalan opens a test","confidence":0.62,"notebook":"Visit 2 sharpens two branches and opens a metabolic one.\n\nTebentafusp resistance is no longer hypothetical. PMID:42165161 documents acquired resistance at 30 months via genomic loss of the HLA haplotype bearing the A*02:01 restriction element in a progressing metastasis — the exact escape route L2 predicted, now with human genomic evidence rather than [INFERRED] status. This makes antigen-agnostic or allele-agnostic salvage the priority, not merely an alternative for A*02:01-negative patients: HLA-haplotype loss kills any pHLA-directed ImmTAC including PRAME/brenetefusp if the lost haplotype carries the restriction element, so PRAME rescue must be genotype-matched to the *retained* haplotype [INFERRED]. PMID:41598579 quantifies the class (ORR only 5–12% yet mOS 16.0→21.7 mo; week-12 ctDNA clearance and early rash as benefit markers) and PMID:41964902 supplies the engineering menu (masking, armed cytokine/costim constructs, OV/checkpoint combinations). L2 → CANDIDATE, with ctDNA-guided serial HLA/B2M genotyping as the assay backbone (PMID:41798271 independently supports ctDNA as surrogate).\n\nL1 gains independent clinical-landscape corroboration: darovasertib in NADOM neoadjuvant/adjuvant and darovasertib+crizotinib in metastatic disease, plus DYP688, a PMEL17-directed ADC that also suppresses GNAQ/11 signalling — a second, HLA-unrestricted shot at the Gq node that belongs inside this lead (PMID:41798271). L1 → CANDIDATE. Caution on the stratification plan: PMID:42073538 reports nuclear BAP1 loss in 53/58 (91.4%) enucleated tumours with, paradoxically, *longer* disease-free survival — biologically implausible as stated and most likely enucleation-cohort selection plus IHC scoring drift. I therefore downgrade BAP1 IHC alone as an organoid stratifier and will require sequencing/chromosome-3 status.\n\nNew metabolic branch: UM is arginine-auxotrophic through ASS1 loss, and pegargiminase (ADI-PEG20) downregulates Fanconi-anaemia pathway genes and synergises with melphalan to raise double-strand breaks (PMID:42322017). This is mechanistically attractive because hepatic-artery melphalan is already delivered to the liver-dominant compartment, so the combination is a repurposing move with an existing delivery route [INFERRED]. Caveat: 2D ASS1-deficient cell lines only, and PMID:42108204 showed commercial UM lines systematically overcall efficacy.\n\nAdjacent and speculative: PMID:41766295 reports BAP1 loss enforcing a low-metabolic state via mTORC1/p70S6K1 suppression and NF-κB-dependent immune cold-ness. A cell adapted to nutrient stress may be *more* dependent on arginine salvage or, conversely, refractory to antimetabolites — this intersection with pegargiminase is testable and worth its own low-confidence lead.\n\nDead/dormant: NCT01979523 and NCT01587352 remain results-free and stay closed. L3, L4 unchanged.","leadChanges":[{"id":"L1","title":"PKC inhibition (darovasertib) as the obligate backbone in GNAQ/GNA11/CYSLTR2-mutant uveal melanoma, with rational partners against MAPK rebound and YAP/TAZ outp","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.68},{"id":"L2","title":"Next-generation ImmTAC/T-cell engagers plus innate priming for HLA-A*02:01-negative and post-tebentafusp metastatic UM","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.68},{"id":"L5","title":"Arginine auxotrophy (ASS1 loss) as a liver-directed synthetic lethality: pegargiminase plus hepatic melphalan via Fanconi-anaemia pathway suppression","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L6","title":"BAP1-loss nutrient-stress adaptation (mTORC1/p70S6K1 suppression, NF-kB-dependent immune coldness) as a metabolic and immunological vulnerability","level":"LEAD","status":"NEW","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["In post-tebentafusp progression biopsies, what is the relative frequency of HLA-haplotype loss vs B2M/antigen-presentation defects vs gp100 downregulation, and can week-12 ctDNA non-clearance prospectively flag it early?","Does PRAME-directed brenetefusp retain activity when the retained HLA haplotype is intact, and is haplotype-matched allele selection feasible in practice?","Is ASS1 loss frequent enough in patient-derived UM organoids and hepatic metastases to support a pegargiminase + regional melphalan trial, and does FA-pathway suppression reproduce outside 2D lines?","Does BAP1-null mTORC1-low quiescence sensitise to or protect from arginine/amino-acid deprivation, and what is the correct genomic (not IHC) assay for BAP1 stratification?","What is the clinical dataset behind DYP688 (PMEL17 ADC) — response rate, ocular/pigmentary toxicity, and does it work in Gq-pathway-mutant disease after darovasertib?","Do the ESMO-EURACAN guideline and the CoMpass phase 3 readout provide any metastasis-free-survival signal for immunogenic primary ablation with bel-sar?"],"nextQueries":["\"uveal melanoma\" AND (ASS1 OR \"arginine deprivation\" OR ADI-PEG20 OR pegargiminase OR melphalan) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"uveal melanoma\" AND (DYP688 OR PMEL17 OR \"antibody-drug conjugate\" OR brenetefusp OR PRAME) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"uveal melanoma\" AND BAP1 AND (mTORC1 OR metabolic OR \"nutrient stress\" OR \"NF-kB\" OR \"synthetic lethal\") AND SRC:MED"],"papersShown":[{"pmid":"41964902","doi":"10.1093/oncolo/oyag129","year":2026,"isNew":true,"title":"Landscape of T-cell engagers in solid tumors"},{"pmid":"41766295","doi":"10.1097/cmr.0000000000001089","year":2026,"isNew":true,"title":"Recent advances in the molecular genetic mechanisms and immune microenvironment of uveal melanoma"},{"pmid":"42322017","doi":"10.1111/pcmr.70104","year":2026,"isNew":true,"title":"Pegargiminase Suppresses the Fanconi Anemia Pathway and Promotes Melphalan-Induced DNA Double-Strand Breaks in Uveal Melanoma"},{"pmid":"42055344","doi":"10.1016/j.jbc.2026.113087","year":2026,"isNew":true,"title":"Steroid receptor coactivators in immunity - From function to emerging translational opportunities"},{"pmid":"41798271","doi":"10.1159/000549994","year":2026,"isNew":true,"title":"Uveal Melanoma: Changing Paradigms of Treatment"},{"pmid":"42267753","doi":"10.3322/caac.70091","year":2026,"isNew":true,"title":"Radiation therapy, cytogenetic prognostication, novel systemic chemotherapy, and patient perspective in an adult with choroidal melanoma"},{"pmid":"42073538","doi":"10.3390/cancers18081211","year":2026,"isNew":true,"title":"Clinicopathological Characteristics and BAP1 Expression in an Enucleation-Based Uveal Melanoma Cohort: A Single-Center Croatian Experience with Long-Term Follow-Up"},{"pmid":"42020098","doi":"10.1016/j.esmoop.2026.106888","year":2026,"isNew":true,"title":"Uveal melanoma: ESMO-EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up"},{"pmid":"41598579","doi":"10.3390/jcm15020641","year":2026,"isNew":true,"title":"Bispecific T-Cell Engagers, Cell Therapies, and Other Non-Checkpoint Immunotherapies for Metastatic Uveal Melanoma: A Narrative Review"},{"pmid":"42165161","doi":"10.1111/tan.70764","year":2026,"isNew":true,"title":"Escape From Synthetic T Cell Activator Tebentafusp by Genomic HLA Loss: A Case Report"}],"trialsShown":[{"nct":"NCT07338968","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"A Long-Term Follow-Up Study of Subjects Completing the AU-011-301(CoMpass) for Early Choroidal Melanoma"},{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT03025256","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Intravenous and Intrathecal Nivolumab in Treating Patients With Leptomeningeal Disease"},{"nct":"NCT04588662","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Prospective Natural History Study in Uveal Melanoma"},{"nct":"NCT04855435","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Safety and Preliminary Efficacy of MBS8(1V270) in Cancer Patients With Advanced Solid Tumours"},{"nct":"NCT01979523","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Trametinib With or Without GSK2141795 in Treating Patients With Metastatic Uveal Melanoma"},{"nct":"NCT06007690","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Phase 3 Randomized, Masked, Controlled Trial to Evaluate Efficacy and Safety of Belzupacap Sarotalocan (AU-011) Treatment Compared to Sham"},{"nct":"NCT01587352","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Vorinostat in Treating Patients With Metastatic Melanoma of the Eye"}],"usage":{"input":9995,"output":6451},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"uveal melanoma\" AND (darovasertib OR IDE196 OR \"protein kinase C inhibitor\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"uveal melanoma\" AND (tebentafusp OR ImmTAC OR PRAME OR brenetefusp) AND (resistance OR \"HLA loss\" OR biomarker) AND SRC:MED"],"evidenceIds":["PMID:41964902","PMID:41766295","PMID:42322017","PMID:42055344","PMID:41798271","PMID:42267753","PMID:42073538","PMID:42020098","PMID:41598579","PMID:42165161","NCT07338968","NCT07636785","NCT03025256","NCT04588662","NCT04855435","NCT01979523","NCT06007690","NCT01587352"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787164881558","cycle":79,"visit":2,"ts":"2026-08-19T18:41:21.558Z","cancer":{"key":"juvenile myelomonocytic leukemia","name":"juvenile myelomonocytic leukemia","mondo":{"id":"MONDO:0011908","name":"juvenile myelomonocytic leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Keep MEK inhibition as the JMML backbone (trametinib monotherapy response, PMID:42077120) but drop the anti-IL-17A arm in favour of reversible IL-1beta blockade because of MEK-associated airway mucosal necrosis in RASopathy infants (PMID:42503445), and test pacritinib (JAK2/IRAK1) as a single agent ","confidence":0.55,"notebook":"**Visit 2 notebook.** The pack is thin on JMML biology and rich on RASopathy pharmacovigilance; the net effect is to reshape the MEK backbone rather than the inflammasome hypothesis.\n\nTwo new clinical anchors bear directly on L1. PMID:42077120 reports response to trametinib monotherapy in JMML without HSCT — the first pack evidence that MEK inhibition alone is cytoreductive in this disease, which validates the backbone that every triplet in this programme is layered onto. Against that, PMID:42503445 documents extensive upper/lower airway mucosal sloughing and severe supraglottic scarring in a trametinib-treated Noonan infant. That is a hard constraint on L1 as written: IL-17A is the axis of mucosal barrier and antifungal defence [KNOWN], so stacking secukinumab/ixekizumab on a MEK inhibitor in infants plausibly compounds mucosal injury [INFERRED]. I am therefore de-prioritising the anti-IL-17A arm and re-specifying the inflammatory arm as downstream IL-1β blockade (anakinra, short half-life, reversible) ± celecoxib, which spares the IL-17/Th17 mucosal axis. L1 net: WEAKENED as designed, backbone strengthened. PMID:42256976 (RAF1 Noonan HCM/PH responding to trametinib, death after tapering) raises a separate programme-wide question — MEK inhibition may be suppressive, not curative, with rebound on withdrawal; JMML VAF kinetics on/off trametinib become a required read-out [SPECULATIVE for JMML].\n\nNew lead from the trial set: NCT07033598 (pacritinib vs hydroxyurea in proliferative CMML) offers a repurposable agent whose target set — JAK2, IRAK1, ACVR1 [KNOWN] — sits exactly at the intersection of JMML's defining GM-CSF/JAK2-STAT5 hypersensitivity and the IL-1R→IRAK1→NF-κB arm downstream of the NLRP3/IL-1β axis in L1. This is a single-molecule test of two of my leads at once, in a monocytic RAS-enriched adult surrogate.\n\nPMID:42172315 (multiplexed single-cell profiling of pathogenic SHP2 variants; same-hotspot variants yielding divergent cell states, catalytic-dead ≠ knockout) becomes an enabling lead: my inflammatory-axis data are E76K-specific, and allele-resolved transcriptional maps are the way to decide which PTPN11 genotypes should be triaged to SHP2 inhibition versus MEK versus inflammasome blockade.\n\nPMID:42568796 (NRAS-G12D JMML with bilateral testicular infiltration; two azacitidine cycles then haplo-HSCT, molecular remission) undercuts the decitabine-superiority framing of L3 — azacitidine bridged effectively here, n=1 — and adds a sanctuary-site problem HMA pharmacology must address. L3 weakened, reframed as agent-choice-plus-compartment-penetration. PMID:41204420 supplies only generic DNMTi resistance/combination context.\n\nL5 (CD69) is retired per the pre-committed rule: no JMML-specific CD69 data appeared.","leadChanges":[{"id":"L1","title":"IL-17A/NLRP3/PTGS2 inflammatory axis blockade combined with MEK inhibition in PTPN11-mutant JMML","level":"LEAD","status":"WEAKENED","confidence":0.58},{"id":"L6","title":"Pacritinib as a dual GM-CSF/JAK2-STAT5 and IL-1R/IRAK1 node inhibitor in JMML","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L7","title":"Allele-resolved PTPN11 variant-to-phenotype map as the stratifier for SHP2 vs MEK vs inflammasome-directed therapy","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L3","title":"Hypomethylating agent selection (decitabine vs azacitidine) as a modifiable pre-HSCT variable in JMML","level":"LEAD","status":"WEAKENED","confidence":0.35},{"id":"L5","title":"CD69 blockade to reverse Treg-dominated marrow niche in RAS-mutant myelomonocytic leukemia","level":"LEAD","status":"RETIRED","confidence":0.12}],"unverifiedCitations":0,"openQuestions":["Does trametinib monotherapy in JMML clear the mutant clone (serial VAF) or only suppress counts, and what happens to disease and to RASopathy comorbidities on dose tapering/discontinuation?","What is the real mucosal/airway toxicity rate of MEK inhibitors in infants with RASopathies, and does it forbid any IL-17A-directed combination while permitting anakinra?","Does pacritinib (JAK2/IRAK1/ACVR1) suppress GM-CSF-independent colony formation and IL-1beta release in primary JMML, and what does NCT07033598 show in proliferative CMML?","Which PTPN11 alleles beyond E76K carry the NLRP3/IL-1beta/PTGS2 inflammatory transcriptional signature, and do germline Noonan MPD alleles differ from somatic JMML alleles?","In JMML-only data, do decitabine and azacitidine differ in CR and post-HSCT relapse, and do either penetrate extramedullary sanctuary sites such as testis?","Is venetoclax resistance in JMML MCL-1/BCL-xL-driven, and does MEK or SHP2 pre-treatment re-prime BCL2 dependence in primary samples?"],"nextQueries":["(\"juvenile myelomonocytic leukemia\" OR \"chronic myelomonocytic leukemia\") AND (pacritinib OR IRAK1 OR \"JAK2\" OR \"GM-CSF hypersensitivity\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(trametinib OR \"MEK inhibitor\") AND (RASopathy OR \"Noonan syndrome\" OR \"juvenile myelomonocytic\") AND (toxicity OR mucositis OR \"adverse event\" OR discontinuation OR rebound OR \"variant allele frequency\") AND SRC:MED AND","\"juvenile myelomonocytic leukemia\" AND (venetoclax OR \"BH3 profiling\" OR MCL1 OR BCL2L1 OR apoptosis) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"papersShown":[{"pmid":"41204420","doi":"10.1002/ijc.70197","year":2026,"isNew":true,"title":"DNA methyltransferase inhibitors in hematological malignancies and solid tumors"},{"pmid":"41521321","doi":"10.1186/s13045-025-01775-2","year":2026,"isNew":true,"title":"Molecularly targeted therapy and immunotherapy in leukemias"},{"pmid":"42503445","doi":"10.1002/lary.70749","year":2026,"isNew":true,"title":"MEK Inhibitor Associated Airway Injury in an Infant With Noonan Syndrome: A Case Report"},{"pmid":"42077120","doi":"10.1002/1545-5017.70370","year":2026,"isNew":true,"title":"Response to trametinib Monotherapy Without Hematopoietic Stem Cell Transplant in Juvenile Myelomonocytic Leukemia"},{"pmid":"42057423","doi":"10.1016/j.xhgg.2026.100621","year":2026,"isNew":true,"title":"Genetic activation of ERK2 recapitulates core neurodevelopmental features of Rasopathy syndromes in mice"},{"pmid":"42256976","doi":"10.1002/ccr3.72831","year":2026,"isNew":true,"title":"Trametinib Therapy for Hypertrophic Cardiomyopathy and Pulmonary Hypertension in a Child With RAF1-Related Noonan Syndrome (p.Ser257Leu): A Case Report"},{"pmid":"41862719","doi":"10.1007/s00405-026-10113-2","year":2026,"isNew":true,"title":"Largely preserved vestibular function despite severe-to-profound hearing loss in Noonan syndrome spectrum disorders"},{"pmid":"42172315","doi":"10.1126/sciadv.aea9389","year":2026,"isNew":true,"title":"Multiplexed single-cell transcriptomics reveals diverse phenotypic outcomes for pathogenic SHP2 variants"},{"pmid":"42071218","doi":"10.1186/s13578-026-01579-y","year":2026,"isNew":true,"title":"Cadmium impairs heart ventricular formation and disrupts polysialylated-NCAM/FGF receptor signaling in Xenopus tadpoles"},{"pmid":"42568796","doi":"10.1016/j.lrr.2026.100601","year":2026,"isNew":true,"title":"Bilateral testicular infiltration as the initial presentation of NRAS-mutant juvenile myelomonocytic leukemia: rapid molecular remission following azacitidine and haploidentical st"}],"trialsShown":[{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"},{"nct":"NCT07302776","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"TACrolimus Targeted Immunosuppression Cessation in ALlogeneic HCT"},{"nct":"NCT07143669","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Screening Study for KIT D816V Mutated Mast Cell Disease in Select Populations"},{"nct":"NCT04708054","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS"}],"usage":{"input":10419,"output":7787},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"juvenile myelomonocytic leukemia\" OR \"Noonan syndrome\" ) AND (trametinib OR \"MEK inhibitor\" OR SHP2 OR \"SHP099\" OR \"RMC-4630\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"juvenile myelomonocytic leukemia\" AND (methylation OR \"hypomethylating\" OR azacitidine OR decitabine OR relapse) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"evidenceIds":["PMID:41204420","PMID:41521321","PMID:42503445","PMID:42077120","PMID:42057423","PMID:42256976","PMID:41862719","PMID:42172315","PMID:42071218","PMID:42568796","NCT06904066","NCT06566742","NCT05600894","NCT07033598","NCT06001385","NCT07302776","NCT07143669","NCT04708054"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787164655249","cycle":78,"visit":2,"ts":"2026-08-19T18:37:35.249Z","cancer":{"key":"atypical teratoid rhabdoid tumor","name":"atypical teratoid rhabdoid tumor","mondo":{"id":"MONDO:0020560","name":"atypical teratoid rhabdoid tumor"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise DCAF5 degrader development and PHIP/NuRD synthetic lethality as mechanism-matched SMARCB1-null vulnerabilities, run the corin-vs-PHIP polarity experiment in isogenic ATRT lines, and hold B7-H3 CAR T at LEAD pending ATRT-subgroup antigen density given TME B7-H3 sink; polyamine lead retired","confidence":0.5,"notebook":"This visit brought no new ATRT-specific CoREST/LSD1 data — the targeted LSD1/HDAC query returned nothing on corin — so L1 stays at 0.55 with its gating question (CNS exposure, infant neurodevelopmental toxicity) unanswered. It did, however, arrive obliquely corroborated and complicated. PMID:41946722 shows by genome-wide CRISPR across hundreds of lines that broad SWI/SNF disruption creates a specific dependency on the chromatin reader PHIP, which ubiquitinates and suppresses NuRD; without PHIP, NuRD accumulates at promoters and silences transcription lethally. That is the same physics L1 rests on — SWI/SNF loss leaves HDAC1/2-containing corepressors unopposed — but the therapeutic polarity is inverted: corin relieves CoREST repression to force differentiation, whereas PHIP inhibition *deepens* NuRD repression to kill. Both cannot be trivially true at the same loci; the discriminating experiment (isogenic SMARCB1-null ATRT lines, corin ± PHIP knockout, ATAC/RNA-seq at shared promoters) is now the most informative epigenetics assay in the programme. New lead L6 opened; window caveat noted — PHIP haploinsufficiency causes a neurodevelopmental syndrome [KNOWN], which matters in an 18-month-median population.\n\nPMID:41680284 (rhabdoid tumour therapeutic development workshop) is the highest-value item: an expert consensus priority list — DCAF5 binders/degraders first, EZH2 *degraders* over inhibitors, MDM2 (rhabdoid tumours are typically TP53 wild-type [KNOWN]), SINE compounds, FGFR/PDGFR in subgroups. New lead L5 built on DCAF5 (restoring residual SWI/SNF assembly rather than exploiting its loss), with EZH2 degrader/MDM2/selinexor combinations as its declared preclinical comparators. This also reframes open question 2: the field's preferred CoREST partner is a degrader, not tazemetostat.\n\nL2 is corroborated but caveated: PMID:41073827 and PMID:40801642 confirm low normal-tissue B7-H3 and paediatric CAR T momentum, but PMID:41073827 documents B7-H3 on TME myeloid cells, abnormal endothelium and CAFs — an antigen sink and an on-target vascular risk, plus context-dependent (contradictory) immunobiology. Held at LEAD, not CANDIDATE: no ATRT-subgroup quantification and no readable ATRT efficacy yet.\n\nL3 weakens. Nothing in the pack supports SMARCB1-loss-driven ERV/interferon derepression; instead PMID:41820710 and PMID:41460355 argue that low-TMB paediatric/adult CNS tumours fail checkpoint blockade at the population level through myeloid exclusion — the exact predicted failure mode. NCT06622941 remains empirical; confidence 0.2.\n\nL4 retired. Two visits, zero ATRT polyamine data; NCT06465199 unchanged; polyamine depletion is absent from the workshop priority list. Re-entry only on ODC1 dependency/polyamine flux data in ATRT-MYC.","leadChanges":[{"id":"L2","title":"Repeated intracerebroventricular B7-H3 CAR T cells for recurrent/refractory ATRT","level":"LEAD","status":"STRENGTHENED","confidence":0.47},{"id":"L3","title":"PD-1 blockade (ONO-4538/nivolumab) in SMARCB1-deficient rhabdoid tumour","level":"LEAD","status":"WEAKENED","confidence":0.2},{"id":"L4","title":"Polyamine depletion (DFMO + AMXT 1501) targeting the MYC-driven ATRT subgroup","level":"LEAD","status":"RETIRED","confidence":0.1},{"id":"L5","title":"DCAF5 degradation to restore residual SWI/SNF assembly in SMARCB1-deficient ATRT, with EZH2-degrader/MDM2/SINE combinations","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L6","title":"PHIP inhibition as SWI/SNF-loss synthetic lethality: weaponising NuRD-mediated promoter silencing in SMARCB1-null ATRT","level":"LEAD","status":"NEW","confidence":0.42}],"unverifiedCitations":0,"openQuestions":["Corin vs PHIP polarity: in isogenic SMARCB1-null ATRT lines, do CoREST inhibition and PHIP loss converge on the same promoters/differentiation programme, or are they mutually antagonistic manipulations of the same corepressor balance?","Is PHIP a dependency in ATRT specifically (not just pan-SWI/SNF-mutant lines), does it require the ubiquitin-adaptor function, and can degradation depth be titrated below the Chung-Jansen neurodevelopmental threshold?","Does any DCAF5 binder/degrader exist as a tool compound, and does genetic DCAF5 loss restore SWI/SNF assembly and kill ATRT-MYC/SHH/TYR and SMARCA4-mutant rhabdoid models in vivo?","Do EZH2 degraders outperform tazemetostat in ATRT preclinical models, and is the MDM2-inhibitor plus selinexor combination tolerable in TP53-wild-type infant rhabdoid models?","What is quantitative B7-H3 surface density across ATRT subgroups versus TME myeloid/endothelial B7-H3, and does the TME compartment act as an antigen sink or a vascular on-target toxicity in ICV CAR T?","Does corin (or any CoREST/EZH2 agent) achieve pharmacologically active CNS exposure, and does it raise or lower B7-H3 antigen density?"],"nextQueries":["(DCAF5 OR \"DDB1-CUL4\") AND (\"rhabdoid\" OR SMARCB1) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(PHIP OR NuRD OR CHD4) AND (SMARCB1 OR \"SWI/SNF\" OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"atypical teratoid\" OR \"rhabdoid tumor\") AND (EZH2 degrader OR selinexor OR MDM2 OR idasanutlin OR corin OR LSD1) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41073827","doi":"10.1007/s10555-025-10294-y","year":2025,"isNew":true,"title":"B7-H3 in the tumor microenvironment: Implications for CAR T cell therapy in pediatric solid tumors"},{"pmid":"40801642","doi":"10.3390/cells14151209","year":2025,"isNew":true,"title":"B7-H3 in Cancer Immunotherapy-Prospects and Challenges: A Review of the Literature"},{"pmid":"41460355","doi":"10.1007/s11060-025-05347-9","year":2025,"isNew":true,"title":"Adaptive immunotherapeutic paradigms in diffuse midline glioma: integrating epigenetic reprogramming, neuron-glioma interactions, and tumor microenvironment modulation"},{"pmid":"41820710","doi":"10.1007/s11060-026-05497-4","year":2026,"isNew":true,"title":"Endogenous immune recruitment in glioblastoma CAR T therapy: cytokine, myeloid, and chemokine circuitry"},{"pmid":"41364143","doi":"10.1007/s12015-025-11029-w","year":2026,"isNew":true,"title":"Bromodomain-Driven Regulation of Stem Cells: A Potential Target for Cancer Therapeutic Intervention"},{"pmid":"41680284","doi":"10.1038/s41416-026-03348-7","year":2026,"isNew":true,"title":"Paediatric Therapeutic Development Workshop on rhabdoid tumours"},{"pmid":"42098732","doi":"10.1186/s12964-026-02932-x","year":2026,"isNew":true,"title":"Synthetic lethality in cancer: mechanism exploration and therapeutic applications"},{"pmid":"41946722","doi":"10.1038/s41467-026-70699-3","year":2026,"isNew":true,"title":"PHIP suppresses NuRD to enable the growth of SWI/SNF-mutant cancers"},{"pmid":"41797932","doi":"10.1016/j.isci.2026.115013","year":2026,"isNew":true,"title":"The dual role of BRD9 in cancer: Mechanistic insights and therapeutic prospects"},{"pmid":"41773019","doi":"10.1093/nar/gkag152","year":2026,"isNew":true,"title":"TDG orchestrates ATF4-dependent gene transcription during retinoic acid-induced cell fate acquisition"}],"trialsShown":[{"nct":"NCT06465199","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Eflornithine (DFMO) and AMXT 1501 for Neuroblastoma, CNS Tumors, and Sarcomas"},{"nct":"NCT03959800","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Molecular Basis of Pediatric Liver Cancer"},{"nct":"NCT04715191","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors"},{"nct":"NCT03793166","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, T"},{"nct":"NCT06622941","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Study to ONO-4538 in Patients With Rhabdoid Tumor"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT04099797","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"C7R-GD2.CAR T Cells for Patients With GD2-expressing Brain Tumors (GAIL-B)"},{"nct":"NCT03911388","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"HSV G207 in Children With Recurrent or Refractory Cerebellar Brain Tumors"}],"usage":{"input":10668,"output":8921},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"rhabdoid tumor\" OR \"atypical teratoid\") AND (LSD1 OR KDM1A OR CoREST OR RCOR2 OR HDAC1) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"atypical teratoid rhabdoid\" OR \"rhabdoid tumor\") AND (B7-H3 OR CD276 OR \"CAR T\" OR PD-L1 OR \"immune microenvironment\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41073827","PMID:40801642","PMID:41460355","PMID:41820710","PMID:41364143","PMID:41680284","PMID:42098732","PMID:41946722","PMID:41797932","PMID:41773019","NCT06465199","NCT03959800","NCT04715191","NCT03793166","NCT06622941","NCT04320888","NCT04099797","NCT03911388"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787164415769","cycle":77,"visit":2,"ts":"2026-08-19T18:33:35.769Z","cancer":{"key":"rhabdomyosarcoma","name":"rhabdomyosarcoma","mondo":{"id":"MONDO:0005212","name":"rhabdomyosarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise B7-H3/CD276 as the lead RMS surface antigen — MGA271 antibody achieves TBR 5.6 in orthotopic RH30, supporting an ADC campaign — and benchmark L1CAM-CAR against B7-H3 CAR/ADC in matched fusion-positive and fusion-negative PDX before further L1CAM investment.","confidence":0.46,"notebook":"Visit 2. The pack's centre of gravity moved from L1CAM to B7-H3. P10 (PMID:42276839) is the most concrete new datum: clinical-grade MGA271 conjugated to IRDye800 gave specific binding across six B7-H3+ sarcoma lines and a tumour-to-background ratio of 5.6 at 144 h in orthotopic RH30 (fusion-positive) xenografts versus 2.7 for isotype. That is not just an imaging result — it is in vivo proof that an intact antibody against B7-H3 accumulates and is retained in RMS tissue, which is the delivery precondition for an ADC [INFERRED]. P2 (PMID:42288687), a paediatric therapeutic development workshop, independently nominates B7-H3/CD276 ADCs as a high priority for RMS alongside FGFR4 CAR/ADC/degrader, direct PAX3::FOXO1 targeting, MYOD1 and P300/CBP and TEAD degraders, ROR2 for MYOD1-L122R disease, and MEK±PI3K/BRAF combinations. I open [L4] for B7-H3 ADC/antibody-guided delivery as a distinct axis from CAR-T.\n\nThe same workshop consensus is mildly adverse for [L1]: a fielded query naming L1CAM returned no new RMS L1CAM literature this visit, and the field's own priority list omits L1CAM while naming B7-H3 and FGFR4. I weaken L1 rather than retire it — the visit-1 construct-resolved potency data (PMID:42336095) stands — but its comparative claim over B7-H3 now needs to be earned in matched models.\n\n[L2] strengthens on two independent reviews. P9 (PMID:41770377) confirms armoured CAR-T as the operative strategy for paediatric solid tumours including RMS. P8 (PMID:42012754) adds a specific, unexpected armouring lever: FOXO1 overexpression improves CAR-T metabolic fitness and persistence. Note the germline/somatic discipline — FOXO1 here is wild-type transgene in the T cell, mechanistically unrelated to the [SOMATIC] PAX3/PAX7-FOXO1 fusion in the tumour, which retains the FOXO1 DNA-binding domain but is an aberrant activator.\n\nNew [L5]: direct PAX3-FOXO1 ablation. P1 (PMID:42425239) shows glycodendrimer (PPI-M3-20) siRNA dendriplexes suppress PAX3-FOXO1 and downstream programmes with tumour growth inhibition in RH30 — but intratumoral only, and the empty vector alone significantly reduced tumour mass, so the specificity of the in vivo effect is unresolved from the abstract. Low confidence accordingly.\n\nUnresolved from visit 1: NCT02567435 remains active with no posted temsirolimus readout; no SSTR2 expression data appeared for NCT06441331; no MYLK4 corroboration, so [L3] persists unchanged at low confidence.","leadChanges":[{"id":"L1","title":"CD28-costimulated L1CAM-CAR T cells for moderate-/low-antigen-density, fusion-positive RMS","level":"LEAD","status":"WEAKENED","confidence":0.4},{"id":"L2","title":"Armoured / multi-antigen CAR platform to break the immune-cold, TGF-beta-suppressed RMS microenvironment","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.5},{"id":"L4","title":"B7-H3/CD276 antibody-drug conjugate and antibody-guided delivery in RMS","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L5","title":"Direct ablation of the PAX3/PAX7-FOXO1 fusion: siRNA nanocarrier delivery and degrader routes","level":"LEAD","status":"NEW","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["How many B7-H3 molecules per cell do fusion-positive and fusion-negative RMS express, and what is the antibody internalisation/lysosomal delivery rate — i.e. is RMS an ADC-permissive or ADC-refractory B7-H3 biology?","In matched orthotopic RMS PDX, does L1CAM.III CAR outperform B7-H3 CAR or B7-H3 ADC at all, or is its value confined to B7-H3-low tumours?","Is the in vivo antitumour effect of PAX3-FOXO1 siRNA dendriplexes target-specific once carrier-alone and scrambled-siRNA controls are run systemically?","What did the phase 3 temsirolimus arm in intermediate-risk RMS (NCT02567435) show — still no posted readout; if negative, retire mTOR-plus-VAC/VI as dead ground.","Do RMS tumours express SSTR2 at densities justifying Lu-177 edotreotide (NCT06441331)? No RMS expression dataset has surfaced in two visits.","Does wild-type FOXO1 overexpression in CAR T cells improve persistence specifically against RMS, and is it additive with dnTGFBRII or IL-15/IL-21 without paediatric cytokine toxicity?"],"nextQueries":["(\"B7-H3\" OR CD276) AND (\"antibody-drug conjugate\" OR ADC OR MGA271 OR vobramitamab OR ifinatamab) AND (sarcoma OR rhabdomyosarcoma OR pediatric) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","rhabdomyosarcoma AND (FGFR4 AND (degrader OR \"CAR T\" OR \"antibody-drug conjugate\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","rhabdomyosarcoma AND (\"PAX3-FOXO1\" OR \"PAX3::FOXO1\") AND (degrader OR PROTAC OR \"p300\" OR CBP OR \"MYOD1\" OR TEAD) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42425239","doi":"10.1016/j.ijpharm.2026.127166","year":2026,"isNew":true,"title":"Dendriplexes in alveolar rhabdomyosarcoma therapy"},{"pmid":"42288687","doi":"10.1038/s41416-026-03483-1","year":2026,"isNew":true,"title":"Paediatric Therapeutic Development Workshop on rhabdomyosarcoma"},{"pmid":"42359225","doi":"10.7759/cureus.109612","year":2026,"isNew":true,"title":"Botryoid Rhabdomyosarcoma of the Uterine Cervix in a Young Adult: Diagnostic Challenge and Aggressive Clinical Course"},{"pmid":"42192903","doi":"10.3390/cancers18101542","year":2026,"isNew":true,"title":"Circulating Tumor Cells in Soft Tissue Sarcoma: Current Evidence and Clinical Implications"},{"pmid":"42183964","doi":"10.1007/s12105-026-01923-1","year":2026,"isNew":true,"title":"A Genomic and Epigenetic Comparative Study of Low-grade Biphenotypic Sinonasal Sarcoma with Metachronous and Synchronous High-grade Rhabdomyosarcomatous Transformation"},{"pmid":"42125161","doi":"10.1002/ccr3.72691","year":2026,"isNew":true,"title":"Clinicopathological Characteristics and Outcomes of Genitourinary Rhabdomyosarcoma in Two Girls"},{"pmid":"42123703","doi":"10.3390/ijms27094125","year":2026,"isNew":true,"title":"Synovial Sarcoma: Molecular Biology, Pathology, and Therapeutic Strategies"},{"pmid":"42012754","doi":"10.1007/s12672-026-04849-w","year":2026,"isNew":true,"title":"FOXO1 in cancer: context-dependent roles, microRNA regulation, and therapeutic opportunities"},{"pmid":"41770377","doi":"10.1007/s10555-026-10317-2","year":2026,"isNew":true,"title":"CAR-T cell therapy for pediatric solid tumors: armored CAR-T cells and beyond"},{"pmid":"42276839","doi":"10.1021/acs.molpharmaceut.6c00259","year":2026,"isNew":true,"title":"Fluorescence-Guided Surgery of Rhabdomyosarcoma Using a B7-H3 Targeted Antibody-Fluorophore Conjugate"}],"trialsShown":[{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"},{"nct":"NCT05210374","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Disulfiram With Copper Gluconate and Liposomal Doxorubicin in Treatment-Refractory Sarcomas"},{"nct":"NCT04715191","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors"},{"nct":"NCT06441331","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Phase I Trial to Determine the Dose and Evaluate the PK and Safety of Lutetium Lu 177 Edotreotide Therapy in Pediatric Participants With SST"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT06239272","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhab"},{"nct":"NCT02567435","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma"},{"nct":"NCT07628634","phase":"EARLY_phase 1","status":"RECRUITING","isNew":false,"title":"Feasibility Study on the Effect of a Methionine-Reduced Diet on Serum Levels in Pts w/ Solid Tumors"}],"usage":{"input":10757,"output":6589},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"rhabdomyosarcoma\" AND (\"PAX3-FOXO1\" OR \"PAX7-FOXO1\") AND (\"surface\" OR \"immunotherapy target\" OR \"transcriptional target\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"rhabdomyosarcoma\" AND (\"L1CAM\" OR \"B7-H3\" OR \"CD276\" OR \"FGFR4\" OR \"somatostatin receptor\" OR SSTR2) AND SRC:MED"],"evidenceIds":["PMID:42425239","PMID:42288687","PMID:42359225","PMID:42192903","PMID:42183964","PMID:42125161","PMID:42123703","PMID:42012754","PMID:41770377","PMID:42276839","NCT07172958","NCT05210374","NCT04715191","NCT06441331","NCT04320888","NCT06239272","NCT02567435","NCT07628634"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787164194702","cycle":76,"visit":2,"ts":"2026-08-19T18:29:54.702Z","cancer":{"key":"ewing sarcoma","name":"Ewing sarcoma","mondo":{"id":"MONDO:0012817","name":"Ewing sarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"No new ES literature this visit; hold ATR synthetic lethality at 0.55 pending independent replication and add two approved-agent repurposing leads (cabozantinib backbone, disulfiram/copper + liposomal doxorubicin) plus a methionine-restriction extension to the polyamine lead.","confidence":0.45,"notebook":"This visit produced no literature: both targeted Europe PMC queries — ES plus ATR inhibitors by name, and ES/FET fusion plus SLFN11/STAG2/replication stress/ATM since 2023 — returned nothing. That null is itself a finding and goes in the notebook so the desk does not re-run identical strings: as of this pack there is no indexed ES-specific ATR-inhibitor clinical or pharmacodynamic report, and no independent replication of the fusion-induced ATM-hypofunction mechanism beyond PMID:41811428. L1 therefore cannot be promoted and is nudged down to 0.55 — the mechanism is unchanged, but a dedicated search failed to corroborate it, and single-paper PDX evidence carries the burden. Open questions 1 and 2 remain unanswered, not answered negatively.\n\nThe trial pack re-lists NCT07172958 (SABRE, recruiting) and NCT06465199 without new results, so L3 and the clinical arm of L4 stand where they were. Three genuinely new entries matter. NCT02243605 (cabozantinib, relapsed osteosarcoma/Ewing, now active-not-recruiting) is the first ES-dedicated repurposing trial of an approved multikinase inhibitor in this programme; VEGFR2/MET/AXL blockade is a stromal-vascular rather than fusion-directed strategy, and prior reports of single-digit-to-moderate response rates in relapsed ES with cabozantinib are [KNOWN] but not citable from this pack — worth a new LEAD at modest confidence, chiefly as an approved-agent backbone for combination with replication-stress agents, with hypertension, hand-foot syndrome and wound complications as the window constraint. NCT05210374 (disulfiram + copper gluconate + liposomal doxorubicin in refractory sarcoma) supplies a proteotoxic-stress angle: CuET inhibits p97/NPL4 segregase [KNOWN], and fusion-driven transcriptional addiction plausibly sensitises ES to proteostasis collapse [SPECULATIVE]; logged as a low-confidence new lead so the disulfiram route is tracked rather than reinvented. NCT07628634 (methionine-reduced diet) is not an ES trial but is mechanistically adjacent to L4: methionine restriction lowers SAM, the aminopropyl donor for spermidine/spermine synthesis, giving a dietary pincer with DFMO/AMXT 1501 — L4 gets a rationale extension, not a real data-based promotion. Selpercatinib (NCT04320888) is recorded as irrelevant: RET alterations are not part of the ES driver landscape, and the fusion anchors here are FLI1/ERG/ETV1/ETV4 [SOMATIC] with EWSR1 [GERMLINE-likely by Monarch classification only].\n\nNCT06820957 (COG, newly diagnosed metastatic ES, phase 2/3) lists only procedures and biospecimen collection in this pack — agents unspecified, so I cannot characterise the arms. Its value to this desk is as a correlative platform where fusion-dose, ATM/pCHK1 and SLFN11 assays could be embedded prospectively.","leadChanges":[{"id":"L1","title":"ATR inhibition as synthetic lethality against fusion-induced ATM hypofunction in FET-rearranged sarcoma","level":"LEAD","status":"WEAKENED","confidence":0.55},{"id":"L5","title":"Cabozantinib as an approved multikinase backbone in relapsed Ewing sarcoma, to be combined rather than escalated alone","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L6","title":"Disulfiram/copper-driven proteotoxic stress (CuET-p97/NPL4) with liposomal doxorubicin in refractory sarcoma","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L4","title":"Polyamine depletion (DFMO + polyamine transport inhibition) exploiting EWSR1::FLI1-driven ODC1","level":"LEAD","status":"STRENGTHENED","confidence":0.38}],"unverifiedCitations":0,"openQuestions":["Are there any registered or reported ATR-inhibitor cohorts (elimusertib/ceralasertib/camonsertib/berzosertib) that actually enrolled ES patients, and has the ATM-hypofunction mechanism of PMID:41811428 been replicated by any independent gro","What ES-specific ORR, PFS and biomarker results has NCT02243605 (cabozantinib) generated, and do responders segregate by VEGF/AXL or by fusion-signature status?","Which agents constitute the arms of NCT06820957 in newly diagnosed metastatic ES, and can fusion-dose, ATM/pCHK1 and SLFN11 correlatives be embedded in its biospecimen protocol?","Does genetic ATG5/ATG7 ablation (not chloroquine) restore PARPi killing in ES, and does the same autophagy axis blunt ATR inhibitors?","Is B7-H3 antigen density in ES metastases sufficient and homogeneous enough for CAR targeting, and has any ES patient on NCT07172958 responded?","Do ES models show CuET/p97-NPL4 sensitivity that tracks with fusion expression level, justifying pursuit of the disulfiram-copper route?"],"nextQueries":["(\"Ewing sarcoma\" OR \"EWSR1\") AND (cabozantinib OR \"VEGFR2\" OR AXL OR MET) AND PUB_YEAR:[2022 TO 2026] AND SRC:MED","(\"Ewing sarcoma\") AND (ATG5 OR ATG7 OR autophagy OR hydroxychloroquine) AND (olaparib OR PARP) AND SRC:MED","(\"Ewing sarcoma\" OR \"EWS-FLI1\" OR \"EWSR1::FLI1\") AND (ODC1 OR polyamine OR DFMO OR eflornithine OR methionine OR \"S-adenosylmethionine\") AND SRC:MED"],"papersShown":[],"trialsShown":[{"nct":"NCT02243605","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Cabozantinib S-malate in Treating Patients With Relapsed Osteosarcoma or Ewing Sarcoma"},{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"},{"nct":"NCT06465199","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Eflornithine (DFMO) and AMXT 1501 for Neuroblastoma, CNS Tumors, and Sarcomas"},{"nct":"NCT05210374","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Disulfiram With Copper Gluconate and Liposomal Doxorubicin in Treatment-Refractory Sarcomas"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT07628634","phase":"EARLY_phase 1","status":"RECRUITING","isNew":false,"title":"Feasibility Study on the Effect of a Methionine-Reduced Diet on Serum Levels in Pts w/ Solid Tumors"},{"nct":"NCT04337177","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With Temozolomide for Treatment of Recurrent Pediatric Solid Tumors"},{"nct":"NCT06820957","phase":"phase 2/phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Testing a New Combination of Anti-cancer Drugs in Patients Newly Diagnosed With Ewing Sarcoma Who Have Cancer That Has Spread to Other Parts"}],"usage":{"input":5429,"output":6008},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Ewing sarcoma\" AND (\"ATR inhibitor\" OR elimusertib OR ceralasertib OR camonsertib OR berzosertib) AND SRC:MED","(\"Ewing sarcoma\" OR \"FET fusion\") AND (SLFN11 OR STAG2 OR \"replication stress\" OR \"ATM\") AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["NCT02243605","NCT07172958","NCT06465199","NCT05210374","NCT04320888","NCT07628634","NCT04337177","NCT06820957"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787163992065","cycle":75,"visit":2,"ts":"2026-08-19T18:26:32.065Z","cancer":{"key":"osteosarcoma","name":"osteosarcoma","mondo":{"id":"MONDO:0009807","name":"osteosarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"B7-H3 is now the strongest actionable axis in osteosarcoma — near-universal membranous expression with osteosarcoma among the highest H-scores (PMID:42251292) plus control-ADC-matched xenograft responses to vobramitamab duocarmazine (PMID:41941262) — so prioritise antigen-density-stratified B7-H3 AD","confidence":0.52,"notebook":"B7-H3 is now the programme's best-evidenced axis and moves up the ladder. Two independent new inputs: a two-centre, treatment-naive IHC cohort of 133 sarcomas found membranous B7-H3 in 97% of samples with osteosarcoma among the highest (median H-score 175) and expression tracking histological grade (PMID:42251292), and a preclinical study showing the duocarmycin ADC vobramitamab duocarmazine (DAR ~2.7) produced objective responses across pediatric solid tumour xenografts including osteosarcoma versus an isotype-linker-matched control ADC (PMID:41941262) — control-matched, so the effect is antigen-directed, not payload leakage. A pan-cancer review adds that clinical benefit concentrates in IHC-overexpressors (PMID:40937367), which is exactly the stratification logic behind the 68Ga-B7-H3 nanobody immunoPET trial (NCT07774533). L2 therefore becomes a CANDIDATE, and I split off a distinct lead for ADC-based delivery (vobra duo, phase I/II NCT03729596 reported in PMID:41941262) because ADC pharmacology (bystander payload, ~40% low-H-score lesions in the cohort) has different antigen-density thresholds than CAR-T; the immunoPET–IHC–response triangulation is the experiment that decides both.\n\nNo new KIF18A-specific data. L1 gains only substrate-prevalence support: chromothripsis in >70% of osteosarcoma with TP53 ~80% and RB1 ~40% loss (PMID:42326738). A polyploidy review reframes WGD as a stress response (PMID:42190013), which generates a testable sequencing hypothesis [INFERRED]: doxorubicin/radiation-induced polyploidisation should manufacture the KIF18A dependency, favouring KIF18A inhibitor after, not with, genotoxic therapy. Caution logged: morphine co-treatment reduced doxorubicin-induced micronuclei and CIN parameters in MG63 while being genotoxic alone (PMID:42565507) — an analgesic confounder for any CIN-score biomarker or genotoxic-priming schedule, and a reason to control opioid exposure in correlative studies. Confidence for L1 nudges up only marginally; Q1 (PDX-panel quantitation) is unanswered.\n\nL3 strengthened modestly: PMID:42326738 independently documents the M2-TAM/Treg/MDSC-dominated, T-cell-poor TIME that attIL12-T/TIL is designed to invert; still no bone-sarcoma efficacy readout from NCT05621668/NCT06474676.\n\nTwo new leads. First, PARP inhibition as radiosensitiser in unresectable axial osteosarcoma, with high-LET (carbon-ion) combinations and cGAS-STING immunogenic conversion as the mechanistic hook (PMID:42228304) layered onto a chromothriptic, replication-stressed genome (PMID:42326738) — attractive because it could warm a cold TIME rather than merely add cytotoxicity. Second, telomere maintenance: longer leukocyte telomere length in treatment-naive bone sarcoma patients versus controls (PMID:42147262) is a host/[GERMLINE]-compartment observation, not tumour maintenance, and must not be conflated — but it justifies interrogating ALT/ATRX-dependent telomere biology and ATR-inhibitor synthetic lethality in osteosarcoma [KNOWN]. Low confidence pending tumour-side data.\n\nUSP7 (L4) and FZD1/homoharringtonine (L5) received nothing this visit; both stay as-is and remain candidates for retirement if visit 3 is silent.","leadChanges":[{"id":"L2","title":"B7-H3 (CD276) antigen-density-stratified targeting with companion immunoPET selection","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.62},{"id":"L6","title":"B7-H3 antibody-drug conjugate (vobramitamab duocarmazine) as antigen-directed cytotoxic delivery in osteosarcoma","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L1","title":"KIF18A inhibition as CIN/whole-genome-doubling-selective synthetic lethality in osteosarcoma","level":"LEAD","status":"STRENGTHENED","confidence":0.62},{"id":"L3","title":"Locally delivered IL-12 via membrane-anchored tumour-targeted T/TIL cells against the immunosuppressive osteosarcoma TME","level":"LEAD","status":"STRENGTHENED","confidence":0.42},{"id":"L7","title":"PARP inhibition as radiosensitiser (including high-LET) in unresectable/axial osteosarcoma with STING-mediated immune conversion","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does 68Ga-B7-H3 nanobody PET SUV correlate quantitatively with IHC H-score per lesion in osteosarcoma, and what threshold predicts response to B7-H3 ADC versus CAR-T?","Is vobramitamab duocarmazine active in low-H-score (H-Score 1-100) osteosarcoma lesions via bystander payload, and does prior chemotherapy alter B7-H3 density (cohort in PMID:42251292 was treatment-naive only)?","Does KIF18A-inhibitor sensitivity track quantitatively with WGD/CIN burden and SAC gene integrity across osteosarcoma PDX panels, and does genotoxic priming (doxorubicin/radiation) increase WGD and thereby sensitivity?","Are p53-independent USP7 substrates demonstrable in TP53-null osteosarcoma, or should L4 be retired for lack of disease-specific evidence?","Is free homoharringtonine (omacetaxine) active against FZD1-high osteosarcoma spheroids/PDX without the bespoke nanocarrier, or should L5 be retired?","Do PARP inhibitors radiosensitise osteosarcoma models specifically, and does carbon-ion plus PARPi generate cGAS-STING-dependent T-cell infiltration sufficient to combine with attIL12 or checkpoint blockade?"],"nextQueries":["(\"osteosarcoma\" OR \"bone sarcoma\") AND (\"B7-H3\" OR CD276) AND (\"antibody-drug conjugate\" OR \"CAR T\" OR immunoPET OR radioligand) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"osteosarcoma\" AND (KIF18A OR \"whole genome doubling\" OR polyploid* OR \"alternative lengthening of telomeres\" OR ATRX OR \"ATR inhibitor\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"osteosarcoma\" AND (\"PARP inhibitor\" OR olaparib OR talazoparib OR \"carbon ion\" OR radiosensiti*) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42190013","doi":"10.1073/pnas.2522063123","year":2026,"isNew":true,"title":"Growth under pressure: The pros and cons of polyploidy induced by stress"},{"pmid":"40937367","doi":"10.2147/itt.s534666","year":2025,"isNew":true,"title":"B7-H3/CD276: Novel Immune Checkpoint and Jack of All Trades"},{"pmid":"42326738","doi":"10.1016/j.bonr.2026.101930","year":2026,"isNew":true,"title":"Genomic landscape and tumor immune microenvironment of osteosarcoma: Bridging mechanistic insights to precision therapeutics"},{"pmid":"42565507","doi":"10.1093/mutage/geag028","year":2026,"isNew":true,"title":"Morphine modulates doxorubicin-induced genomic instability with distinct effects in osteosarcoma and fibroblast cells"},{"pmid":"42259777","doi":"10.1038/s41392-026-02714-4","year":2026,"isNew":true,"title":"Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases"},{"pmid":"42228304","doi":"10.1007/s11912-026-01800-8","year":2026,"isNew":true,"title":"PARP Inhibitors as Radiosensitizers: Current Evidence and Future Directions"},{"pmid":"42147262","doi":"10.14740/wjon2684","year":2026,"isNew":true,"title":"Detection of Longer Leukocyte Telomere Length in Patients With Bone Sarcomas"},{"pmid":"42059258","doi":"10.3892/mmr.2026.13891","year":2026,"isNew":true,"title":"Indium (III) chloride inhibits testicular Leydig cell proliferation by disrupting centrosome copy numbers"},{"pmid":"42251292","doi":"10.1186/s12885-026-16255-0","year":2026,"isNew":true,"title":"B7-H3 membranous expression correlates with histological grading in a two-center cohort of 133 pre-treatment bone and soft tissue sarcoma samples"},{"pmid":"41941262","doi":"10.1158/1078-0432.ccr-25-4767","year":2026,"isNew":true,"title":"Preclinical Activity of the B7-H3-Targeting Antibody-Drug Conjugate Vobramitamab Duocarmazine in Pediatric Solid Tumors"}],"trialsShown":[{"nct":"NCT06859801","phase":"n/a","status":"RECRUITING","isNew":false,"title":"A Multi-Center Observational Trial of Symptomatic, High-Risk Bone Metastases Treated With Percutaneous Ablation and Palliative Radiation The"},{"nct":"NCT07774533","phase":"EARLY_phase 1","status":"RECRUITING","isNew":false,"title":"68Ga-B7-H3 Nanobody ImmunoPET in Osteosarcoma"},{"nct":"NCT06474676","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"T Cell Membrane-Anchored Tumor-Targeted IL12 -Modified TIL Cell Therapy (attIL12-TIL) for Advanced/Metastatic Soft Tissue and Bone Sarcoma P"},{"nct":"NCT06737172","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Functional and Structural Outcomes Following Childhood Bone or Soft Tissue Sarcomas of the Lower Extremity"},{"nct":"NCT06743958","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Prehabilitation in Childhood Soft Tissue or Bone Sarcomas"},{"nct":"NCT02243605","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Cabozantinib S-malate in Treating Patients With Relapsed Osteosarcoma or Ewing Sarcoma"},{"nct":"NCT05621668","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A First-In-Human Phase 1 Trial of T-Cell Membrane-Anchored Tumor Targeted Il12 (Attil12)- T-Cell Therapy in Subjects With Advanced/Metastati"},{"nct":"NCT03900793","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Losartan + Sunitinib in Treatment of Osteosarcoma"}],"usage":{"input":11153,"output":7245},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"osteosarcoma\" AND (KIF18A OR \"whole genome doubling\" OR \"chromosomal instability\" OR \"spindle assembly checkpoint\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"osteosarcoma\" OR \"bone sarcoma\") AND (\"B7-H3\" OR CD276 OR \"CAR T\" OR \"antibody-drug conjugate\" OR IL12) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42190013","PMID:40937367","PMID:42326738","PMID:42565507","PMID:42259777","PMID:42228304","PMID:42147262","PMID:42059258","PMID:42251292","PMID:41941262","NCT06859801","NCT07774533","NCT06474676","NCT06737172","NCT06743958","NCT02243605","NCT05621668","NCT03900793"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787163774999","cycle":74,"visit":2,"ts":"2026-08-19T18:22:54.999Z","cancer":{"key":"wilms tumor","name":"Wilms tumor","mondo":{"id":"MONDO:0006058","name":"Wilms tumor"}},"control":false,"modelLabel":"SCIENCE","summary":"Cabozantinib (NCT02867592, WT-inclusive and now closed to accrual) and trastuzumab deruxtecan (NCT04616560) are the two nearest-term repurposing leads in Wilms tumor and should be pursued for readouts and HER2 IHC entry criteria, while GPC3/B7-H3 CAR-T leads stay provisional pending primary human an","confidence":0.42,"notebook":"Visit 2 returned no literature — zero papers from either Europe PMC query. That is a retrieval failure, not evidence of absence, and it matters most for L1/L2: I still have no primary human series quantifying GPC3 or B7-H3 protein by WT histologic subtype (open Q2 unanswered), so both remain single-trial-citation leads resting on cross-tumour [KNOWN] antigen biology plus [INFERRED] armoring rationale. I nudge both down rather than hold them flat, because a visit that searched specifically for their human prevalence data and found none should cost them something. Next visit I will drop \"CAR T\" from the query and search antigen-by-IHC terms directly, and search nephroblastoma as a synonym.\n\nThe trial sweep is the substance this visit. Two arms are new to the desk and both are repurposing-grade. NCT02867592 puts cabozantinib-S-malate into recurrent/refractory and newly diagnosed Wilms tumor explicitly and is already ACTIVE_NOT_RECRUITING, i.e. a readout exists or is imminent — a multi-RTK inhibitor (MET/VEGFR2/AXL/RET [KNOWN]) hitting the vascular and mesenchymal-invasive axis of blastemal WT, with hypertension, PPE and impaired growth-plate/renal-reserve effects as the window-limiting normal-tissue toxicities in children with a single kidney [KNOWN]. New lead L6. NCT04616560 (trastuzumab deruxtecan) I had only as an open question; it becomes L7. Mechanistically I read T-DXd in WT less as HER2 oncogene addiction — WT is not a HER2-driven tumour [KNOWN] — and more as antigen-anchored delivery of a topoisomerase-I payload to a tumour class already clinically topo-I-sensitive (irinotecan/topotecan in relapsed WT) [KNOWN/INFERRED], with bystander payload diffusion covering HER2-low epithelial heterogeneity [INFERRED]. Its fate hinges on the trial's HER2 IHC entry threshold, which the record here does not state.\n\nNegative/low-yield record so the desk stops re-deriving them: the Pediatric MATCH genotype-matched arms in this pack are poor fits for WT. Selpercatinib (NCT04320888) requires activating RET alterations and tipifarnib (NCT04284774) requires HRAS alterations; neither is a recurrent WT lesion [KNOWN], so NCT03155620 screening is best treated as a tissue/genomics resource for the anaplastic-WT TP53 subset, not as a target hypothesis generator. No lead created.\n\nOne cross-link worth flagging: NCT07645469 pairs WT1 TCR-T with azacitidine — the same hypomethylating logic as L3 (RARB promoter re-expression), here used for antigen upregulation. If that combination is tolerable in children it partially de-risks the HMA half of L3.","leadChanges":[{"id":"L1","title":"IL-15/IL-21-armored GPC3 CAR-T against onco-fetal GPC3 in Wilms tumor","level":"LEAD","status":"WEAKENED","confidence":0.44},{"id":"L2","title":"B7-H3 CAR-T combined with TGF-beta-insensitive (dTbetaRII) antigen-specific T cells for relapsed embryonal WT","level":"LEAD","status":"WEAKENED","confidence":0.42},{"id":"L6","title":"Cabozantinib as MET/VEGFR2/AXL blockade in recurrent Wilms tumor — readout-ready repurposing","level":"LEAD","status":"NEW","confidence":0.32},{"id":"L7","title":"Trastuzumab deruxtecan as antigen-anchored topoisomerase-I payload delivery in relapsed WT (not HER2 addiction)","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["What is the Wilms tumor stratum outcome (ORR, PFS, biomarker correlates) reported from cabozantinib in NCT02867592, and were MET/AXL/VEGFR expression correlates collected?","What HER2 IHC/ISH threshold does NCT04616560 use, and what is HER2 protein prevalence across WT epithelial, blastemal and stromal components in primary human series?","What is GPC3 and B7-H3 protein prevalence by WT histologic subtype in primary pathology cohorts (searched with IHC/nephroblastoma terms, not CAR-T terms)?","Do TRIM28-, DIS3L2- or CTR9-mutant Wilms tumors show a distinct exploitable dependency, and are the reported cases germline or somatic?","Does germline BRCA2 in WT predisposition produce any somatic HR-deficiency signature that would justify a PARP-inhibitor hypothesis?","Which relapse mechanisms after COG/SIOP chemotherapy in high-risk WT are drug-addressable, and does anaplastic (TP53-mutant) WT define a separable therapeutic subgroup?"],"nextQueries":["(\"Wilms tumor\" OR nephroblastoma) AND (immunohistochemistry OR \"protein expression\") AND (GPC3 OR \"glypican-3\" OR CD276 OR B7-H3 OR HER2 OR ERBB2) AND SRC:MED","(\"Wilms tumor\" OR nephroblastoma) AND (cabozantinib OR MET OR AXL OR VEGFR2 OR \"receptor tyrosine kinase\") AND (xenograft OR \"phase 2\" OR response) AND SRC:MED","(\"Wilms tumor\" OR nephroblastoma) AND (relapse OR refractory OR anaplastic) AND (TP53 OR \"clonal evolution\" OR \"resistance mechanism\" OR \"single-cell\") AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"papersShown":[],"trialsShown":[{"nct":"NCT07645469","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"FH-WT1-E50 TCR T Cells With Azacitidine for the Treatment of Minimal Residual Disease Positive Acute Myeloid Leukemia"},{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"},{"nct":"NCT04616560","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Trastuzumab Deruxtecan (DS-8201a) for the Treatment of Recurrent or Refractory Osteosarcoma, Wilms Tumor, and Desmoplastic Small Round Cell "},{"nct":"NCT04715191","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT03155620","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin L"},{"nct":"NCT02867592","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumor"},{"nct":"NCT04284774","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Trea"}],"usage":{"input":5694,"output":5171},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Wilms tumor\" AND (GPC3 OR \"glypican-3\" OR B7-H3 OR CD276 OR \"CAR T\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","\"Wilms tumor\" AND (TRIM28 OR DIS3L2 OR CTR9 OR \"IGF2\" OR \"loss of imprinting\") AND (dependency OR vulnerability OR inhibitor) AND SRC:MED"],"evidenceIds":["NCT07645469","NCT07172958","NCT04616560","NCT04715191","NCT04320888","NCT03155620","NCT02867592","NCT04284774"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787163581980","cycle":73,"visit":2,"ts":"2026-08-19T18:19:41.980Z","cancer":{"key":"retinoblastoma","name":"retinoblastoma","mondo":{"id":"MONDO:0008380","name":"retinoblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"With an empty literature pack, retire the PTM lead, downgrade the organoid-derived sunitinib lead, and record CDK4/6 inhibition (NCT04040205 selection logic) as mechanistically closed in RB1-null retinoblastoma; next visit must supply WERI-Rb1/Y79 dependency data and retinoblastoma GPC2/HLA-I expres","confidence":0.33,"notebook":"No new literature was returned this visit — both queries came back empty, which is itself informative: after two evidence-bearing sweeps, there is still zero retrieved primary data on CDK7/CDK9/CDK12 dependency in RB1-null retinoblastoma and zero retrieved retinoblastoma-specific GPC2 expression data. The queries were probably over-constrained (they demanded the mechanism keyword and the disease keyword in the same record); I am rewriting them rather than concluding absence of biology, but confidences drop because nothing independent arrived.\n\nTrial delta. NCT05650749 has moved from open recruiting to ENROLLING_BY_INVITATION, so the GPC2 CAR-T vehicle for metastatic retinoblastoma is now a closed-access single-site study — the practical route to retinoblastoma-specific antigen and response data narrows, and the antigen-quantification gap (question 3) still has to be closed from banked specimens (NCT01109394, NCT03050268) rather than from trial accrual. L2 weakened to 0.35; mechanism unchanged, feasibility worse. NCT07633756 remains recruiting but is still RB1-negative leiomyosarcoma only — a lineage-distant read-through for L1, no retinoblastoma primary data. L1 weakened to 0.40.\n\nNew this pack: NCT04040205 (abemaciclib in bone/soft-tissue sarcoma selected for CDK-pathway alteration). This is a useful negative anchor, not support. Contemporary CDK4/6i development selects tumours with lesions *upstream* of RB — CDKN2A loss, CCND/CDK4 amplification — which mechanistically requires retained RB1 protein for the G1 brake to be re-imposed [KNOWN]. That is incompatible with biallelic RB1 loss, the defining lesion here. I am recording as a closed question: CDK4/6 inhibition should not be re-proposed for RB1-null retinoblastoma; if the CRISPR-organoid CDK4/6i signal (P1) is real, those organoids were almost certainly RB1-proficient/MYCN-amplified or the effect was off-target [INFERRED]. Question 2 is therefore answered in the direction of retiring the idea, and it drags L4's provenance with it — the same unverified organoid abstract is the sole source for sunitinib, so L4 falls to 0.12 and dies next visit without target deconvolution.\n\nL3 retired as pre-committed: no named E3 ligase, DUB or SUMO enzyme with a retinoblastoma genetic dependency appeared. Review-level PTM narrative will not be re-entered without a dependency screen hit.\n\nNext I need: (i) any CRISPR/DRIVE/DepMap-style dependency data in WERI-Rb1/Y79, ideally naming transcriptional CDKs, aurora/PLK1 or MYCN cofactors; (ii) retinoblastoma immune landscape (HLA class I, T-cell infiltrate) to gate L2 at all; (iii) local-delivery pharmacology as the true window argument for any transcriptional-CDK agent.","leadChanges":[{"id":"L1","title":"CDK7 / transcriptional-CDK inhibition as synthetic lethality with RB1 loss and MYCN amplification in retinoblastoma","level":"LEAD","status":"WEAKENED","confidence":0.4},{"id":"L2","title":"GPC2-directed CAR T cells for metastatic/extraocular retinoblastoma","level":"LEAD","status":"WEAKENED","confidence":0.35},{"id":"L3","title":"PTM-enzyme pharmacology (ubiquitin/SUMO/acetylation circuits) around the RB-E2F axis, with immunotherapy combination","level":"LEAD","status":"RETIRED","confidence":0.05},{"id":"L4","title":"Sunitinib repurposing (multi-RTK inhibition) validated in CRISPR retinal organoid retinoblastoma models","level":"LEAD","status":"WEAKENED","confidence":0.12}],"unverifiedCitations":0,"openQuestions":["Do any published CRISPR/RNAi dependency datasets in WERI-Rb1, Y79 or RB1-/- retinal organoids nominate transcriptional CDKs (CDK7/9/12/13) versus alternative essentials (PLK1, AURKB, MYCN cofactors, MCL1)?","What is measured GPC2 surface density and positivity frequency in retinoblastoma primaries, vitreous seeds and metastatic/CSF deposits, and does it track with MYCN amplification?","What is the retinoblastoma immune landscape — HLA class I expression, T/NK infiltration, ocular immune privilege — and does it permit any adoptive-cell or checkpoint strategy?","Which intravitreal/intra-arterial agents achieve tumoricidal ocular exposure, and is any transcriptional-CDK inhibitor formulable for local delivery to create the therapeutic window?","Can the CRISPR cone-precursor organoid drug screen (source of the sunitinib/CDK4/6i claim) be traced to a primary paper stating RB1 and MYCN status of the models?"],"nextQueries":["(\"WERI-Rb1\" OR \"Y79\" OR \"retinoblastoma\") AND (\"CRISPR screen\" OR \"dependency\" OR \"essential gene\" OR \"DepMap\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","\"retinoblastoma\" AND (\"HLA class I\" OR \"tumor microenvironment\" OR \"tumour microenvironment\" OR \"immune infiltrate\" OR \"single-cell RNA\") AND SRC:MED AND PUB_YEAR:[2019 TO 2026]","(\"glypican-2\" OR GPC2) AND (\"CAR T\" OR immunotoxin OR \"antibody-drug conjugate\" OR expression) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"papersShown":[],"trialsShown":[{"nct":"NCT05650749","phase":"phase 1","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"GPC2 CAR T Cells for Relapsed or Refractory Neuroblastoma and Metastatic Retinoblastoma"},{"nct":"NCT01109394","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Comprehensive Omics Analysis of Pediatric and Adult Solid Tumors and Establishment of a Repository for Related Biological Studies"},{"nct":"NCT07633756","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Phase 1b, Open-Label Study Of REC-617, A Selective CDK7 Inhibitor, In Patients With Metastatic Or Unresectable RB1-Negative Leiomyosarcoma"},{"nct":"NCT04040205","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Abemaciclib for Bone and Soft Tissue Sarcoma With Cyclin-Dependent Kinase (CDK) Pathway Alteration"},{"nct":"NCT03567642","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study of the Combination of Osimertinib, Platinum and Etoposide for Patients With Metastatic EGFR Mutant Lung Cancers"},{"nct":"NCT03655223","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Early Check: Expanded Screening in Newborns"},{"nct":"NCT01783535","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":5287,"output":5470},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"retinoblastoma\" OR \"RB1-deficient\" OR \"RB1 loss\") AND (\"CDK7\" OR \"CDK9\" OR \"CDK12\" OR \"transcriptional addiction\" OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"retinoblastoma\" AND (\"GPC2\" OR \"glypican-2\" OR \"CAR T\" OR \"immune microenvironment\" OR \"HLA class I\") AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"evidenceIds":["NCT05650749","NCT01109394","NCT07633756","NCT04040205","NCT03567642","NCT03655223","NCT01783535","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787163386647","cycle":72,"visit":7,"ts":"2026-08-19T18:16:26.647Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"ASC4OPT (PMID:42026180) prospectively confirms asciminib as non-cross-resistant salvage after ≥2 TKIs (MMR 43.6% at W96) while showing 200 mg QD escalation rescues only 17.5% and 40 mg BID beats 80 mg QD — promote the sequential ATP-site→allosteric switch to DOSSIER and reframe de-escalation/optimis","confidence":0.62,"notebook":"Fresh pack is thin on my mutation-spectrum questions but carries one genuine trial readout and one concurrent-dual-occupancy anecdote.\n\nASC4OPT (PMID:42026180, NCT04948333) is the first phase 3b quantification of asciminib after ≥2 TKIs: MMR 39.4% at W48, 43.6% at W96 in patients not in MMR at entry, and 86.7% of baseline-MMR intolerant patients retained MMR. That is independent, prospective corroboration of the non-cross-resistance premise of L8, which I promote to DOSSIER — with the explicit caveat that the reverse direction (asciminib-emergent myristoyl-pocket variant rescued by an ATP-site agent, PMID:39996897) remains a single case, and no kinase-domain NGS accompanies the ASC4OPT non-responders. The trial also sets a hard ceiling: of 40 patients escalated to 200 mg QD, only 17.5% reached MMR at W96 — dose escalation is a weak salvage lever, which redirects late failures towards mutation-directed switching or LSC-state biology rather than more asciminib.\n\nSecond, ASC4OPT's 40 mg BID arm outperformed 80 mg QD at both timepoints (43.4/45.8% vs 35.4/41.5%) at identical daily dose. [INFERRED] Depth tracks time-above-threshold (trough), not peak — mechanistically consistent with the flumatinib Cmax/trough dissociation (PMID:42338759), where DMR required a concentration floor. This strengthens L9: schedule, not fraction of label dose, is the de-escalation variable, and TDM should read trough for efficacy. Confidence 0.35→0.45.\n\nThird, PMID:41376545 reports combined asciminib plus olverembatinib in blast-phase CML — the first concurrent myristoyl-pocket + ATP-site exposure in the literature, olverembatinib being T315I-active [KNOWN]. Title only, no abstract, single case, blast phase; it does not resurrect frontline concurrent blockade (NCT03906292 still silent for a sixth visit) but it does match the narrow niche I pre-specified for L1: T315I/compound-mutant or advanced-phase disease where sequential switching has failed. Small upgrade, 0.50→0.55, scope narrowed to advanced phase/T315I salvage.\n\nL10 weakens: PMID:40858806 remains abstract-inaccessible for a second visit, and the only fresh venetoclax-plus-TKI framing is a Ph+ ALL review (PMID:42094005), a different disease. NCT02689440 is silent again; the frontline retirement stands.\n\nPMID:41437812 (two Ph+ acute leukaemia episodes with divergent Ig/TCR rearrangements over 17 years of persistent BCR::ABL1) is title-only but, if the letter shows independent lymphoid transformations from one persistent clone, it is strong support for L6's multipotent persistent-LSC framing; flagged, not scored.\n\nControl check: the desk reaffirms the canonical axis — BCR::ABL1 [SOMATIC] fusion kinase, ATP-site plus allosteric inhibition (PMID:42339511, PMID:42026180) — and its programme is now entirely about depth, sequence, exposure and persistence, not target discovery.","leadChanges":[{"id":"L8","title":"Sequential ATP-site to allosteric switch: asciminib as non-cross-resistant salvage after ponatinib and in T315I disease","level":"DOSSIER","status":"STRENGTHENED","confidence":0.75},{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55},{"id":"L9","title":"Concentration-floor (TDM-anchored) de-escalation: reduce exposure to a measured pharmacokinetic threshold, not to a fraction of label dose","level":"LEAD","status":"STRENGTHENED","confidence":0.45},{"id":"L10","title":"BCL2 co-dependence confined to multi-TKI/asciminib-resistant CML: venetoclax plus ponatinib as salvage","level":"LEAD","status":"WEAKENED","confidence":0.24}],"unverifiedCitations":1,"openQuestions":["Does ASC4OPT (NCT04948333) report kinase-domain NGS at failure, and what fraction of the 200 mg QD escalation non-responders (82.5%) carry T315I-containing compound mutants or myristoyl-pocket variants versus no mutation at all?","Is the 40 mg BID advantage over 80 mg QD in ASC4OPT reproduced with PK, i.e. does asciminib trough (not Cmax) predict MMR/MR4.5, and what is the derived DMR trough floor?","What are the dose levels, duration, molecular depth, cytopenia and arterial-event profile of concurrent asciminib plus olverembatinib in blast phase (PMID:41376545), and does any series exist beyond this case?","Do the two Ph+ acute leukaemia episodes with divergent Ig/TCR rearrangements (PMID:41437812) demonstrate independent lymphoid transformations arising from one persistent BCR::ABL1+ multipotent clone, and does that change TFR risk counsellin","Beyond the single A337V case, what is the published frequency/spectrum of asciminib-emergent myristoyl-pocket mutations and which ATP-site agent rescues each?","Are TFR attempts being made after asciminib-based salvage, and are any TFR cohorts stratified by ELTS, e13a2 vs e14a2, and ASXL1/RUNX1 status?"],"nextQueries":["\"chronic myeloid leukemia\" AND asciminib AND (pharmacokinetic* OR trough OR Ctrough OR exposure-response OR \"therapeutic drug monitoring\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic myeloid leukemia\" AND (olverembatinib OR ponatinib) AND asciminib AND (combination OR concurrent OR \"blast phase\" OR T315I OR \"compound mutation\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic myeloid leukemia\" AND (\"leukemic stem cell\" OR persistence OR \"treatment-free remission\") AND (\"single-cell\" OR TRIM28 OR SETDB1 OR \"gene regulatory network\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"41880688","doi":"10.1016/j.pharmr.2026.100128","year":2026,"isNew":true,"title":"Targeting of kinases to treat neurodegenerative diseases"},{"pmid":"40823259","doi":"10.1016/j.lrr.2025.100533","year":2025,"isNew":true,"title":"Mechanisms and signaling pathways of tyrosine kinase inhibitor resistance in chronic myeloid leukemia: A comprehensive review"},{"pmid":"41129068","doi":"10.1002/cncr.70113","year":2025,"isNew":true,"title":"A tour of leukemia progress in 2025, viewed through the MD Anderson leukemia research lens"},{"pmid":"41437812","doi":"10.3324/haematol.2025.288671","year":2026,"isNew":true,"title":"Two episodes of Ph&lt;sup&gt;+&lt;/sup&gt; acute leukemia with divergent &lt;i&gt;Ig/TCR&lt;/i&gt; rearrangements in two patients with persistent &lt;i&gt;BCR&lt;/i&gt;::&lt;i&gt;A"},{"pmid":"42026180","doi":"10.1038/s41375-026-02965-8","year":2026,"isNew":true,"title":"ASC4OPT: asciminib treatment optimization study in patients with chronic myeloid leukemia in chronic phase previously treated with two or more tyrosine kinase inhibitors"},{"pmid":"42094005","doi":"10.3389/fimmu.2026.1809757","year":2026,"isNew":true,"title":"Toward a chemotherapy and allo-HSCT free future: the evolution of treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia"},{"pmid":"41376545","doi":"10.3324/haematol.2025.289085","year":2026,"isNew":true,"title":"Combined asciminib and olverembatinib in blast-phase chronic myeloid leukemia"},{"pmid":"40287957","doi":"10.1158/2643-3230.bcd-25-0036","year":2025,"isNew":true,"title":"Overcoming B-ALL Resistance to Targeted and Immune Therapies by Rational Combination Strategies"},{"pmid":"42339511","doi":"10.1002/cam4.72019","year":2026,"isNew":false,"title":"Asciminib Provides Better Efficacy and Favorable Safety and Tolerability Against Investigator-Selected Tyrosine Kinase Inhibitors in East Asian Patients With Newly Diagnosed Chroni"},{"pmid":"42303626","doi":"10.1038/s41392-026-02729-x","year":2026,"isNew":false,"title":"Non-receptor tyrosine kinase signaling pathways and therapeutic implications"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":13854,"output":6995},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic myeloid leukemia\" AND asciminib AND (\"A337V\" OR \"P465S\" OR \"F359\" OR \"myristoyl\" OR \"compound mutation\") AND (sequential OR switch OR dasatinib OR ponatinib) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic myeloid leukemia\" AND venetoclax AND (ponatinib OR asciminib OR \"BH3 profiling\" OR MCL1) AND (resistant OR persistence OR \"stem cell\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:41880688","PMID:40823259","PMID:41129068","PMID:41437812","PMID:42026180","PMID:42094005","PMID:41376545","PMID:40287957","PMID:42339511","PMID:42303626","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787163172405","cycle":71,"visit":2,"ts":"2026-08-19T18:12:52.405Z","cancer":{"key":"medulloblastoma","name":"medulloblastoma","mondo":{"id":"MONDO:0007959","name":"medulloblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Visit 2 produced no literature (over-constrained queries); the only new material is trial-level, so open a low-confidence antigen-agnostic RNA-DC/adoptive-T immunotherapy lead (NCT06514898) plus a matched-kinase-basket lead (NCT03598244/NCT04320888/NCT05057702), weaken the unsupported BBB lead, and ","confidence":0.34,"notebook":"Visit 2 returned zero papers from both Europe PMC queries. That is a query-design failure, not a biological result: both strings stacked four AND-clauses plus `SRC:MED`, which is over-constrained for a disease with ~1500 annual cases. Nothing in the ELP1/SUFU germline-vulnerability question (OQ1) or the Group 3 replication-stress-vs-transcription-CDK question (OQ2) can be answered or scored this visit, and no lead earns promotion — the ladder stays flat. Recorded so the desk does not repeat it: conjunctive queries with `SRC:MED` on a rare pediatric tumour return null; drop to two clauses next visit.\n\nThe trial slate is the only new material. Four registrations are new to the pack. NCT06514898 is the first primary MB immunotherapy protocol the desk has seen and partially answers OQ4: the antigen chosen is not GD2, B7-H3 or HER2 but total tumour RNA — an antigen-agnostic DC vaccine paired with xenogeneic-primed adoptive lymphocyte transfer, autologous HSC support and pembrolizumab. Mechanistically this is a rational answer to MB's low mutational burden and absence of a validated surface antigen [KNOWN]: polyclonal RNA-templated priming does not require a known epitope, and HSC rescue plus lymphodepletion addresses the homeostatic-proliferation requirement for ALT engraftment [INFERRED]. It is phase 1 with no efficacy data in the pack, so I open it at low confidence and explicitly note that MHC-I downregulation in MYC-amplified Group 3 would blunt any T-cell-dependent arm [SPECULATIVE].\n\nNCT03598244 (savolitinib/MET), NCT04320888 (selpercatinib/RET, Pediatric MATCH) and NCT05057702 (molecular tumour board) together constitute infrastructure rather than a hypothesis. I open one low-confidence lead covering them because the actionable question is quantitative: does relapsed MB harbour RET fusions/activating mutations or MET amplification at a frequency that justifies screening? I have no MB frequency data and will not assume one — MB is a histology of eligibility, not a stated biological target, in either basket.\n\nL5 (subgroup-differential BBB) is weakened. Its only citation remains a BBB review with no MB data, and a second visit has produced nothing MB-specific; it gets one targeted query next visit and is retired if that also returns null. L1–L4 are unchanged: their trial citations reappear in the pack but reappearance is not new evidence, and I decline to score it as corroboration.\n\nNext visit must be literature-productive: broad two-clause queries on ELP1, on MYC/MYCN replication-stress and transcription-CDK dependencies, and on MB immunotherapy antigens.","leadChanges":[{"id":"L6","title":"Antigen-agnostic total-tumour-RNA DC vaccine + xenogeneic-primed adoptive lymphocyte transfer under PD-1 blockade in MB","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L7","title":"Genotype-matched kinase inhibition at MB relapse: RET and MET as screenable but unquantified alterations","level":"LEAD","status":"NEW","confidence":0.15},{"id":"L5","title":"Subgroup-differential BBB integrity as the determinant of CNS drug exposure in MB","level":"LEAD","status":"WEAKENED","confidence":0.15}],"unverifiedCitations":0,"openQuestions":["Does ELP1 loss [GERMLINE] in SHH-MB create a measurable translational-stress/proteostasis vulnerability (ISR, GCN2/PERK, HSP90, tRNA-modification enzymes) with any primary data?","In MYC/MYCN-amplified Group 3/4 MB, is replication-stress targeting (TOP1/ATR/CHK1/PARP) or transcription-CDK targeting (CDK7/CDK9/CDK12) better supported in vivo, and has any study compared them in the same model?","What is the frequency of RET fusions/activating mutations and MET amplification in relapsed MB by molecular subgroup — is basket screening justified?","Has the total-tumour-RNA DC vaccine / adoptive lymphocyte platform produced any published response or immune-correlative signal in MB or other pediatric brain tumours, and does MYC amplification correlate with MHC-I/B2M loss in MB?","Is there any MB-specific measurement of intratumoural drug exposure or vascular permeability stratified by subgroup (last chance for L5)?","Which radiosensitisers other than atovaquone have been evaluated under fractionated craniospinal rather than focal irradiation, and did any reduce spinal relapse?"],"nextQueries":["\"medulloblastoma\" AND ELP1","\"medulloblastoma\" AND (\"replication stress\" OR CDK7 OR CDK9 OR ATR OR CHK1)","\"medulloblastoma\" AND (\"CAR T\" OR \"dendritic cell vaccine\" OR B7-H3 OR GD2 OR \"MHC class I\")"],"papersShown":[],"trialsShown":[{"nct":"NCT06161519","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"PLX038 in Primary Central Nervous System Tumors Containing MYC or MYCN Amplifications"},{"nct":"NCT04696029","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"DFMO as Maintenance Therapy for Molecular High/Very High Risk and Relapsed Medulloblastoma"},{"nct":"NCT05057702","phase":"NA","status":"RECRUITING","isNew":false,"title":"Individualized Treatment Plan in Children and Young Adults With Relapsed Medulloblastoma and Ependymoma"},{"nct":"NCT06514898","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Adoptive T Cell Therapy, DC Vaccines, and Hematopoietic Stem Cells Combined With Immune checkPOINT Blockade in Patients With Medulloblastoma"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT06624371","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Atovaquone Combined With Radiation in Children With Malignant Brain Tumors"},{"nct":"NCT04337177","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With Temozolomide for Treatment of Recurrent Pediatric Solid Tumors"},{"nct":"NCT03598244","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Savolitinib in Treating Patients With Recurrent or Refractory Primary CNS Tumors"}],"usage":{"input":5426,"output":4930},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"medulloblastoma\") AND (ELP1 OR SUFU OR \"germline predisposition\") AND (vulnerability OR dependency OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"medulloblastoma\" AND (\"Group 3\" OR MYC)) AND (\"replication stress\" OR ATR OR CHK1 OR PARP OR CDK7 OR \"transcriptional addiction\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["NCT06161519","NCT04696029","NCT05057702","NCT06514898","NCT04320888","NCT06624371","NCT04337177","NCT03598244"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787162981390","cycle":70,"visit":2,"ts":"2026-08-19T18:09:41.390Z","cancer":{"key":"neuroblastoma","name":"neuroblastoma","mondo":{"id":"MONDO:0005072","name":"neuroblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Zero-paper evidence pack: no lead advances; weaken L4 (no neuroblastoma-enrolling SSTR2 alpha vehicle), flag NCT04755205 olfactory neuroblastoma as an off-target entity, and open a derived correlative lead nesting FCGR3A genotype and ADRN/MES antigen profiling inside the frontline dinutuximab phase ","confidence":0.42,"notebook":"**Visit 2 — null-evidence visit; no promotions.** The Europe PMC pack returned zero papers on both queries, so no lead can advance: the ladder requires new evidence-bearing literature and there is none. Two of my six open questions (ALK/lorlatinib resistance; ADRN–MES antigen coupling) have now failed retrieval once each and remain unanswered — this is a retrieval failure, not evidence of absence [INFERRED]. The queries were over-conjuncted (four AND-blocks plus SRC:MED), which for a paediatric-rare-tumour corpus plausibly returns nothing; I am decomposing them for next visit rather than concluding the literature is silent.\n\nTrial pull was almost entirely a re-listing of visit 1 (T1, T2, T3, T6, T7, T8 all previously logged, all still recruiting, none with posted results). Three notebook entries so the desk does not re-mine them: (i) NCT04755205 \"olfactory neuroblastoma\" is esthesioneuroblastoma, an olfactory-epithelial/neuroectodermal tumour, *not* peripheral sympathetic-nervous-system neuroblastoma [KNOWN] — it is off-target for this programme and must not be used to corroborate any lead; (ii) NCT01005654 (endocrine neoplasm molecular natural history) is likewise off-target except as a possible SSTR2/paraganglioma comparator; (iii) NCT06479811 [212Pb]VMT-alpha-NET still lists no neuroblastoma cohort, so the SSTR2-directed alpha hedge in L4 has no neuroblastoma-enrolling vehicle. I therefore mark **L4 WEAKENED** (0.40→0.35): its only neuroblastoma anchor is an early-phase-1 [211At]MABG study with no readout, and the lineage-orthogonal hedge is unavailable in-indication.\n\nOne mechanistic refinement to **L1** that the trial text forces: the hu14.18K322A backbone (NCT07549321) is temozolomide + irinotecan, i.e. actively lymphodepleting/myelosuppressive. Infused UCB-NK cells would be delivered into a cytotoxic window; lymphodepletion may aid engraftment but TMZ is directly NK-toxic [INFERRED], so any combination must specify NK infusion timing relative to day 1–5 chemotherapy and measure donor-NK persistence, not just response. This is a design constraint, not new support — L1 confidence unchanged.\n\nNew derived lead (**L5**): NCT06172296 is a frontline phase 3 dinutuximab platform that already includes biospecimen collection and serial bone-marrow sampling. Rather than propose another trial, embed the correlative programme that answers OQ1/OQ3 inside it — germline FCGR3A-158V/F and FCGR2A-131H/R genotyping [GERMLINE] against event-free survival, plus single-cell ADRN/MES scoring with ST8SIA1/GPC2/CD276/SLC6A2 quantification on serial marrow. Hypothesis: 158F carriers are the ADCC-deficient subgroup in whom NK augmentation (L1) or MHC-independent CAR targeting (L2) should be tested first. Purely derived, low confidence.","leadChanges":[{"id":"L4","title":"Alpha-emitter radiopharmaceuticals and the ADRN-state dependence of NET-mediated uptake","level":"LEAD","status":"WEAKENED","confidence":0.35},{"id":"L5","title":"FcgammaR-genotype and ADRN/MES antigen stratification nested inside the frontline dinutuximab phase 3","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["What lorlatinib/crizotinib clinical response and acquired-resistance mutation data exist in ALK-mutant or ALK-amplified neuroblastoma (ALK F1174L, R1275Q, compound mutations, MYCN co-amplification as a modifier), and why has this literature","What is the quantitative single-cell co-expression of ST8SIA1/GD2, GPC2, CD276/B7-H3 and SLC6A2/NET across ADRN versus MES states, and does any antigen pair cover both states?","Does EZH2 or DNMT inhibition restore MHC-I and GD2 synthase in MYCN-amplified models, i.e. can one epigenetic agent enable both immunotherapy and re-differentiation?","Is there any controlled evidence that adoptive NK infusion adds benefit over anti-GD2 alone, and how does temozolomide/irinotecan timing affect infused NK persistence?","Which myeloid-directed intervention (CSF1R, CD47, adenosine A2AR) most reliably reverses MDSC/TAM-mediated anti-GD2 resistance in neuroblastoma models?","Are LIN28B, LMO1, HACE1 or PHOX2B tractable beyond lineage/predisposition markers, and which are germline versus somatic in neuroblastoma?"],"nextQueries":["(neuroblastoma AND lorlatinib) OR (neuroblastoma AND \"ALK inhibitor\" AND resistance)","neuroblastoma AND (\"mesenchymal\" OR \"adrenergic\") AND (\"GD2\" OR \"antigen escape\")","neuroblastoma AND (\"MHC class I\" OR \"EZH2 inhibitor\" OR tazemetostat)"],"papersShown":[],"trialsShown":[{"nct":"NCT06172296","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Dinutuximab With Chemotherapy, Surgery and Stem Cell Transplantation for the Treatment of Children With Newly Diagnosed High Risk Neuroblast"},{"nct":"NCT07767630","phase":"EARLY_phase 1","status":"RECRUITING","isNew":false,"title":"Safety, Tolerability, and Preliminary Efficacy of [211At]MABG in Patients With Relapsed or Refractory Neuroblastoma"},{"nct":"NCT06479811","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"[212Pb]VMT-Alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive Gastrointestinal Neuroendocrine Tumors, Pheochromocytoma/Par"},{"nct":"NCT04755205","phase":"n/a","status":"RECRUITING","isNew":false,"title":"A Natural History Study of Children and Adults With Olfactory Neuroblastoma"},{"nct":"NCT01005654","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Prospective Comprehensive Molecular Analysis of Endocrine Neoplasms"},{"nct":"NCT07549321","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"A Safety and Efficacy Study of hu14 in High-Risk Neuroblastoma Patients"},{"nct":"NCT05650749","phase":"phase 1","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"GPC2 CAR T Cells for Relapsed or Refractory Neuroblastoma and Metastatic Retinoblastoma"},{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"}],"usage":{"input":5688,"output":4152},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"neuroblastoma\" AND (ALK OR lorlatinib OR crizotinib) AND (resistance OR mutation OR trial) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"neuroblastoma\" AND (\"adrenergic\" OR \"mesenchymal\" OR \"ADRN\" OR \"plasticity\") AND (\"GD2\" OR \"MHC class I\" OR \"antigen loss\" OR \"EZH2\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["NCT06172296","NCT07767630","NCT06479811","NCT04755205","NCT01005654","NCT07549321","NCT05650749","NCT07172958"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787162799205","cycle":69,"visit":2,"ts":"2026-08-19T18:06:39.205Z","cancer":{"key":"adrenocortical carcinoma","name":"adrenocortical carcinoma","mondo":{"id":"MONDO:0006639","name":"adrenal cortex carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Two independent 2025-2026 ACC-specific sources (PMID:42433381, PMID:40736645) establish glucocorticoid-driven immune depletion as the leading mechanistic account of checkpoint failure in ACC, promoting the cortisol/GR-blockade-plus-PD-1 hypothesis to CANDIDATE while a pembrolizumab-induced adrenal c","confidence":0.46,"notebook":"The pack is thin on cell-cycle biology and rich on the steroid–immune axis, which reverses the relative standing of L1 and L3.\n\nNothing in this pack touches WEE1, adavosertib, RSK1, MELK or checkpoint kinases in ACC despite a query written for exactly that; P2–P8 are pan-cancer bioinformatics on cervical/hepatic tumours (DUBs, RNF40, TIGD5, YBX1, TONSL, AARS1) with no ACC-specific data and no in vivo ACC work. Recorded as a null result: L1 remains a single-report hypothesis (PMID:42601067) with no independent corroboration at two visits, so confidence drops. I am explicitly ruling out chasing YBX1/TONSL/AARS1 as ACC leads — pan-cancer TCGA correlation without ACC-level validation is not a therapeutic hypothesis and the desk should not re-propose it.\n\nL3 gains two independent, ACC-specific sources. PMID:42433381 characterises ACC as relatively immune-depleted and explicitly shaped by glucocorticoid signalling, hypoxia, senescence and myeloid suppression, with immune ecotypes as the strongest ACC-level human evidence; it also honestly flags that CAF-mediated exclusion and metabolite mechanisms are extrapolated, and that the cleanest glucocorticoid-immunosuppression data come from cortisol-producing adenoma, not ACC. PMID:40736645 supplies the clinical frame: up to 50% of ACC is hypercortisolaemic, cortisol secretion marks worse prognosis, steroidogenesis inhibitors are first-line for severe hypercortisolism, GR antagonists act fast but are hard to monitor (mitotane also corrupts cortisol/ACTH readouts), and it raises ICI combination as a forward direction. Two evidence-bearing visits, four verified citations, independent corroboration — L3 moves to CANDIDATE, but capped near 0.5 because cohort-level correlation of hypercortisolism with ICI failure still does not exist.\n\nP10 (PMID:42065769) is the important safety constraint: pembrolizumab precipitated adrenal crisis in a mitotane-pretreated, post-adrenalectomy ACC patient via immune adrenalitis on already-compromised reserve. Any GR-antagonist- or steroidogenesis-inhibitor-plus-ICI design therefore inherits a real hypoadrenal hazard, and it exposes a confound I had not separated: replacement-dose glucocorticoid (often supraphysiologic under mitotane's accelerated clearance) is itself systemic GR agonism that could blunt the ICI arm. That becomes new lead L4, and it sharpens the NCT05286814 contradiction (systemic dexamethasone alongside an IL-12 immunocytokine).\n\nUnresolved and now urgent: ZNRF3/CTNNB1 WNT tractability produced nothing for a second visit; next queries must force it.","leadChanges":[{"id":"L1","title":"Adaptive WEE1 induction as the actionable vulnerability of TP53-mutant ACC after RSK1/multikinase inhibition","level":"LEAD","status":"WEAKENED","confidence":0.38},{"id":"L3","title":"Tumour-derived cortisol as a targetable immune-evasion axis: GR antagonism to enable checkpoint therapy","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.5},{"id":"L4","title":"Replacement-dose glucocorticoid stewardship as a modifiable determinant of checkpoint-inhibitor efficacy in ACC","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does baseline hypercortisolism or 24h urinary free cortisol predict ORR/PFS failure on PD-1-based therapy in ACC cohorts of n>20 (NCT02721732, NCT03333616, NCT06900595 correlatives)?","Does cumulative hydrocortisone/dexamethasone exposure independently associate with reduced ICI benefit in ACC, separable from tumour cortisol secretion?","Is there any 2023-2026 evidence for tractable WNT targeting in ZNRF3-mutant or CTNNB1-mutant ACC (porcupine, TNKS, beta-catenin/TCF disruptors), and does WNT activation drive T-cell exclusion in ACC specifically?","Does any ACC dataset independently confirm WEE1/PKMYT1 or ATR dependency, and is that dependency confined to the proliferative rather than steroid-high subtype?","What resistance mechanism dominates after VEGFR/MET-TKI plus PD-1 in ACC, and are on-treatment biopsy data emerging from NCT06900595?","In GR-antagonist-plus-ICI designs, can adrenal insufficiency risk be managed without administering GR agonist doses that defeat the mechanism?"],"nextQueries":["(\"adrenocortical carcinoma\" AND (ZNRF3 OR CTNNB1 OR \"Wnt\" OR porcupine OR tankyrase OR beta-catenin)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"adrenocortical carcinoma\" AND (pembrolizumab OR nivolumab OR avelumab OR cemiplimab) AND (cohort OR \"response rate\" OR retrospective OR biomarker)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"adrenocortical\" AND (PKMYT1 OR adavosertib OR ceralasertib OR \"ATR inhibitor\" OR \"synthetic lethal\" OR \"CRISPR screen\")) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"papersShown":[{"pmid":"40736645","doi":"10.1007/s11154-025-09989-y","year":2025,"isNew":true,"title":"Management of cushing's syndrome in patients with adrenocortical cancer: state of the art and future perspectives"},{"pmid":"42138186","doi":"10.3892/ijo.2026.5892","year":2026,"isNew":true,"title":"Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review)"},{"pmid":"41775084","doi":"10.1016/j.tranon.2026.102722","year":2026,"isNew":true,"title":"Single-cell analysis of TIGD genes in hepatocellular carcinoma: Prognostic value and functional characterization"},{"pmid":"42059264","doi":"10.3892/or.2026.9126","year":2026,"isNew":true,"title":"E3 ubiquitin ligase RNF40: Structure, function and its context‑dependent roles in tumorigenesis (Review)"},{"pmid":"42196325","doi":"10.3390/ijms27104340","year":2026,"isNew":true,"title":"YBX1 Expression Marks Proliferative Tumour States with Context-Dependent Genomic Instability: A Pan-Cancer Analysis"},{"pmid":"42002539","doi":"10.1002/cnr2.70551","year":2026,"isNew":true,"title":"Comprehensive Bioinformatic Analysis of TONSL Expression in Pan-Cancer"},{"pmid":"41952148","doi":"10.1186/s12935-026-04288-1","year":2026,"isNew":true,"title":"Comprehensive pan-cancer analysis of AARS1, a newly identified lactyltransferase in human cancers"},{"pmid":"41817780","doi":"10.1007/s12672-026-04698-7","year":2026,"isNew":true,"title":"TONSL promotes hepatocellular carcinoma progression and radioresistance by orchestrating DNA damage repair and cell cycle dynamics"},{"pmid":"42433381","doi":"10.3389/fimmu.2026.1853359","year":2026,"isNew":true,"title":"Adrenal tumor microenvironment: hormone-immune crosstalk, molecular heterogeneity, and immunotherapeutic opportunities"},{"pmid":"42065769","doi":"10.1007/s12672-026-05019-8","year":2026,"isNew":true,"title":"Pembrolizumab induced life threatening adrenal crisis in a patient with recurrent adrenocortical carcinoma after unilateral adrenalectomy"}],"trialsShown":[{"nct":"NCT06487481","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Study of Preoperative Radiation Therapy in Participants With Resectable Recurrent Abdominal Adrenocortical Carcinoma"},{"nct":"NCT03604198","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Extension Study to Evaluate the Safety of Long-Term Use of Relacorilant in Patients With Cushing Syndrome"},{"nct":"NCT06900595","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Testing the Addition of an Anti-Cancer Drug, Cabozantinib to the Immunotherapy Drug Cemiplimab (REGN2810), in Adolescents and Adults With Ad"},{"nct":"NCT03333616","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Nivolumab Combined With Ipilimumab for Patients With Advanced Rare Genitourinary Tumors"},{"nct":"NCT02867592","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumor"},{"nct":"NCT02721732","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Pembrolizumab in Treating Patients With Rare Tumors That Cannot Be Removed by Surgery or Are Metastatic"},{"nct":"NCT03583710","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Mitotane With or Without Cisplatin and Etoposide After Surgery in Treating Patients With Stage I-III Adrenocortical Cancer With High Risk of"},{"nct":"NCT05286814","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"PDS01ADC in Combination With Hepatic Artery Infusion Pump (HAIP) and Systemic Therapy for Subjects With Metastatic Colorectal Cancer, Intrah"}],"usage":{"input":10727,"output":6387},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"adrenocortical carcinoma\" AND (WEE1 OR adavosertib OR RSK1 OR MELK OR \"cell cycle checkpoint\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"adrenocortical carcinoma\" AND (cortisol OR hypercortisolism OR glucocorticoid) AND (immunotherapy OR \"PD-1\" OR \"checkpoint\" OR \"T cell\")) AND SRC:MED"],"evidenceIds":["PMID:40736645","PMID:42138186","PMID:41775084","PMID:42059264","PMID:42196325","PMID:42002539","PMID:41952148","PMID:41817780","PMID:42433381","PMID:42065769","NCT06487481","NCT03604198","NCT06900595","NCT03333616","NCT02867592","NCT02721732","NCT03583710","NCT05286814"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787162593902","cycle":68,"visit":2,"ts":"2026-08-19T18:03:13.902Z","cancer":{"key":"head and neck squamous cell carcinoma","name":"head and neck squamous cell carcinoma","mondo":{"id":"MONDO:0010150","name":"head and neck squamous cell carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Reframe the HNSCC PI3K/AKT lead around PIK3CA-activating (not PTEN-null) selection with ERK1/2 co-blockade, and use existing biomarker-bearing HNSCC trials (NCT02734537, NCT05136196) as the cheapest tests of the FOXA2/LAMC2 and IRF9 hypotheses.","confidence":0.42,"notebook":"This was a review-heavy, low-information pack: both fielded queries returned narrative reviews rather than the HNSCC-specific primary data I asked for, and no lead earns promotion.\n\nQ2 comes back partly negative. The precision-PI3K review (PMID:40564038 [NEW]) frames the entire approved-drug landscape around *activating* PIK3CA/AKT1/2/MTOR mutations, not PTEN loss; PTEN-null stratification appears in the prostate literature (PMID:41525007 [NEW]), not head and neck. The pack contains zero HNSCC AKT-inhibitor-plus-platinum data. So L2 is weakened on the drug side: the FOXA2→LAMC2→PI3K/AKT organoid mechanism stands, but the actionable biomarker is more likely a PIK3CA hotspot than PTEN deletion, and PTEN loss must be treated as a synthetic-lethality problem (PI3Kβ/SGK1/PARP) that this pack does not address [INFERRED]. Two constructive additions: ERK1/2 co-targeting as the named escape route for PI3K blockade (PMID:40943615 [NEW]), which supersedes my vague \"RTK feedback\" wording; and NCT02734537, a post-operative RT ± cisplatin trial with prospective laboratory biomarker analysis — a specimen bank in which FOXA2/LAMC2-high could be tested as a platinum-benefit predictor without a new drug study.\n\nQ1 is unanswered: no TCR-T or TCR-mimic footprint for E6*(aa49-110), and no E7_11-19 outcome report. What did surface cuts mildly against L1 — therapeutic-vaccine reviews state that E6/E7 targeting is limited by heterogeneous intratumoural antigen expression and that clonality/expression level should be formal antigen-selection criteria (PMID:41571571 [NEW]; PMID:42179134 [NEW]). That is the same failure mode as my predicted E6 splice-isoform loss, now with independent support, so L1 drops to 0.50 and requires antigen-expression QC per patient.\n\nL4 gets a clinical home rather than new mechanism: BiCaZO (NCT05136196 [NEW]) runs cabozantinib (VEGFR2/MET TKI) plus nivolumab in HNSCC with mandated on-treatment biopsies — the natural setting to test IRF9 nuclear/cytoplasmic ratio as a resistance biomarker for VEGFR2-TKI class, not just apatinib. Held at 0.25; Oroxin B remains a tool compound.\n\nL3 unchanged in mechanism but the myeloid/pembrolizumab combination field in HNSCC is now three-deep (NCT06508606, NCT06806852, NCT04958239 [NEW]); BI 765179's target is not disclosed in the record and I will not guess it.\n\nNew lead: PGE2/VEGF/IL-6-driven suppression of dendritic-cell cross-presentation is the named bottleneck for peptide/nucleic-acid HPV vaccines (PMID:41758201) — a repurposing-first arm (COX-2/EP4 blockade + E6/E7 vaccine + pembrolizumab) in HPV+ OPSCC.\n\nTNFRSF10B/ING1 (Q3) remain citation-free after two visits — next visit must query them directly or I retire them from the anchor narrative.","leadChanges":[{"id":"L2","title":"PI3K/AKT blockade to resensitise cisplatin-resistant HNSCC in FOXA2/LAMC2-high or PTEN-null tumours","level":"LEAD","status":"WEAKENED","confidence":0.32},{"id":"L1","title":"High-avidity HPV16 E6* (aa49-110)-directed TCR-T for HPV+ oropharyngeal SCC; deprioritise E7_11-19","level":"LEAD","status":"WEAKENED","confidence":0.5},{"id":"L4","title":"IRF9 nuclear translocation as a reversible node of apatinib (VEGFR2 TKI) resistance","level":"LEAD","status":"WEAKENED","confidence":0.25},{"id":"L5","title":"Relieving PGE2/VEGF/IL-6-mediated suppression of dendritic-cell cross-presentation to rescue therapeutic HPV E6/E7 vaccination in HPV+ OPSCC","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Is there any primary (non-review) preclinical or clinical evidence for PI3K/AKT inhibitor plus platinum or plus cetuximab-RT specifically in HNSCC models, and does any HNSCC dataset show PTEN-null synthetic lethality with PI3Kbeta, SGK1 or ","Does an E6*(aa49-110) or any HPV16 E6-directed TCR-T/TCR-mimic bispecific programme exist in the literature or trial registries, and has the E7_11-19 TCR-T trial reported response, persistence or antigen-loss data?","TNFRSF10B (DR5) and ING1 remain citation-free after two visits: is there caspase-8-intact-dependent DR5 agonist activity in HNSCC, and does ING1 loss create an exploitable dependency, or should both Monarch anchors be retired from this prog","What is the disclosed target of BI 765179 (NCT04958239) and of AZD6750 (NCT07115043) and ABBV-711 (NCT07241039), and do any of them sit on the myeloid/innate-checkpoint axis that L3 depends on?","What resistance and relapse mechanisms have been reported for neoadjuvant pembrolizumab in HNSCC (KEYNOTE-689 and similar), since L1, L3 and the new vaccine lead all layer onto that backbone?","Does PGE2/EP2-EP4 blockade increase cDC1 cross-presentation or vaccine-induced CD8 responses in any head and neck or HPV+ model, as opposed to the general reviews cited so far?"],"nextQueries":["(\"head and neck squamous cell carcinoma\" OR HNSCC) AND (TNFRSF10B OR \"DR5\" OR \"TRAIL receptor\" OR ING1) AND (agonist OR apoptosis OR caspase-8) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"head and neck\" OR oropharyngeal) AND (\"neoadjuvant pembrolizumab\" OR KEYNOTE-689 OR \"resistance to PD-1\") AND (biomarker OR relapse OR \"acquired resistance\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"head and neck squamous\" OR HNSCC) AND (\"PTEN loss\" OR \"PIK3CA mutant\") AND (\"synthetic lethal\" OR PI3Kbeta OR SGK1 OR PARP OR alpelisib OR capivasertib) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"papersShown":[{"pmid":"40564038","doi":"10.3390/biomedicines13061319","year":2025,"isNew":true,"title":"The Precision-Guided Use of PI3K Pathway Inhibitors for the Treatment of Solid Malignancies"},{"pmid":"41525007","doi":"10.1007/s44446-025-00056-w","year":2026,"isNew":true,"title":"Targeting the PI3K/AKT/mTOR signaling pathway in prostate cancer: Molecular dysregulation, therapeutic advances, and future directions"},{"pmid":"40943615","doi":"10.3390/ijms26178696","year":2025,"isNew":true,"title":"Current and Emerging Therapies for Targeting the ERK1/2 &amp; PI3K Pathways in Cancer"},{"pmid":"41593888","doi":"10.1080/07853890.2026.2620191","year":2026,"isNew":true,"title":"Application of artificial intelligence in head and neck squamous cell carcinoma"},{"pmid":"41571571","doi":"10.1080/21645515.2025.2610899","year":2026,"isNew":true,"title":"Toward next-generation therapeutic HPV vaccines: A review on expanding the antigen repertoire and an integrated bioinformatics selection framework"},{"pmid":"41756688","doi":"10.1016/j.bioactmat.2026.02.014","year":2026,"isNew":true,"title":"Advances in delivery technologies-powered cancer vaccines"},{"pmid":"41281471","doi":"10.4251/wjgo.v17.i11.109923","year":2025,"isNew":true,"title":"Targeting the Osteopontin-regulated PI3K/AKT signaling pathway: A molecular approach to overcome drug resistance and metastasis in gastrointestinal tumors"},{"pmid":"42179134","doi":"10.1080/21645515.2026.2676391","year":2026,"isNew":true,"title":"Clinical research progress and challenges of vaccine for human papillomavirus-associated cancers"},{"pmid":"41758201","doi":"10.1080/07853890.2026.2635774","year":2026,"isNew":true,"title":"Opportunities and challenges for cancer immunotherapy based on antigen cross-presentation"},{"pmid":"41491954","doi":"10.1080/2162402x.2025.2608436","year":2026,"isNew":true,"title":"Unlocking the therapeutic potential of immuno-radiotherapy: insights from preclinical and clinical research"}],"trialsShown":[{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT06508606","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"AK117 (Anti-CD47 mAb) Plus Cetuximab or AK104 (Anti-PD-1/CTLA-4 bsAb) as Second-Line Therapy in Recurrent/Metastatic Head and Neck Squamous "},{"nct":"NCT04958239","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Test BI 765179 Alone and in Combination With Ezabenlimab in Patients With Advanced Cancer (Solid Tumors) and BI 765179 in Combina"},{"nct":"NCT07241039","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Study to Assess the Adverse Events, Change in Disease Activity, and How Oral ABBV-711 Tablets Move Through the Body as a Monotherapy and i"},{"nct":"NCT02734537","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Radiation Therapy With or Without Cisplatin in Treating Patients With Stage III-IVA Squamous Cell Carcinoma of the Head and Neck Who Have Un"},{"nct":"NCT06995508","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Olanzapine for Managing Anorexia in Head and Neck Cancer Patients Undergoing Chemoradiation, MACRO Trial"},{"nct":"NCT05136196","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"BiCaZO: A Study Combining Two Immunotherapies (Cabozantinib and Nivolumab) to Treat Patients With Advanced Melanoma or Squamous Cell Head an"},{"nct":"NCT06806852","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Test Whether Treatment With BI 770371 in Combination With Pembrolizumab With or Without Cetuximab Helps People With Head and Neck"}],"usage":{"input":10842,"output":6994},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"head and neck\" OR oropharyngeal) AND (\"TCR-T\" OR \"T cell receptor\" OR \"adoptive cell therapy\") AND (HPV16 OR E6 OR E7) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"head and neck squamous cell carcinoma\" AND (PTEN OR \"PIK3CA\" OR capivasertib OR alpelisib OR \"AKT inhibitor\") AND (cisplatin OR platinum OR \"synthetic lethality\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:40564038","PMID:41525007","PMID:40943615","PMID:41593888","PMID:41571571","PMID:41756688","PMID:41281471","PMID:42179134","PMID:41758201","PMID:41491954","NCT07115043","NCT06508606","NCT04958239","NCT07241039","NCT02734537","NCT06995508","NCT05136196","NCT06806852"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787162380110","cycle":67,"visit":2,"ts":"2026-08-19T17:59:40.110Z","cancer":{"key":"mesothelioma","name":"mesothelioma","mondo":{"id":"MONDO:0005065","name":"mesothelioma"}},"control":false,"modelLabel":"SCIENCE","summary":"Targeted searches returned no new papers, so mark down the NF2/TEAD (L1) and CRIg+ macrophage (L3) leads as single-source and unreplicated, and open a human correlative-platform lead exploiting the BAP1 germline surveillance cohorts (NCT04431024, NCT03830229, NCT00242723, NCT00715611) to test NF2/BA","confidence":0.42,"notebook":"No new literature this visit: both fielded Europe PMC queries — NF2/TEAD/YAP × mesothelioma × inhibitor/resistance (2023–2026) and BAP1 × EZH2/tazemetostat/synthetic-lethal (2022–2026) — returned zero records. That is not neutral. It means the two mechanistic pillars of this programme are each still resting on a single source: L1 and L3 both derive entirely from PMID:42208538, and L2's synthetic-lethality premise is carried by a review (PMID:42257802) rather than by primary data. Unreplicated after a targeted search is weaker than unreplicated before one, so I am marking L1 down (0.55→0.50) and L3 down (0.35→0.30) and L2 down (0.40→0.35) rather than holding them flat. None of my six open questions was answered; the TEAD compound, dose, route, and the tumour-cell-intrinsic versus macrophage-intrinsic Hippo dependency in PMID:42208538 remain unknown, and no fresh trial in the pack tests a TEAD inhibitor in any indication — so the L1 combination remains a paper proposal with no clinical vehicle.\n\nThe trial pack does add three registrations not previously in the dossier: NCT04431024 (prospective dual-energy CT, liquid biopsy and minimally invasive surgical surveillance in BAP1 carriers), NCT00242723 (serial blood/tissue cell changes in pleural and lung cancers), and NCT00715611 (P/D plus chemotherapy plus pleural IMRT). Together with NCT03830229 these constitute something the desk did not have: a human tissue and cavity-fluid pipeline in defined [GERMLINE] BAP1 carriers and in surgically resected pleural disease. That is the cheapest route to resolving questions 2 and 4 in humans rather than in mice — whether NF2 copy-number loss and BAP1 loss co-occur or are exclusive, and whether BAP1-null lesions show the CRIg+/CD206+ myeloid phenotype and reduced MHC-I. I open L4 as a correlative-platform lead on that basis, explicitly not a treatment proposal: EZH2 inhibition in healthy heterozygous carriers is unacceptable [KNOWN — cytopenias, secondary T-cell malignancy signal], so interception here means detection and mechanism, not chemoprevention.\n\nNote for the record so the desk stops re-proposing it: single-agent EZH2 inhibition in BAP1-null mesothelioma has already produced disease control without meaningful objective response [KNOWN]; NCT04104776's listed interventions (tulmimetostat, enzalutamide) show no mesothelioma-specific or BAP1-selected arm, so it cannot serve as the confirmatory read-out I hoped for. Fianlimab (NCT07234058) still sits unassigned mechanistically — LAG-3 blockade is T-cell-intrinsic and would not obviously touch a macrophage-driven niche [INFERRED], which makes it a useful discriminating comparator if translational samples are collected. Next visit must either find independent NF2/TEAD replication or begin retiring L1/L3 toward a single merged lead.","leadChanges":[{"id":"L1","title":"TEAD inhibition to reverse NF2-loss-driven resistance to mesothelin CAR T cells in pleural mesothelioma","level":"LEAD","status":"WEAKENED","confidence":0.5},{"id":"L2","title":"BAP1-loss-associated EZH2 dependency as a combination scaffold, not monotherapy","level":"LEAD","status":"WEAKENED","confidence":0.35},{"id":"L3","title":"CRIg+ macrophage / retinoic-acid niche as a cavity-specific immunosuppression target","level":"LEAD","status":"WEAKENED","confidence":0.3},{"id":"L4","title":"Human correlative platform in BAP1 germline carriers to test the NF2/myeloid resistance model before building drug combinations on it","level":"LEAD","status":"NEW","confidence":0.45}],"unverifiedCitations":0,"openQuestions":["Is there ANY independent replication (any species, any lab) of the NF2-loss to YAP/TEAD to CRIg+ macrophage axis in mesothelioma, or does L1/L3 stand or fall on PMID:42208538 alone?","In human pleural mesothelioma cohorts, are NF2 copy-number loss and BAP1 loss co-occurring or mutually exclusive, and does BAP1 status track with MHC-I/B2M loss?","Which chemokine receptor and which RAR isoform mediate CRIg+ macrophage recruitment, and is any approved antagonist (CCR2/CCR5, RARalpha) available for intracavitary repurposing?","Is any TEAD palmitoylation-site inhibitor in first-in-human trials in NF2-altered disease, with a reported dose, schedule and renal safety signal?","Is WT1 [GERMLINE-likely per KG anchor] tractable as a mesothelioma vaccine/TCR target in current literature, and what is the somatic-versus-predisposition split?","Does LAG-3 blockade (fianlimab, NCT07234058) collect translational myeloid endpoints that could discriminate T-cell-intrinsic from macrophage-mediated resistance?"],"nextQueries":["(\"mesothelioma\" OR \"NF2-mutant\") AND (\"TEAD inhibitor\" OR \"VT3989\" OR \"IK-930\" OR \"palmitoylation\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"mesothelioma\" AND (\"macrophage\" OR \"myeloid\" OR \"CRIg\" OR \"VSIG4\") AND (\"pleural\" OR \"cavity\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"mesothelioma\" OR \"BAP1\") AND (\"WT1\" AND (vaccine OR \"TCR\" OR immunotherapy)) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"papersShown":[],"trialsShown":[{"nct":"NCT04104776","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas"},{"nct":"NCT00242723","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Evaluation of Cell Changes in Blood and Tissue in Cancers of the Lung, Esophagus and Lung Lining"},{"nct":"NCT03830229","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Long Term Follow-Up of Patients With Mesothelioma and Individuals With Germline Mutations in BAP1"},{"nct":"NCT05001880","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Chemotherapy With or Without Immunotherapy for Peritoneal Mesothelioma"},{"nct":"NCT04431024","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Prospective Evaluation of High Resolution Dual Energy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and Minimally Invasive Su"},{"nct":"NCT00715611","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Pleurectomy/Decortication (Neo) Adjuvant Chemotherapy and Intensity Modulated Radiation Therapy to the Pleura in Patients With Locally Advan"},{"nct":"NCT07234058","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Trial Assessing Fianlimab Plus Cemiplimab Plus Chemotherapy or Cemiplimab Plus Chemotherapy in Patients With Pleural Mesothelioma"},{"nct":"NCT06885697","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Anti-Mesothelin TNaive/SCM hYP218 (TNhYP218) CAR T Cells in Participants With Mesothelin-Expressing Solid Tumors Including Mesothelioma"}],"usage":{"input":5319,"output":5982},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"mesothelioma\" OR \"diffuse pleural mesothelioma\") AND (\"NF2\" OR \"TEAD\" OR \"YAP\") AND (inhibitor OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"mesothelioma\" AND (\"BAP1\" AND (\"EZH2\" OR tazemetostat OR \"synthetic lethal\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["NCT04104776","NCT00242723","NCT03830229","NCT05001880","NCT04431024","NCT00715611","NCT07234058","NCT06885697"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787162179778","cycle":66,"visit":2,"ts":"2026-08-19T17:56:19.778Z","cancer":{"key":"hepatocellular carcinoma","name":"hepatocellular carcinoma","mondo":{"id":"MONDO:0007256","name":"hepatocellular carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Read ROSETTA HCC-206 (NCT07291076) with mandatory VETC scoring and a bleeding-event primary safety focus, because complete VETC enriched atezolizumab-bevacizumab response 66% vs 37% (PFS HR 0.42) while VEGF-containing IO carried 2x the grade >=3 bleeding of durvalumab-tremelimumab.","confidence":0.35,"notebook":"This visit's pack largely missed its brief: the fibrolamellar/PRKACA query returned a tyrosinemia case report (PMID:42293468) and no PKA-directed pharmacology, and the CTNNB1/Wnt-immune-evasion query returned nothing on Wnt at all. Open questions 3 and 4 are therefore unanswered, not answered negatively — the queries were malformed (the \"inhibitor OR target\" conjunct and the immune-evasion conjunct over-constrained). L1, L2, L3, L5 receive no new evidence and persist unchanged; no retirement is justified by absence.\n\nWhat did arrive is a coherent pair on the IO+VEGF class, and it reframes L4 from a cost argument into a stratification-plus-safety argument. VETC (vessels encapsulating tumour clusters) at ≥55% of tumour area gave ORR 66% vs 37% and PFS HR 0.42 under atezolizumab+bevacizumab in 208 patients with a 163-patient validation cohort (PMID:42067189). [INFERRED] VETC is a sinusoidal, pericyte-poor, VEGF-dependent vascular architecture, so its enrichment for benefit is plausibly a bevacizumab-arm effect rather than a checkpoint effect — the abstract is truncated and the validation cohort mixes 99 atezo-bev with 64 durva-treme, so the desk cannot yet say whether VETC predicts VEGF blockade specifically or prognosis generally. That is the single most decisive next read. Against this, the VEGF component carries measurable cost: any-grade bleeding 22.8% vs 13.3% and grade ≥3 bleeding 14.5% vs 7.3% for atezo-bev vs durvalumab±tremelimumab across 490 patients, despite the DT/D group having *more* varices and larger spleens (PMID:42061924) — a confound running against the observed direction, which strengthens it. Pumitamig+ipilimumab (NCT07291076) stacks VEGF neutralisation on dual checkpoint blockade; ROSETTA HCC-206 must be read for bleeding first, response depth second, and should be VETC-stratified.\n\nNew lead: tumour vascular architecture as a shared delivery/response biomarker. Beside VETC, HAIC+toripalimab vs HAIC+sorafenib gave near-identical 6-month PFS (63.9% vs 61.1%) with divergent mOS (20.9 vs 16.4 months) in a non-comparative randomised phase 2 (PMID:42266185); no superiority is claimable, but arterial delivery makes intratumoral exposure — the same axis as the ABCG2/efflux hypothesis in L5 — architecture-dependent. Histopathology reviews reinforce macrovascular/microvascular invasion and macrotrabecular-massive subtype as orthogonal stratifiers (PMID:42281878).\n\nSecond new lead, low confidence: plectin as the obligate effector of plecstatin's anti-invasive activity in SNU-475 HCC, PLEC-knockout-null and coupled to eIF2α-Ser51/ATF4 integrated stress response (PMID:41467448). [KNOWN] PLEC loss causes epidermolysis bullosa with muscular dystrophy, so the window argument is adverse and must precede any escalation.\n\nNotebook flags: TLR3 agonism can be tumour-supportive in epithelial cancers (PMID:42278599) — a caution for L2's TLR-adjuvanted vaccine arm. VMD-102 (NCT07636785) and BAY 3547926 (NCT06764316) are mechanism-undisclosed HCC first-in-human assets; watchlist only, no lead.","leadChanges":[{"id":"L4","title":"PD-L1xVEGF bispecific (pumitamig) +/- ipilimumab as first-line HCC, priced against existing IO+VEGF","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.42},{"id":"L6","title":"Tumour vascular architecture (VETC / macrovascular pattern) as a shared delivery-and-response biomarker across anti-VEGF systemic and hepatic-arterial regimens","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L7","title":"Plectin cytolinker as the obligate effector of plecstatin anti-invasive activity in mesenchymal HCC","level":"LEAD","status":"NEW","confidence":0.15}],"unverifiedCitations":0,"openQuestions":["Is the VETC effect on atezolizumab-bevacizumab outcome VEGF-arm-specific or merely prognostic - does complete VETC predict benefit in the durvalumab+tremelimumab (VEGF-free) subgroup of the same validation cohort?","For DNAJB1-PRKACA fibrolamellar HCC, what direct PKA-catalytic, Aurora, or mTOR-directed evidence exists? (query failed this visit and must be re-run without over-constraining conjuncts)","Does AXIN1/CTNNB1-mutant Wnt activation predict resistance to PD-L1xVEGF bispecifics, and is Porcupine/TCF-beta-catenin/TEAD co-targeting tractable? (still unanswered)","Is the ABHD17C lenvatinib-resistance effect hydrolase-activity dependent, and which palmitoylated substrate (N-RAS, MET, EGFR) mediates it?","Does ABHD17C-high status cause the CD8-poor microenvironment, making depalmitoylase inhibition a TKI-plus-IO sensitiser in immunocompetent models?","Can TLR-agonist adjuvanted HCC vaccines be de-risked given evidence that TLR signalling in epithelial cancer cells can be tumour-supportive (stemness, therapy resistance) rather than immunogenic?"],"nextQueries":["(\"fibrolamellar\" OR \"DNAJB1-PRKACA\") AND (PRKACA OR \"protein kinase A\" OR therapy) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"hepatocellular carcinoma\") AND (CTNNB1 OR AXIN1) AND (\"immune exclusion\" OR \"beta-catenin\" OR TEAD OR porcupine) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"hepatocellular carcinoma\") AND (\"vessels encapsulating tumor clusters\" OR VETC OR \"macrotrabecular-massive\") AND (bevacizumab OR atezolizumab OR HAIC OR response) AND SRC:MED"],"papersShown":[{"pmid":"42293468","doi":"10.1016/j.radcr.2026.05.001","year":2026,"isNew":true,"title":"Hepatocellular carcinoma in a child with hereditary tyrosinemia type I despite early NTBC therapy: When should we suspect it?"},{"pmid":"42067189","doi":"10.1016/j.jhepr.2026.101874","year":2026,"isNew":true,"title":"Vessels encapsulating tumor clusters predict better outcomes in advanced hepatocellular carcinoma treated with atezolizumab-bevacizumab"},{"pmid":"42281878","doi":"10.5500/wjt.v16.i2.115879","year":2026,"isNew":true,"title":"Multifaceted role of histopathology in liver transplantation for hepatocellular carcinoma: A narrative review towards precision prognosis"},{"pmid":"42278599","doi":"10.3390/ijms27115075","year":2026,"isNew":true,"title":"Toll-like Receptor 3 as a Context-Dependent Molecular Switch in Epithelial Cancers: Balancing Cell Death and Tumor-Supportive Programs"},{"pmid":"42266185","doi":"10.1002/mco2.70805","year":2026,"isNew":true,"title":"Hepatic Arterial Infusion Chemotherapy plus either Toripalimab or Sorafenib as First-line Therapy for Locally Advanced Hepatocellular Carcinoma: A Non-comparative, Randomized Phase"},{"pmid":"42211006","doi":"10.1016/j.bbrep.2026.102616","year":2026,"isNew":true,"title":"Integrating CRISPR genome editing with liver organoid and hiPSC-derived microfluidic platforms to model metabolic dysfunction-associated steatotic liver disease"},{"pmid":"42061924","doi":"10.1016/j.jhepr.2026.101818","year":2026,"isNew":true,"title":"Multicenter study of bleeding and thromboembolic events with durvalumab tremelimumab vs. atezolizumab and bevacizumab in advanced HCC"},{"pmid":"41467448","doi":"10.1002/1878-0261.70186","year":2026,"isNew":true,"title":"Plecstatin inhibits hepatocellular carcinoma tumorigenesis and invasion through cytolinker plectin"}],"trialsShown":[{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT06084884","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Phase I/II Study to Evaluate AZD5851 in GPC3+ Advanced/Recurrent Hepatocellular Carcinoma"},{"nct":"NCT06979219","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Streamlining Radioembolization for Small HCC"},{"nct":"NCT06764316","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A First-in-human Study to Learn About the Safety of BAY 3547926 and How Well it Works in Participants With Advanced Liver Cancer"},{"nct":"NCT07727759","phase":"n/a","status":"RECRUITING","isNew":false,"title":"CT Volumetry and Hepatic Vascular Deformation Mapping to Predict Post-Hepatectomy Liver Failure"},{"nct":"NCT07291076","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Evaluate the Safety and Tolerability of Pumitamig Alone or In Combination With Ipilimumab in Participants With First-Line Advance"},{"nct":"NCT07620574","phase":"phase 3","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Long-Term Extension Study for Participants Previously Enrolled in an Exelixis-Sponsored Study"},{"nct":"NCT06944483","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Same-day Radioembolization for Large HCC"}],"usage":{"input":10760,"output":7188},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"DNAJB1-PRKACA\" OR \"fibrolamellar\") AND (inhibitor OR target OR \"protein kinase A\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"hepatocellular carcinoma\") AND (CTNNB1 OR AXIN1 OR \"Wnt\") AND (\"immune evasion\" OR \"immunotherapy resistance\" OR \"checkpoint\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42293468","PMID:42067189","PMID:42281878","PMID:42278599","PMID:42266185","PMID:42211006","PMID:42061924","PMID:41467448","NCT07636785","NCT06084884","NCT06979219","NCT06764316","NCT07727759","NCT07291076","NCT07620574","NCT06944483"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787161919730","cycle":65,"visit":2,"ts":"2026-08-19T17:51:59.730Z","cancer":{"key":"gastric cancer","name":"gastric cancer","mondo":{"id":"MONDO:0001056","name":"gastric cancer"}},"control":false,"modelLabel":"SCIENCE","summary":"Reorient the gastric DDR programme onto an ATM/CDK12-stratified ATR/PARP question (not MUTYH), and open two new leads — CPT1A/CD36 lipid blockade plus PD-1 in MSS immune-cold GC, and KRAS G12D degradation with ARV-806 — while RPRD1B-TOPBP1 waits for independent corroboration.","confidence":0.42,"notebook":"No gastric RPRD1B/CREPT/TOPBP1 primary work returned this visit despite a targeted 2023–2026 query; the absence of any independent corroboration is itself a data point, so L1 drops to 0.45 rather than holding. The one usable addition is pharmacological: tuvusertib's N-glucuronide M1 is CYP-inert and carries low DDI risk (PMID:42142224), which makes a clinical ATR-inhibitor + fluoropyrimidine backbone at least metabolically tractable [INFERRED] — relevant because the L1 arm (ii) depends on combining ATRi with 5-FU without additive marrow/crypt toxicity. Two DDR reviews reframe L5. ATM loss is stated to sensitise to both ATR and PARP inhibitors (PMID:42025253), and pan-cancer DDR synthesis links defects to both synthetic lethality and immune-microenvironment opportunity (PMID:42054804); meanwhile PARP dual-inhibitor review flags HRD-dependency and haematologic toxicity as the two ceilings on PARPi expansion (PMID:41395847). L5 therefore pivots: the pre-specified stratum for NCT04550494/NCT04644068 gastric signal should be ATM/CDK12/BRCA-altered, with MUTYH [GERMLINE, base-excision repair] carried explicitly as the negative control hypothesis, not the lead. L5 stays LEAD (0.3) — corroboration is review-grade only.\n\nL2 gains external support but not replication: a pan-cancer review states FAO inhibitor + antitumour drug combinations reverse resistance preclinically (PMID:40514365), and a gastric-specific review names FAO, CD36, FASN and SREBP1 as TIME determinants with ICB-combination potential (PMID:40901479). Neither reproduces the SNHG15–miR-451a–CAV1 ceRNA chain, so the lncRNA remains the weak link; confidence to 0.42 on the FAO-dependency claim only.\n\nThe gastric lipid–immune axis is a distinct hypothesis from platinum resistance and enters as a new lead (L6): in MSS/immune-cold GC, tumour and myeloid FAO/CD36-driven lipid handling suppresses CD8 effector function and expands Tregs/MDSCs (PMID:40901479), predicting that CPT1A/CD36 blockade plus PD-1 is the rational conversion strategy — testable inside the taxane+nivolumab context of PARAMUNE (NCT06203600), and worth watching AZD6750+rilvegostomig (NCT07115043) for gastric cohorts (agent mechanism undisclosed in the pack; do not assume). Second new lead (L7): ARV-806, a KRAS G12D degrader now in phase 1/2 (NCT07023731), gives the first direct handle on the Monarch KRAS anchor in gastric adenocarcinoma; degradation rather than occupancy may blunt the RTK/wild-type-RAS reactivation route seen with covalent G12C agents [KNOWN/SPECULATIVE], with PIK3CA co-mutation the expected bypass. Also noted for the notebook: NCT07646574 pursues non-surgical management after neoadjuvant immunotherapy in dMMR/MSI-H GC — the immunotherapy problem is now definitionally the MSS subset, which is where L6 must earn its keep.","leadChanges":[{"id":"L1","title":"RPRD1B(CREPT)-TOPBP1 axis as the druggable node of 5-FU resistance in gastric cancer","level":"LEAD","status":"WEAKENED","confidence":0.45},{"id":"L2","title":"CAV1-driven fatty-acid beta-oxidation as a metabolic vulnerability in oxaliplatin-resistant gastric cancer","level":"LEAD","status":"STRENGTHENED","confidence":0.42},{"id":"L5","title":"Biomarker question, not yet a lead: PARP inhibitor sensitivity in DNA-repair-altered gastric cancer including MUTYH carriers","level":"LEAD","status":"STRENGTHENED","confidence":0.3},{"id":"L6","title":"Lipid-metabolic reprogramming of the gastric immune microenvironment to convert MSS/immune-cold GC to ICB-responsive","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L7","title":"KRAS G12D targeted degradation (ARV-806) in KRAS-mutant gastric adenocarcinoma","level":"LEAD","status":"NEW","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["Does any independent group reproduce RPRD1B/CREPT-driven TOPBP1 upregulation in gastric cancer, and is RPRD1B-low normal gastric/marrow expression sufficient for a therapeutic window?","In gastric cohorts of NCT04550494 and NCT04644068, do ATM-null (IHC-confirmed) and CDK12-altered tumours show PARPi/ATRi responses while MUTYH carriers do not?","Does CPT1A or CD36 blockade plus PD-1 increase CD8 effector function in MSS/immune-cold gastric models, and does the effect require tumour-cell or myeloid FAO?","Is the SNHG15-miR-451a-CAV1 chain reproducible in independent gastric datasets, or should L2 be reduced to a CPT1A-dependency claim with CAV1 as a mere correlate?","What is the prevalence and co-mutation structure (PIK3CA, ERBB2, CDH1/CTNNA1) of KRAS G12D in gastric adenocarcinoma, and are G12D gastric PDX available to test ARV-806-class degraders?","Is there any gastric-specific primary data on the G3BP1-14-3-3zeta-Bax complex, or should L3 be retired next visit for lack of perturbation evidence?"],"nextQueries":["(\"gastric cancer\" OR \"gastric adenocarcinoma\") AND (RPRD1B OR CREPT OR TOPBP1) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"gastric cancer\" AND (CD36 OR CPT1A OR FASN OR SREBP1) AND (\"PD-1\" OR \"PD-L1\" OR immunotherapy OR \"CD8\") AND SRC:MED","(\"gastric cancer\" OR \"gastroesophageal\") AND (\"KRAS G12D\" OR \"KRAS degrader\" OR ATM OR CDK12) AND (inhibitor OR resistance) AND SRC:MED"],"papersShown":[{"pmid":"40514365","doi":"10.1038/s41420-025-02554-1","year":2025,"isNew":true,"title":"The role and mechanism of fatty acid oxidation in cancer drug resistance"},{"pmid":"40901479","doi":"10.3389/fimmu.2025.1639823","year":2025,"isNew":true,"title":"The impact of aberrant lipid metabolism on the immune microenvironment of gastric cancer: a mini review"},{"pmid":"41652992","doi":"10.1111/jcmm.71052","year":2026,"isNew":true,"title":"Insights Into circRNA-Mediated Lipid Metabolism in Cancer Progression"},{"pmid":"41693699","doi":"10.1080/14756366.2026.2621477","year":2026,"isNew":true,"title":"Palladium-catalysed synthesis of small-molecule epigenetic inhibitors as anticancer therapeutics"},{"pmid":"41395847","doi":"10.1080/14756366.2025.2598478","year":2026,"isNew":true,"title":"Antitumor activity and structure-activity relationship of poly (ADP-ribose) polymerase (PARP)-based dual inhibitors"},{"pmid":"42317522","doi":"10.1016/j.mtbio.2026.103316","year":2026,"isNew":true,"title":"Advances in oncolytic virus delivery strategies and challenges in clinical translation"},{"pmid":"42142224","doi":"10.1007/s13318-026-01006-0","year":2026,"isNew":true,"title":"Structure Elucidation and Initial Characterization of a N-glucuronide Metabolite (M1) of Tuvusertib"},{"pmid":"42054804","doi":"10.1016/j.neo.2026.101315","year":2026,"isNew":true,"title":"Molecular landscape and clinical translation of DNA damage response alterations in solid tumors: A pan-cancer perspective on precision oncology"},{"pmid":"42025253","doi":"10.1016/j.neo.2026.101309","year":2026,"isNew":true,"title":"Ataxia telangiectasia mutated (ATM) kinase as a predictive biomarker in clinical oncology: implications for a precision treatment approach"},{"pmid":"42254186","doi":"10.1097/ms9.0000000000005073","year":2026,"isNew":true,"title":"Epstein-Barr virus-associated lymphoepithelioma-like intrahepatic cholangiocarcinoma with concurrent hepatitis B virus infection: case report and literature review"}],"trialsShown":[{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT07646574","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":false,"title":"Non-surgical Management After NIT for dMMR/MSI-H GC"},{"nct":"NCT06203600","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"Adding Nivolumab to Usual Treatment for People With Advanced Stomach or Esophageal Cancer, PARAMUNE Trial"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04550494","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations"},{"nct":"NCT07001748","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"Testing the Addition of Paclitaxel Administered Into the Abdominal Cavity Combined With Chemotherapy for Patients With Gastric Cancer Spread"},{"nct":"NCT04644068","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies"},{"nct":"NCT05203627","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Telehealth for the Self-Management of Dietary Quality of Life in Patients After Stomach Cancer Surgery"}],"usage":{"input":11190,"output":7283},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"gastric cancer\" OR \"gastric adenocarcinoma\") AND (RPRD1B OR CREPT OR TOPBP1 OR \"ATR inhibitor\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"gastric cancer\" AND (\"fatty acid oxidation\" OR CPT1A OR CAV1 OR \"lipid metabolism\") AND (oxaliplatin OR cisplatin OR resistance) AND SRC:MED"],"evidenceIds":["PMID:40514365","PMID:40901479","PMID:41652992","PMID:41693699","PMID:41395847","PMID:42317522","PMID:42142224","PMID:42054804","PMID:42025253","PMID:42254186","NCT07115043","NCT07646574","NCT06203600","NCT07023731","NCT04550494","NCT07001748","NCT04644068","NCT05203627"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787161703153","cycle":64,"visit":2,"ts":"2026-08-19T17:48:23.153Z","cancer":{"key":"esophageal cancer","name":"esophageal cancer","mondo":{"id":"MONDO:0007576","name":"esophageal cancer"}},"control":false,"modelLabel":"SCIENCE","summary":"Promote the KLF4/MHC-I antigen-presentation lead to CANDIDATE on independent ESCC ICB-resistance evidence, and pair it with a new repurposing lead that simultaneously unblocks DC cross-presentation (PGE2/VEGF) since tumour MHC-I restoration alone is likely insufficient.","confidence":0.5,"notebook":"This visit's pack is largely off-target: four papers (P3, P6, P8, P10 — diabetic-ulcer hydrogels, soil microbiota, islet scaffolds, transplant T-cell exhaustion) and P2 (NSCLC) carry no esophageal content and are recorded as noise so the desk does not re-query these strings. Nothing new touched L3 (Lactobacillus D-lactate/STAT3-K631) or L4 (B7-H3/I-DXd); both persist unchanged, L4 still purely trial-derived (NCT06780111 remains recruiting).\n\nL1 gains its second evidence-bearing visit, but by indirect routes. P4 (PMID:40837744) independently places impaired antigen presentation alongside Treg/MDSC infiltration and PD-L1 signalling as a mechanism of primary and acquired ICB resistance in ESCC, anchored to real negative-tail clinical experience (CheckMate-648, ESCORT-1st), which supplies the disease-level premise my KLF4 lead needs. P9 (PMID:42598083) shows KLF4 behaves as a frequently epigenetically silenced tumour suppressor in HCC and that KLF-family targeting is being approached by PROTAC and cell-type-specific nanoparticle delivery — relevant because re-expression, not degradation, is what we want, so [INFERRED] the tractable route stays epigenetic derepression (HDAC/BET/DNMT) rather than direct KLF4 pharmacology. I promote L1 to CANDIDATE while flagging that the KLF4→MHC-I chromatin link itself is still single-source (PMID:42493491); corroboration is of the premise, not the mechanism.\n\nP7 (PMID:41758201) is the most useful mechanistic constraint of the visit and creates L5: tumour-intrinsic MHC-I restoration may be insufficient because DC cross-presentation is separately suppressed by PGE2, VEGF, IL-6 and IL-10. Two arms of that axis are already repurposable in gastroesophageal disease [KNOWN] (COX-2 inhibition; VEGFR2 blockade with ramucirumab), making a \"restore direct presentation + unblock cross-presentation + PD-1\" triple the logical successor to L1 rather than a competitor.\n\nL2 is nudged rather than promoted. P1 (PMID:38741380) supports the combination framing — PTPs as convergent resistance hubs for both targeted and checkpoint therapy, with PTP inhibitors proposed as sensitisers — and P5 (PMID:40598214) documents non-canonical nuclear PTPN11 function in cholangiocarcinoma, a caveat for interpreting allosteric SHP2i pharmacodynamics beyond p-ERK. Decisively, a query written explicitly for ESCC+SHP2/PTPN11/ERBB2-amplification returned zero esophageal-specific hits: esophageal SHP2 dependency remains unproven and stays at LEAD.\n\nTrials to watch: NCT07217171 (EVOLVE104) enrolls squamous carcinomas and may open to ESCC [SPECULATIVE on target]; NCT07222657 tests cryotherapy before neoadjuvant chemotherapy in EAC — a plausible immunogenic-cell-death platform if biospecimens are collected.","leadChanges":[{"id":"L1","title":"KLF4 re-induction to reopen MHC-I chromatin and rescue PD-1 blockade in esophageal cancer","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.58},{"id":"L2","title":"Allosteric SHP2 inhibition as the drug-tractable node downstream of ERBB2/EGFR in ESCC","level":"LEAD","status":"STRENGTHENED","confidence":0.38},{"id":"L5","title":"Dual restoration of direct and cross-presentation: PGE2/VEGF blockade layered onto MHC-I re-induction plus PD-1 in antigen-presentation-low ESCC","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Which agent induced KLF4 in PMID:42493491, at what exposure, and is the MHC-I/CD8 rescue abolished in KLF4-null and B2M-null isogenics?","Do HLA-ABC/B2M-low ESCC tumours prospectively predict PD-1 failure in the CheckMate-648/ESCORT-1st-type non-responder population, and does KLF4 protein track with them?","Do MHC-I-low and cross-presentation-suppressed (PTGS2/PGE2-high, cDC1-poor) phenotypes co-segregate in ESCC or define separate strata requiring different combinations?","Is there any esophageal-specific SHP2/PTPN11 dependency genotype (ERBB2/EGFR amplification, NF1 loss), and does SHP2i plus anti-ERBB2 give synergy over additivity in RTK-amplified ESCC PDX?","What is CD276/B7-H3 prevalence and intensity in ESCC vs EAC, and does it co-vary with antigen-presentation loss (would decide whether L4 survives)?","Does intratumour Lactobacillus/D-lactate burden (L3) also modulate immunotherapy response, or only ferroptosis sensitivity?"],"nextQueries":["(\"esophageal squamous cell carcinoma\" AND (\"HLA class I\" OR B2M OR \"antigen presentation\") AND (\"PD-1\" OR pembrolizumab OR nivolumab) AND biomarker) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"esophageal\" AND (PGE2 OR PTGS2 OR EP4 OR \"cDC1\" OR \"cross-presentation\") AND (immunotherapy OR \"immune checkpoint\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","((\"B7-H3\" OR CD276) AND (esophageal OR \"esophageal squamous\") AND (expression OR ADC OR immunohistochemistry)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"38741380","doi":"10.1002/cac2.12548","year":2024,"isNew":true,"title":"Protein tyrosine phosphatases: emerging role in cancer therapy resistance"},{"pmid":"41373672","doi":"10.3390/ijms262311517","year":2025,"isNew":true,"title":"Advances in Targeted Therapy for Non-Small-Cell Lung Cancer: Current Progress and Future Directions"},{"pmid":"41909502","doi":"10.1016/j.bioactmat.2026.03.034","year":2026,"isNew":true,"title":"Intelligent-responsive hydrogel synergistically mediates immune remodel-antibacterial-angiogenesis cascade for diabetic foot ulcer repair"},{"pmid":"40837744","doi":"10.4251/wjgo.v17.i8.109489","year":2025,"isNew":true,"title":"Unmasking immune checkpoint resistance in esophageal squamous cell carcinoma: Insights into the tumor microenvironment and biomarker landscape"},{"pmid":"40598214","doi":"10.1186/s12964-025-02318-5","year":2025,"isNew":true,"title":"Lycorine hydrochloride inhibits cholangiocarcinoma through cholesterol biosynthesis and PTPN11 nuclear translocation"},{"pmid":"42178725","doi":"10.1080/19490976.2026.2675089","year":2026,"isNew":true,"title":"Soil-derived microbiota induces T regulatory cells and protect against mouse colitis, metabolic disease, and sepsis"},{"pmid":"41758201","doi":"10.1080/07853890.2026.2635774","year":2026,"isNew":true,"title":"Opportunities and challenges for cancer immunotherapy based on antigen cross-presentation"},{"pmid":"42306051","doi":"10.1016/j.bioactmat.2026.03.001","year":2026,"isNew":true,"title":"Co-transplantation of pancreatic islets with adipose-derived mesenchymal stem cells in vascularized kidney ECM scaffolds to restore type 1 diabetes mellitus"},{"pmid":"42598083","doi":"10.1016/j.iliver.2026.100252","year":2026,"isNew":true,"title":"Regulatory roles and translational potential of the Kruppel-like factor family in liver disease"},{"pmid":"42233094","doi":"10.1016/j.gendis.2025.101965","year":2026,"isNew":true,"title":"The multifaceted landscape of T cell exhaustion in organ transplantation: From molecular mechanisms (epigenetics, transcription, metabolism) to induction strategies"}],"trialsShown":[{"nct":"NCT06203600","phase":"phase 2/phase 3","status":"RECRUITING","isNew":false,"title":"Adding Nivolumab to Usual Treatment for People With Advanced Stomach or Esophageal Cancer, PARAMUNE Trial"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT06748911","phase":"NA","status":"RECRUITING","isNew":false,"title":"Navicam for Detection of Barrett's Esophagus"},{"nct":"NCT00242723","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Evaluation of Cell Changes in Blood and Tissue in Cancers of the Lung, Esophagus and Lung Lining"},{"nct":"NCT07222657","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Liquid Nitrogen Spray Cryotherapy Prior to Neoadjuvant Systemic Therapy in Esophageal Adenocarcinoma"},{"nct":"NCT07182149","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Phase 1 Study of NRM-823 in Participants With Locally Advanced or Metastatic Refractory Solid Tumors"},{"nct":"NCT07217171","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"A Study Evaluating the Safety, Efficacy, and Pharmacokinetics (PK) of EVOLVE104 in Participants With Advanced Urothelial and Squamous Cell C"},{"nct":"NCT06780111","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Substudy 06E: Umbrella Study of Combination Therapies in Esophageal Cancer (MK-3475-06E/KEYMAKER-U06)"}],"usage":{"input":11512,"output":6615},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"KLF4\" AND (\"MHC class I\" OR \"antigen presentation\" OR \"immune evasion\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"esophageal squamous cell carcinoma\" AND (SHP2 OR PTPN11 OR \"ERBB2 amplification\") AND (inhibitor OR combination OR resistance)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:38741380","PMID:41373672","PMID:41909502","PMID:40837744","PMID:40598214","PMID:42178725","PMID:41758201","PMID:42306051","PMID:42598083","PMID:42233094","NCT06203600","NCT07023731","NCT06748911","NCT00242723","NCT07222657","NCT07182149","NCT07217171","NCT06780111"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787161495162","cycle":63,"visit":3,"ts":"2026-08-19T17:44:55.162Z","cancer":{"key":"small cell lung cancer","name":"small cell lung cancer","mondo":{"id":"MONDO:0008433","name":"small cell lung carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Fresh reviews corroborate SCLC as a plasticity/antigen-escape disease and elevate B7-H3 (ifinatamab deruxtecan) to near-registrational status, while ADC design literature reframes the DLL3-negative YAP1+ persister as a bystander-kill problem solvable with non-internalizing/cleavable-linker payloads.","confidence":0.6,"notebook":"**Visit 3 notebook.** The pack is review-heavy and contains no new SCLC primary experiment; I treat it as corroborative and format/regulatory intelligence, not as efficacy data, and I record two informative search failures.\n\nWhat changed. PMID:42147254 reframes SCLC as a lineage-state disease analogous to haematologic antigen escape: NE↔non-NE transitions driven by epigenetic/transcriptional reprogramming rather than new mutations, with DLL3/SEZ6/TROP2-directed engagers and ADCs showing activity but limited by exactly that plasticity. This is independent corroboration of the L1/L3/L5 architecture built on PMID:42019833, and it is the first citation in the programme to state the \"no new genetic alteration\" point explicitly. PMID:42306740 supplies the clinical frame: 60–70% first-line ORR but only 10–20% durable response, an immune-excluded/\"cold\" microenvironment, and tarlatamab/lurbinectedin as the only later-line options — i.e. the engager is the standard the desk must beat, not merely validate. PMID:41560619 puts ifinatamab deruxtecan in the predicted 2026 regulatory-review cohort, converting L3's B7-H3 arm from concept to a near-registrational agent; it also flags bispecific ADCs (izalontamab brengitecan) as a live format.\n\nMechanistically new: PMID:41866709 and PMID:42070121 identify antigen loss, tumour heterogeneity and *impaired endocytosis* as the ADC failure triad, with non-internalizing/extracellular-release linkers and bystander payload diffusion as the countermeasure. That maps directly onto our escape state: a DLL3−/SEZ6−, YAP1+ persister sitting adjacent to antigen-positive cells is a bystander problem, not only a target-switch problem. New lead L6. Notebook negative to prevent re-proposal: rovalpituzumab tesirine failed on the DLL3-ADC axis [KNOWN], so any DLL3-ADC re-entry must be payload/linker-differentiated, not target-differentiated.\n\nLead moves. L1 stays CANDIDATE at 0.66 — I deliberately withheld DOSSIER promotion despite the arithmetic, because both new citations are reviews and the programme still holds zero patient-level efficacy or antigen-kinetics data. L3 promoted to CANDIDATE (0.62) on I-DXd's late-stage status plus ADC design principles. L4 nudged to 0.37: PMID:41542910 (501 multispecifics, 112 formats) establishes that a DLL3-anchored CD2-costimulatory format is engineerable, nothing more. L5 weakened to 0.22 — a targeted LSD1/KDM1A/EZH2/Notch-plasticity query returned no SCLC experiment showing prevention or reversal of subtype switching; if visit 4 repeats this, retire. Search failure two: NCT07115043 still does not disclose AZD6750's target or SCLC eligibility — I am dropping that thread. Open question 5 (RB1/TP53-null synthetic lethality) remains unaddressed for a third visit; it now becomes a primary query rather than a hope.","leadChanges":[{"id":"L1","title":"DLL3xCD3 T-cell engagers as lineage-restricted therapy in neuroendocrine SCLC","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.66},{"id":"L3","title":"Sequenced B7-H3 / TROP2 ADC coverage of the YAP1-emergent post-engager escape state","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.62},{"id":"L6","title":"Bystander-capable / non-internalizing ADC payload design to kill antigen-negative SCLC persister compartments","level":"LEAD","status":"NEW","confidence":0.32},{"id":"L4","title":"CD2-based tumour-dependent costimulation to widen the DLL3 engager dose window in unfit SCLC","level":"LEAD","status":"STRENGTHENED","confidence":0.37},{"id":"L5","title":"Epigenetic blockade of subtype plasticity to prevent, not chase, antigen loss","level":"LEAD","status":"WEAKENED","confidence":0.22}],"unverifiedCitations":0,"openQuestions":["Is there any citable synthetic-lethal handle for RB1/TP53-null SCLC (Aurora A/B, CHK1, WEE1, ATR, PARP+temozolomide, schlafen/SLFN11-stratified)? Unaddressed for three visits and now the top-priority query.","In relapsed SCLC, do DLL3+ and YAP1+/B7-H3+ compartments coexist spatially in the same lesion (mandating concurrent engager + B7-H3 ADC or a bystander-capable payload) or replace each other temporally (permitting sequencing)?","What are the internalization kinetics of DLL3, SEZ6 and B7-H3 in NE versus YAP1+ persister states - i.e. is impaired endocytosis (PMID:41866709) a real SCLC persister feature that would favour non-internalizing/extracellular-release ADC des","What is the CD58 expression status of SCLC and of the YAP1-emergent state, and is CD58 loss an independent engager-resistance route in this disease?","Does the NCT07203053 PS 2 read-out show efficacy loss or toxicity-driven discontinuation - is the engager ceiling in unfit patients cytokine/T-cell-fitness-limited or tumour-biology-limited?","Are there emerging ifinatamab deruxtecan or SEZ6-ADC efficacy data in DLL3-engager-pretreated patients, and is antigen profiling used for selection?"],"nextQueries":["(\"small cell lung\" OR SCLC) AND (WEE1 OR CHK1 OR \"Aurora\" OR ATR OR PARP OR SLFN11 OR \"synthetic lethal\") AND (RB1 OR TP53 OR \"replication stress\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"small cell lung\" OR SCLC) AND (\"ifinatamab\" OR \"B7-H3\" OR CD276 OR SEZ6 OR \"antigen heterogeneity\" OR \"bystander effect\") AND (\"tarlatamab\" OR \"prior DLL3\" OR relapsed OR resistance) AND SRC:MED AND PUB_YEAR:[2024 TO 2","(\"small cell lung\" OR SCLC OR \"neuroendocrine\") AND (CD58 OR \"CD2\" OR \"CD28-negative\" OR costimulation OR \"cytokine release\") AND (\"T cell engager\" OR bispecific) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41560619","doi":"10.1080/19420862.2026.2614669","year":2026,"isNew":true,"title":"Antibodies to watch in 2026"},{"pmid":"41542910","doi":"10.1080/19420862.2026.2613548","year":2026,"isNew":true,"title":"The making of multispecific immunoglobulins - a clinical perspective"},{"pmid":"41866709","doi":"10.1080/10717544.2026.2645769","year":2026,"isNew":true,"title":"Extracellular payload release from non-internalizing antibody-drug conjugates: mechanisms and linker technologies"},{"pmid":"42322272","doi":"10.1080/2162402x.2026.2671491","year":2026,"isNew":true,"title":"Pooled analysis of 2 clinical trials of first-line chemoimmunotherapy for metastatic microsatellite stable colorectal cancer MEDITREME and METIMMOX studies"},{"pmid":"42070121","doi":"10.1080/2162402x.2026.2667160","year":2026,"isNew":true,"title":"Trial watch: antibody-drug conjugates in cancer therapy"},{"pmid":"42003422","doi":"10.1080/15476286.2026.2662721","year":2026,"isNew":true,"title":"Integrating bulk and single-cell transcriptomic data to construct a risk model for histidine metabolism-related epithelial cell features in lung adenocarcinoma, predicting prognosi"},{"pmid":"41800605","doi":"10.1080/07853890.2026.2640457","year":2026,"isNew":true,"title":"Preclinical advances and mechanistic insights of CAR-T therapy for acute myeloid leukemia: from target iteration to microenvironment regulation"},{"pmid":"41630477","doi":"10.1080/21645515.2026.2615515","year":2026,"isNew":true,"title":"A data-driven cartography of NSCLC vaccine research: Quantifying the paradigm shift toward immuno-oncology combination therapies"},{"pmid":"42147254","doi":"10.3389/fonc.2026.1821271","year":2026,"isNew":true,"title":"Reframing small cell lung cancer: therapeutic lessons from hematologic malignancies"},{"pmid":"42306740","doi":"10.21037/jtd-2026-1-0320","year":2026,"isNew":true,"title":"Research progress on immune microenvironment and biomarkers of small cell lung cancer"}],"trialsShown":[{"nct":"NCT07774520","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Randomized Study to Evaluate the Efficacy of a Reduced Starting Dose of Lazertinib (Leclaza) and Preemtive Magnesium Supplementation to Pr"},{"nct":"NCT07203053","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Trial of Tarlatamab in Patients With Pretreated Extensive-stage Small Cell Lung Cancer (ES-SCLC) and ECOG PS 2"},{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT04181060","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Osimertinib With or Without Bevacizumab as Initial Treatment for Patients With EGFR-Mutant Lung Cancer"},{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT07472517","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"DAREON ® -Lung-1: A Study in People With Advanced Small Cell Lung Cancer to Compare Obrixtamig Plus Atezolizumab, Carboplatin, and Etoposide"},{"nct":"NCT06194448","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"To Evaluate the Efficacy/Safety of Osimertinib Prior to CRT and Maintenance of it With Stage III, Unresectable NSCLC With EGFR Mutations"},{"nct":"NCT06406465","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A UGT1A1 Genotype-Directed Study of Belinostat Pharmacokinetics and Toxicity"}],"usage":{"input":12056,"output":8060},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"SCLC\" OR \"small cell lung\") AND (\"B7-H3\" OR CD276 OR \"ifinatamab\" OR TROP2 OR \"sacituzumab\") AND (relapsed OR resistance OR \"antibody-drug conjugate\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"small cell lung\" AND (LSD1 OR KDM1A OR EZH2 OR \"Notch\") AND (\"DLL3\" OR plasticity OR \"subtype switch\" OR persister)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41560619","PMID:41542910","PMID:41866709","PMID:42322272","PMID:42070121","PMID:42003422","PMID:41800605","PMID:41630477","PMID:42147254","PMID:42306740","NCT07774520","NCT07203053","NCT07115043","NCT04181060","NCT07636785","NCT07472517","NCT06194448","NCT06406465"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787161273851","cycle":62,"visit":3,"ts":"2026-08-19T17:41:13.851Z","cancer":{"key":"cholangiocarcinoma","name":"cholangiocarcinoma","mondo":{"id":"MONDO:0019087","name":"cholangiocarcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"In BTC, prioritise two synthetic-lethal repurposing plays now supported by independent data — DNMTi+PARPi (senescence/inflammatory-driven, corroborated in organoids/PDX/autochthonous models) and PRMT5 inhibition in the 12.8% MTAP-deleted subset that overlaps CDKN2A-null FGFRi-refractory disease — wh","confidence":0.62,"notebook":"The CDKN2A/CDK4-6-plus-FGFRi query returned nothing on-topic in CCA — after a targeted search, there is still no published clinical or preclinical dataset testing palbociclib/abemaciclib with pemigatinib or futibatinib in FGFR2-fusion disease. That gap is now a logged finding, not an oversight; open question 1 remains untested and the combination stays hypothesis-only.\n\nWhat did arrive is a large prospective genomic cohort (P8, PMID:42360806; n=1254, FDA-authorised NGS) that reshapes two leads. First, it independently confirms the co-alteration resistance axis in L1 but names a different partner than PMIREAL did: co-occurring TP53/RAS-pathway alterations, not CDKN2A, marked inferior outcome in FGFR2- and IDH1-driven tumours, while SMAD4 did so in ERBB2-driven disease. Second, longitudinal profiling showed FGFR-, IDH-, BRAF- and NTRK-driven tumours retain the primary driver at progression (only ERBB2-driven tumours lost it) — mechanistic support for continued driver blockade post-progression, which is the premise of both L1 (co-alteration-directed combination) and L7 (tinengotinib after FGFRi). Targeted therapy improved PFS but not OS overall, which keeps expectations sober. P5 (PMID:41912087; 5123 BTC) adds that FGFR2, IDH1, KRAS, TP53, CDKN2A and BAP1 prevalences differ markedly between Eastern and Western iCCA — a generalisability constraint on any biomarker-stratified design including NCT06439485.\n\nNew lead L8: MTAP deletion in 12.8% of BTC (P8) — [KNOWN] 9p21 MTAP is co-deleted with CDKN2A, raising intracellular MTA and creating PRMT5 dependency. This is a synthetic-lethal route to exactly the CDKN2A-null subset that L1 flags as FGFRi-refractory, and MTA-cooperative PRMT5 inhibitors offer a wider window than first-generation PRMT5i [INFERRED]. MDM2 amplification (6.5%) and MET amplification (1.5%) are logged as secondary emergent targets.\n\nL5 moves to CANDIDATE. P2 (PMID:40520005) is a genuinely independent group with four new patient-derived CCA lines, organoids, CDX, PDX and a hydrodynamic-tail-vein autochthonous model: DNMTi monotherapy was near-inert, PARPi was the synergy partner, and the mechanism reported is DNA damage plus senescence and inflammatory-pathway induction with cell-cycle suppression — not the OGFR/HR-impairment mechanism of PMID:41463187. Two datasets, one combination, two mechanisms: the schedule question sharpens (does the effect require functional HRD at all, or is it senescence/interferon-driven?). Reviews P1/P4/P6 corroborate only the general principle that DNMTi needs a combination partner in solid tumours.\n\nL4 gains prevalence support (KRAS 17% in BTC, P8) and a mechanistic combination rationale from the SHP2/GI-TME review (P10), but still no CCA-specific ARV-806 efficacy.","leadChanges":[{"id":"L5","title":"Epigenetically induced BRCAness: azacitidine (DNMT3B axis) plus PARP inhibitor in biliary tract cancer","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.58},{"id":"L8","title":"PRMT5 inhibition in MTAP-deleted biliary tract cancer, enriched in the CDKN2A-null FGFRi-refractory subset","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L1","title":"Covalent pan-FGFR inhibition (futibatinib) and combination FGFR/VEGF/PD-L1 blockade in FGFR2-fusion cholangiocarcinoma","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.78},{"id":"L4","title":"KRAS G12D degradation (ARV-806) in the KRAS-mutant, predominantly extrahepatic/gallbladder cholangiocarcinoma subset","level":"LEAD","status":"STRENGTHENED","confidence":0.45}],"unverifiedCitations":0,"openQuestions":["Is the DNMTi+PARPi effect in CCA HR-dependent (RAD51-foci loss) or senescence/SASP- and immune-dependent, and does that determine whether priming-then-PARPi beats concurrent dosing?","What is the MTAP/CDKN2A co-deletion concordance in FGFR2-fusion CCA, and does MTAP IHC identify an FFPE-deployable PRMT5i-eligible subset within the FGFRi-refractory population?","Does TP53/RAS-pathway co-alteration outperform CDKN2A as the predictive marker of FGFR inhibitor failure when both are tested in the same cohort?","Given documented driver retention at progression in FGFR2-fusion CCA, does continuing FGFR blockade plus a co-alteration-directed agent beat switching agents entirely — and how does tinengotinib's post-FGFRi activity segregate by kinase-dom","Do the Eastern-versus-Western prevalence differences in FGFR2/IDH1/KRAS/CDKN2A invalidate cross-regional extrapolation of biomarker-stratified BTC trial results?","Do the KG correlated anchors ROS1 (fusion) and PTPN3 appear as recurrent events in the large 1254- and 5123-sample BTC genomic cohorts, or should they be retired as small-series artefacts?"],"nextQueries":["(cholangiocarcinoma OR \"biliary tract cancer\") AND (MTAP OR PRMT5 OR MAT2A OR \"methylthioadenosine\") AND SRC:MED","(cholangiocarcinoma OR \"biliary tract cancer\") AND (\"ROS1\" OR PTPN3) AND (fusion OR rearrangement OR prevalence) AND SRC:MED","(cholangiocarcinoma OR \"biliary tract cancer\") AND (senescence OR SASP OR \"STING\" OR \"cGAS\") AND (\"PARP inhibitor\" OR decitabine OR azacitidine) AND SRC:MED"],"papersShown":[{"pmid":"41335282","doi":"10.1186/s43556-025-00373-5","year":2025,"isNew":true,"title":"Epigenetic drugs in cancer therapy: mechanisms, immune modulation, and therapeutic applications"},{"pmid":"40520005","doi":"10.7150/ijbs.110947","year":2025,"isNew":true,"title":"PARP inhibitor augments anti-tumor efficacy of DNMT inhibitor by inducing senescence in cholangiocarcinoma"},{"pmid":"40939889","doi":"10.1016/j.jare.2025.08.057","year":2026,"isNew":true,"title":"Epigenetic orchestration of cancer-immune dynamics: mechanisms, technologies, and clinical advancements"},{"pmid":"41762718","doi":"10.1080/17501911.2026.2637418","year":2026,"isNew":true,"title":"DNA methyltransferase inhibitors in oncology: clinical progress, limitations and future directions"},{"pmid":"41912087","doi":"10.1016/j.jhep.2026.03.029","year":2026,"isNew":true,"title":"Global patterns of mutational profiles in biliary tract cancer"},{"pmid":"41673722","doi":"10.1186/s40164-026-00760-w","year":2026,"isNew":true,"title":"Targeting epigenetic methylation: emerging diagnosis and therapeutic strategies in cancer"},{"pmid":"42185943","doi":"10.1002/2056-4538.70094","year":2026,"isNew":true,"title":"A subset of high-grade sarcomas with myogenic differentiation are associated with recurrent FGFR fusions"},{"pmid":"42360806","doi":"10.1158/1078-0432.ccr-26-0428","year":2026,"isNew":true,"title":"Molecular and Clinical Determinants of Targeted Therapy Treatment in Biliary Tract Cancer"},{"pmid":"42345853","doi":"10.3390/antib15030049","year":2026,"isNew":true,"title":"Improving Gallbladder Cancer Outcomes with Antibody-Based Therapies and Immunological Profiling: A Literature Review"},{"pmid":"42310679","doi":"10.1186/s12967-026-08477-4","year":2026,"isNew":true,"title":"SHP2 as a pivotal modulator of the tumor microenvironment in gastrointestinal cancers: from mechanisms to targeted therapies"}],"trialsShown":[{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04645160","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Evaluating Efficacy of Tivozanib (AV-951) in Biliary Tract Cancers"},{"nct":"NCT01915225","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Obtaining Solid Tumor Tissue From People Having Biopsy or Surgery for Certain Types of Cancer"},{"nct":"NCT03212274","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations"},{"nct":"NCT07043387","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Streamlining Radioembolization for CCC and Metastatic Liver Cancer"},{"nct":"NCT06048133","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of Gemcitabine, Cisplatin, AB680 and AB122 During First Line Treatment of Advanced Biliary Tract Cancers (QUIC)"},{"nct":"NCT04891289","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Gemcitabine and Oxaliplatin Chemotherapy With or Without a Floxuridine and Dexamethasone Pump in People With Cholangiocarcinoma That Cannot "},{"nct":"NCT06439485","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Phase I/II Trial of Pemigatinib in Combination With Atezolizumab and Bevacizumab for Treatment of Advanced Cholangiocarcinoma With FGFR2 Fus"}],"usage":{"input":13654,"output":7732},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"cholangiocarcinoma\" OR \"biliary tract cancer\") AND (\"CDKN2A\" OR \"CDK4/6\" OR palbociclib OR abemaciclib) AND (FGFR2 OR pemigatinib OR futibatinib) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"biliary tract cancer\" OR cholangiocarcinoma) AND (azacitidine OR decitabine OR DNMT OR \"induced BRCAness\") AND (\"PARP inhibitor\" OR niraparib OR olaparib) AND SRC:MED"],"evidenceIds":["PMID:41335282","PMID:40520005","PMID:40939889","PMID:41762718","PMID:41912087","PMID:41673722","PMID:42185943","PMID:42360806","PMID:42345853","PMID:42310679","NCT07023731","NCT04645160","NCT01915225","NCT03212274","NCT07043387","NCT06048133","NCT04891289","NCT06439485"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787161054493","cycle":61,"visit":3,"ts":"2026-08-19T17:37:34.493Z","cancer":{"key":"pancreatic cancer","name":"pancreatic cancer","mondo":{"id":"MONDO:0009831","name":"malignant pancreatic neoplasm"}},"control":false,"modelLabel":"SCIENCE","summary":"Pan-RAS(ON) daraxonrasib is now phase-3-validated in previously treated mPDAC (OS 13.2 vs 6.6 mo), so reorganise the RAS programme around it: promote pan-RAS to CANDIDATE, reposition allele-selective G12D degradation as a PI3K-combination strategy (PI3K assembles GAB1/EGFR/SHP2/SOS1-dependent wild-t","confidence":0.66,"notebook":"RASolute-302 is the visit's hinge. Daraxonrasib (RMC-6236), an oral RAS(ON) multiselective tri-complex inhibitor, doubled median OS versus investigator's-choice chemotherapy in previously treated mPDAC (13.2 vs 6.6 months) in a 500-patient randomised phase 3, 91.8% RAS G12 (PMID:42223072), corroborated and contextualised by three independent commentaries/reviews (PMID:42571010, PMID:42557936, PMID:42433811). This converts L6 from a review-level inference into a clinically validated axis: the wild-type-RAS-sparing \"window\" objection I raised in visit 2 is answered empirically — epithelial (mucocutaneous) toxicity is real but manageable at the doses achieving this benefit (PMID:42557936). L6 → CANDIDATE, confidence 0.75. Open question 5 is partly closed: pan-RAS(ON) beats chemotherapy; it has not been compared to mutant-selective agents, so the head-to-head remains live.\n\nThe reciprocal move: allele-selective G12D therapy (L2) is now a second-line-of-argument strategy that must justify itself against an approved pan-RAS backbone. But it gains mechanistic support from PMID:42095550, which directly answers open question 4: PI3K acts *upstream* of wild-type RAS, using phosphoinositide-dependent GAB1 membrane recruitment to nucleate EGFR/SHP2/SOS1-dependent WT-RAS–MAPK complexes; PI3K inhibition sensitised PDAC cells to mutant-selective KRAS inhibitors, including PIK3CA-mutant lines. So PI3K/AKT is not merely a parallel effector rebound but the assembler of the bypass — which predicts that PI3K inhibition should add more to a mutant-selective degrader (ARV-806, NCT07023731) than to daraxonrasib, whose WT-RAS engagement already pre-empts that route [INFERRED]. L2 → CANDIDATE (0.55) on this new primary evidence, with SHP2/SOS1 now framed as downstream of the same PI3K-GAB1 node rather than independent co-targets.\n\nL1: PMID:40723890 (independent lab) corroborates direct CDD-mediated gemcitabine destruction — *Aggregatibacter actinomycetemcomitans* (CDD_L) fully degraded drug and conferred resistance — but partially contradicts the CDD_L-exclusivity claim from PMID:42099454: CDD_S-carrying oral taxa (E. faecalis, S. mutans, P. gingivalis) degraded gemcitabine partially and strain-dependently, and CDD_L/CDD_S were equivalent when expressed in isogenic E. coli. My proposed biomarker must therefore be total cdd carriage plus a functional deamination assay, not cdd_L genotype, and must sample the oral compartment as a plausible source (PMID:41658610, PMID:41300985). Human prevalence data are still absent, so DOSSIER is withheld.\n\nNew lead: post-daraxonrasib resistance and sequencing — ternary-complex-disrupting RAS mutations, increased KRAS abundance, RAS degraders/RAS-cleaving biologics, FTase co-inhibition (darlifarnib+adagrasib), and pharmacology constraints (ABCB1 efflux, OATP1A/1B uptake, CYP3A4 clearance; PMID:42107507).","leadChanges":[{"id":"L6","title":"Pan-RAS(ON) tri-complex inhibition as the wild-type-bypass-proof alternative to allele-selective G12D therapy","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.75},{"id":"L2","title":"KRAS G12D targeted degradation (ARV-806) in PDAC","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.55},{"id":"L1","title":"cdd_L+ intratumoral Enterobacter as an antibiotic-reversible driver of gemcitabine inactivation","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.66},{"id":"L8","title":"Post-daraxonrasib resistance: sequencing RAS degraders, RAS-cleaving biologics and prenylation-bypass co-inhibition after pan-RAS failure","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["In daraxonrasib-treated mPDAC, what is the relative frequency of ternary-complex-disrupting RAS mutations versus KRAS amplification/overabundance versus non-RAS cell-state escape in progression ctDNA/biopsies?","Does PI3K inhibition add pERK/pAKT suppression and survival benefit specifically to mutant-selective KRAS agents (predicted) and less so to pan-RAS(ON) (predicted), and is the GAB1-membrane-recruitment readout a usable pharmacodynamic bioma","Is there any remaining niche for allele-selective G12D therapy (ARV-806, DN022150, HRS-4642) after pan-RAS phase 3 success — first-line, maintenance, chemo-combinability, or lower epithelial toxicity?","What fraction of human PDAC resections carry cdd+ bacteria by total-isoform assay with functional gemcitabine-deamination activity, does oral carriage of Aggregatibacter/CDD_S taxa predict intratumoral carriage, and does either predict neoa","Does daraxonrasib-induced TME remodelling relieve PD-1/PD-L1 refractoriness in PDAC, and can it be combined with gemcitabine/nab-paclitaxel given CYP3A4/ABCB1/OATP-dependent PK?","Does LIF blockade lower intratumoral pSTAT3 in PDAC patients on gemcitabine/nab-paclitaxel, and is IL-6/OSM gp130 redundancy the escape?"],"nextQueries":["(\"pancreatic ductal adenocarcinoma\" AND (daraxonrasib OR \"RMC-6236\" OR \"RASolute\") AND (\"acquired resistance\" OR ctDNA OR biopsy OR \"ternary complex\")) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","(pancrea* AND (\"cytidine deaminase\" OR \"CDD\" OR Gammaproteobacteria OR Aggregatibacter) AND (resection OR cohort OR prevalence OR \"tumor microbiome\") AND gemcitabine) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"pancreatic\" AND (PI3K OR PIK3CA OR GAB1 OR SHP2 OR SOS1) AND (\"KRAS inhibitor\" OR \"RAS(ON)\" OR G12D) AND (combination OR resistance)) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]"],"papersShown":[{"pmid":"42223072","doi":"10.1056/nejmoa2605555","year":2026,"isNew":true,"title":"Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer"},{"pmid":"41658610","doi":"10.3389/fmed.2026.1737582","year":2026,"isNew":true,"title":"Decoding the microbial blueprint of pancreatic cancer"},{"pmid":"40723890","doi":"10.3390/biom15071018","year":2025,"isNew":true,"title":"Role of Oral Bacteria in Mediating Gemcitabine Resistance in Pancreatic Cancer"},{"pmid":"41300985","doi":"10.3390/cancers17223618","year":2025,"isNew":true,"title":"Microbiota and Pancreatic Cancer: New Therapeutic Frontiers Between Engineered Microbes, Metabolites and Non-Bacterial Components"},{"pmid":"42571850","doi":"10.1016/j.jare.2026.08.030","year":2026,"isNew":true,"title":"From KRAS inhibition to tumor adaptation: mechanistic layers of resistance and therapeutic strategies"},{"pmid":"42571010","doi":"10.1186/s13045-026-01834-2","year":2026,"isNew":true,"title":"The KRAS targeting revolution in metastatic pancreatic cancer: insights from the landmark RASolute-302 trial and emerging allele-specific strategies at ASCO 2026"},{"pmid":"42557936","doi":"10.1111/cas.70497","year":2026,"isNew":true,"title":"Daraxonrasib and Beyond: Pan-RAS Inhibition, Resistance, and Next-Generation Strategies"},{"pmid":"42095550","doi":"10.1158/0008-5472.can-25-3625","year":2026,"isNew":true,"title":"PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition"},{"pmid":"42433811","doi":"10.1097/ms9.0000000000005188","year":2026,"isNew":true,"title":"From pancreatic ductal adenocarcinoma to non-small cell lung cancer: daraxonrasib in the RASolute 302 trial - a pan-RAS(ON) breakthrough or the next evolution in targeting diverse "},{"pmid":"42107507","doi":"10.1016/j.phrs.2026.108226","year":2026,"isNew":true,"title":"Daraxonrasib (RMC-6236) pharmacokinetics: impact of transporters and drug-metabolizing enzymes on a first-in-class pan-RAS molecular glue"}],"trialsShown":[{"nct":"NCT04999969","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic "},{"nct":"NCT05692323","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Supervised Prehabilitation Program for Patients With Pancreatic Cancer"},{"nct":"NCT07226154","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Prediction of Neoadjuvant Chemotherapy Response in Pancreatic Cancer"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04550494","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations"},{"nct":"NCT04644068","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies"},{"nct":"NCT03454035","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Ulixertinib/Palbociclib in Patients With Advanced Pancreatic and Other Solid Tumors"},{"nct":"NCT01174121","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer"}],"usage":{"input":13421,"output":8281},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"pancreatic ductal adenocarcinoma\" AND (\"pan-RAS\" OR \"RMC-6236\" OR \"RMC-9805\" OR \"tri-complex\") AND (resistance OR trial OR response)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"pancreatic\" AND (\"cytidine deaminase\" OR cdd OR Gammaproteobacteria) AND (\"human\" OR resection OR cohort OR biomarker) AND gemcitabine) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42223072","PMID:41658610","PMID:40723890","PMID:41300985","PMID:42571850","PMID:42571010","PMID:42557936","PMID:42095550","PMID:42433811","PMID:42107507","NCT04999969","NCT05692323","NCT07226154","NCT07023731","NCT04550494","NCT04644068","NCT03454035","NCT01174121"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787160825130","cycle":60,"visit":6,"ts":"2026-08-19T17:33:45.130Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"First mutation-level data at asciminib failure (A337V, rescued by dasatinib) argue for mutation-directed sequential ATP-site/allosteric switching rather than concurrent dual-site blockade; tapering before cessation adds nothing to TFR, and venetoclax+ponatinib reopens BCL2 only in asciminib-resistan","confidence":0.62,"notebook":"This visit finally supplies the mutation-level data the desk has asked for twice, and it cuts against concurrent dual-site blockade. PMID:39996897 [NEW] reports frontline asciminib failure driven by the myristoyl-pocket variant A337V, rescued to deep molecular response by second-line dasatinib. Mechanistically that confirms the pocket is escapable by a single point mutation but that escape is orthogonal: A337V does not perturb the ATP cleft, so an ATP-site TKI remains fully active [INFERRED from the case]. Combined with the editorial reframing of dual BCR::ABL1 inhibition in Ph+ disease as possibly better sequential than concurrent (PMID:42305468), the rationale for simultaneous occupancy weakens: mutation-directed sequencing appears to capture most of the benefit without stacking cardiovascular/hepatic toxicity. L1 is therefore weakened again (fifth consecutive visit with no dual-occupancy efficacy data; NCT03906292 still unreported), while L8 is strengthened — asciminib salvage now has a defined failure mode with a defined exit, and the reciprocal sequence (asciminib→ATP-site) is documented alongside the ponatinib→asciminib direction. PMID:42033491 [NEW] corroborates that myristoyl-pocket mutations confer variable, mutation-specific TKI sensitivity and flags ASXL1/RUNX1 acquisition as progression drivers (touching the KG RUNX1 [SOMATIC] anchor), plus TERN-701/ELVN-001/olverembatinib as next ATP-site entrants.\n\nPMID:41778234 [NEW] explains part of my evidence drought: in US community practice, kinase-domain profiling is applied unsystematically and its use was not associated with more failure/warning events — so real-world mutation spectra at asciminib failure will remain sparse unless trial datasets are queried directly. Open question 1 is now partially answered (A337V exists, is dasatinib-sensitive) but the frequency and the T315I-compound question stay open.\n\nL7 gains its first prospectively-relevant comparison: in 39 TFR attempts, abrupt standard-dose cessation, tapering, and upfront dose reduction gave equivalent TFR maintenance (61/59/59%) with no progressions and universal MMR regain (PMID:40647447 [NEW]). De-escalation before cessation is thus safe but not advantageous — I record this so the desk stops treating tapering as a depth-enhancing manoeuvre. No ELTS/transcript/ASXL1 stratification again; question 3 unanswered.\n\nReopening BCL2, narrowly: PMID:40858806 [NEW] reports venetoclax plus ponatinib in asciminib-resistant CML — CML-specific, in a resistant niche, unlike the retired early-chronic-phase dasatinib+venetoclax hypothesis whose trial (NCT02689440) remains silent. Title only, no abstract; I cannot judge n, phase, or depth of response. New low-confidence lead L10, not a resurrection of the retired one.\n\nCalibration note: the desk continues to converge on the solved mechanism — BCR::ABL1 [SOMATIC] fusion, ATP-site inhibition as backbone — with all live work at the margins (allosteric sequencing, exposure floors, TFR immunology).","leadChanges":[{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"WEAKENED","confidence":0.5},{"id":"L8","title":"Sequential ATP-site to allosteric switch: asciminib as non-cross-resistant salvage after ponatinib and in T315I disease","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.68},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.63},{"id":"L10","title":"BCL2 co-dependence confined to multi-TKI/asciminib-resistant CML: venetoclax plus ponatinib as salvage","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Beyond the single A337V case (PMID:39996897), what is the frequency and spectrum of asciminib-emergent myristoyl-pocket variants (A337V, P465S, F359, W464, and T315I-containing compound mutants), and which ATP-site agent rescues each?","In the ~21 T315I patients from NCT02081378 who never achieved MMR on asciminib 200 mg BID, is failure explained by compound mutants, prior ponatinib exposure, or non-mutational (LSC-state) resistance?","What are the actual design and results of venetoclax plus ponatinib in asciminib-resistant CML (PMID:40858806) - patients or models, dose levels, depth and duration of response, and any BH3/MCL1 profiling?","Do any TFR cohorts report outcomes stratified by ELTS, e13a2 vs e14a2 transcript, and ASXL1/RUNX1 status, and does dose reduction before cessation remain neutral in higher-risk strata?","Are there agent-specific exposure floors (trough/Cmax) for maintaining MR4/MR4.5 during dasatinib, nilotinib-tablet or asciminib de-escalation, analogous to the flumatinib Cmax_2h thresholds?","Has NCT03906292 or any asciminib+ATP-site combination cohort reported MR4.5, kinase-domain NGS at failure, or TFR attempts that would revive concurrent dual-site blockade?"],"nextQueries":["\"chronic myeloid leukemia\" AND asciminib AND (\"A337V\" OR \"P465S\" OR \"F359\" OR \"myristoyl\" OR \"compound mutation\") AND (sequential OR switch OR dasatinib OR ponatinib) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic myeloid leukemia\" AND venetoclax AND (ponatinib OR asciminib OR \"BH3 profiling\" OR MCL1) AND (resistant OR persistence OR \"stem cell\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic myeloid leukemia\" AND (\"therapeutic drug monitoring\" OR trough OR Cmax OR \"exposure-response\") AND (\"dose reduction\" OR de-escalation OR \"MR4.5\" OR \"deep molecular response\") AND SRC:MED AND PUB_YEAR:[2024 TO 20"],"papersShown":[{"pmid":"40647447","doi":"10.3390/cancers17132148","year":2025,"isNew":true,"title":"Real-World Evidence of Treatment-Free Remission Strategies and Outcomes in Chronic Myeloid Leukemia"},{"pmid":"42065050","doi":"10.32604/or.2025.075217","year":2026,"isNew":true,"title":"Therapeutic Targets for Overcoming BCR::ABL1 Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia"},{"pmid":"41724089","doi":"10.1016/j.htct.2026.106257","year":2026,"isNew":true,"title":"Is asciminib an effective tyrosine kinase inhibitor for chronic myeloid leukemia patients with tyrosine kinase inhibitor resistance?"},{"pmid":"42305468","doi":"10.21037/tcr-2026-1-0219","year":2026,"isNew":true,"title":"Reconsidering dual &lt;i&gt;BCR::ABL1&lt;/i&gt; inhibition in Philadelphia chromosome-positive acute lymphoblastic leukemia: is sequential better than concurrent?"},{"pmid":"39996897","doi":"10.3390/curroncol32020097","year":2025,"isNew":true,"title":"Treatment-Emergent Resistance to Asciminib in Chronic Myeloid Leukemia Patients Due to Myristoyl-Binding Pocket-Mutant of <i>BCR::ABL1/A337V</i> Can Be Effectively Overcome with Da"},{"pmid":"41778234","doi":"10.21873/cdp.10518","year":2026,"isNew":true,"title":"&lt;i&gt;BCR::ABL1&lt;/i&gt; Mutational Profiling in US Patients With Chronic-phase Chronic Myeloid Leukemia on Tyrosine Kinase Inhibitors"},{"pmid":"42033491","doi":"10.1007/s11899-026-00778-1","year":2026,"isNew":true,"title":"Targeting the BCR::ABL1 Kinase: Advances Beyond Imatinib in Chronic Myeloid Leukemia"},{"pmid":"40858806","doi":"10.1038/s41375-025-02732-1","year":2025,"isNew":true,"title":"Venetoclax in combination with ponatinib for the treatment of asciminib-resistant chronic myeloid leukemia"},{"pmid":"41751307","doi":"10.3390/biomedicines14020408","year":2026,"isNew":true,"title":"Evolving Therapeutic Algorithms in Chronic Myeloid Leukemia: Integrating Efficacy, Safety, and Survivorship"},{"pmid":"41873276","doi":"10.7759/cureus.103951","year":2026,"isNew":true,"title":"Digital Medicine and Artificial Intelligence in Chronic Myeloid Leukemia: Current Applications, Challenges, and Future Directions"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":13658,"output":7270},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic myeloid leukemia\" AND asciminib AND (\"mutation\" OR \"A337V\" OR \"P465S\" OR \"F359\" OR \"compound mutation\") AND (resistance OR failure) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","\"chronic myeloid leukemia\" AND (\"treatment-free remission\" OR TFR) AND (\"dose reduction\" OR de-escalation OR downgrading) AND (ASXL1 OR ELTS OR \"transcript type\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:40647447","PMID:42065050","PMID:41724089","PMID:42305468","PMID:39996897","PMID:41778234","PMID:42033491","PMID:40858806","PMID:41751307","PMID:41873276","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787160602887","cycle":59,"visit":3,"ts":"2026-08-19T17:30:02.887Z","cancer":{"key":"glioblastoma","name":"glioblastoma","mondo":{"id":"MONDO:0018177","name":"glioblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"BT317 (dual LonP1/CT-L proteasome inhibitor) validates LonP1 as a druggable, ROS-dependent dependency in patient-derived glioma stem-like cells, promoting the LonP1 lead to CANDIDATE and making brain-exposure measurement plus a ClpP-agonist (ONC201) versus LonP1-inhibitor comparison the next decisiv","confidence":0.44,"notebook":"This visit answered Question 1 in the affirmative and changed L1's status. LonP1 chemical matter exists and has been tested in the right disease context: BT317, a coumarinic-compound-4 derivative, inhibits both LonP1 and chymotrypsin-like proteasome activity, drives ROS-dependent apoptosis in established malignant astrocytoma lines and patient-derived glioma stem-like cultures, and gain/loss-of-function genetics show LonP1 is necessary and sufficient for BT317 sensitivity (PMID:40088962). The abstract is truncated where combination activity is described (\"had activity as a single agent but, more importantly, enhance…\"), so I will not claim TMZ synergy or any in vivo/orthotopic result from it, and CNS exposure of BT317 remains unstated. Two independent reviews catalogue the medicinal chemistry: competitive protease-site versus allosteric ATPase-site inhibitors, with allosteric ATPase blockade argued as the preferred route (PMID:38156441), and CDDO/derivatives plus obtusilactone A as the current selective-ish tool set (PMID:40305312). L1 therefore moves LEAD→CANDIDATE: two evidence-bearing visits, new independent literature, and a named brain-tumour-tested molecule. Mechanistically this reframes L1 from \"resensitiser\" to proteotoxic/ROS co-cytotoxin whose partner is proteasome CT-L blockade rather than a biguanide; the ATF4/UPRmt adaptation node (PMID:42462827) predicts ISR feedback as the escape route.\n\nA genuinely new axis: mitochondrial AAA+ proteases can be drugged by hyperactivation as well as inhibition — dordaviprone/ONC201 activating ClpP is the stated proof of concept (PMID:41655698). Since ONC201 is an approved agent in H3K27M-altered glioma [KNOWN], testing whether ClpP agonism and LonP1 inhibition are synergistic or mutually buffering in H3-wildtype GBM is the cheapest high-value experiment in the programme (new L7).\n\nThe dedicated MCT1/MCT4/LDHA-in-vivo-glioma query again returned no primary GBM experiment (Question 3 unanswered for a second visit); I now treat that absence as informative and mark L2 WEAKENED and L6 WEAKENED. What did arrive is primary but extracranial: in gastric cancer, H3K18la activates HAS2, driving c-MYC nuclear translocation and CD274/PD-L1 transcription; 2-DG/oxamate or LDHA/LDHB double knockdown lowers H3K18la and restores CD8 cytotoxicity in vivo (PMID:42021123). That corroborates lactylation→immune evasion, not lactylation→DNA repair, so Question 4 stays open and L6 should probably be re-pointed at immunometabolic rather than repair-capacity radiosensitisation.\n\nHypoxia also constrains effectors, not just tumour cells: 1% O2 collapses NK mitochondrial content and cytotoxicity, unrescued by CD70-CAR-IL-15, but restored by pharmacological or CRISPR DRP1 loss (PMID:41706678, context PMID:41799416) — a new low-confidence lead for the GBM hypoxic core.","leadChanges":[{"id":"L1","title":"LonP1 inhibition to resensitise glioblastoma to temozolomide (MGMT-independent)","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.56},{"id":"L7","title":"ClpP hyperactivation (dordaviprone/ONC201) versus LonP1 inhibition — opposing mitochondrial protease modalities in H3-wildtype GBM","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L2","title":"Block glycolytic lactate flux to reverse BMAL1-lactylation-driven bevacizumab resistance","level":"CANDIDATE","status":"WEAKENED","confidence":0.44},{"id":"L6","title":"Lactate-supply blockade as a hypoxia-core radiosensitiser in glioblastoma","level":"LEAD","status":"WEAKENED","confidence":0.26},{"id":"L8","title":"DRP1 inhibition to rescue NK/CAR-NK effector function in the hypoxic glioblastoma core","level":"LEAD","status":"NEW","confidence":0.24}],"unverifiedCitations":0,"openQuestions":["Does BT317 (or any CDDO-class/allosteric LonP1 ATPase inhibitor) achieve measurable unbound brain and tumour exposure, and is it a P-gp/BCRP substrate?","Does LonP1 inhibition plus CT-L proteasome inhibition synergise with TMZ and with fractionated RT in orthotopic MGMT-methylated versus unmethylated patient-derived GBM in vivo — and does ATF4/UPRmt induction predict escape?","Are ClpP agonism (dordaviprone/ONC201) and LonP1 inhibition synergistic or mutually buffering in H3-wildtype GBM stem-like cells, and does LONP1/CLPP expression stratify response?","Does any primary in vivo glioma experiment show MCT1/MCT4 or LDHA blockade improving bevacizumab, RT or anti-PD-1 efficacy — and if none exists after three targeted searches, should L2 be reclassified as delivery/data-limited rather than me","Is the HAS2/c-MYC/PD-L1 lactylation module operative in GBM, i.e. does LDHA blockade lower tumour PD-L1 and restore CD8 cytotoxicity in orthotopic immunocompetent models?","Does DRP1 loss or inhibition preserve NK/CAR-NK killing of GBM organoids specifically at 1% O2 and in lactate-rich medium, and does it extend killing into pimonidazole-positive tumour regions?"],"nextQueries":["(BT317 OR CDDO OR \"coumarinic compound 4\") AND (LONP1 OR \"Lon protease\" OR proteasome) AND (glioma OR glioblastoma OR pharmacokinetics OR \"brain penetration\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(ONC201 OR dordaviprone OR \"ClpP agonist\") AND (glioblastoma OR \"H3 wildtype\" OR \"glioma stem\") AND (mitochondrial OR OXPHOS OR proteostasis) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(lactylation OR \"H3K18la\" OR LDHA OR SLC16A1) AND (glioma OR glioblastoma) AND (\"PD-L1\" OR \"CD8\" OR macrophage OR radiotherapy) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"38156441","doi":"10.1080/14728222.2023.2298358","year":2024,"isNew":true,"title":"Powering down the mitochondrial LonP1 protease: a novel strategy for anticancer therapeutics"},{"pmid":"40305312","doi":"10.3390/biom15040553","year":2025,"isNew":true,"title":"Modulation of Lonp1 Activity by Small Compounds"},{"pmid":"40088962","doi":"10.1016/j.phrs.2025.107697","year":2025,"isNew":true,"title":"Dual targeting of the mitochondrial Lon peptidase 1 and the chymotrypsin-like proteasome activity as a potential therapeutic strategy in malignant astrocytoma models"},{"pmid":"41799416","doi":"10.1016/j.pscia.2026.100109","year":2026,"isNew":true,"title":"Mechanisms of tumor cell evasion from NK cell-mediated killing and advances in NK cell-based cancer immunotherapy"},{"pmid":"41521420","doi":"10.1080/19490976.2026.2614115","year":2026,"isNew":true,"title":"Probiotic extracellular vesicles reprogram macrophage immunometabolism: From gut crosstalk to host health"},{"pmid":"41655698","doi":"10.1016/j.jbc.2026.111264","year":2026,"isNew":true,"title":"Molecular mechanisms of mitochondrial AAA+ proteases"},{"pmid":"42262932","doi":"10.1080/07853890.2026.2672785","year":2026,"isNew":true,"title":"The regulatory roles of non-coding RNAs in aerobic glycolysis and therapeutic potential in pancreatic ductal adenocarcinoma"},{"pmid":"42021123","doi":"10.1080/19490976.2026.2661416","year":2026,"isNew":true,"title":"&lt;i&gt;Helicobacter pylori&lt;/i&gt; activates histone lactylation to promote gastric cancer progression and immune evasion through the HAS2/c-MYC/PD-L1 axis"},{"pmid":"41995675","doi":"10.1080/21645515.2026.2657074","year":2026,"isNew":true,"title":"Oncolytic virus therapy for hepatocellular carcinoma: A bibliometric analysis of research landscapes, hotspots, and clinical transformation trends from 2000 to mid-2025"},{"pmid":"41706678","doi":"10.1080/13510002.2026.2626181","year":2026,"isNew":true,"title":"DRP1 depletion protects NK cells from hypoxia-induced dysfunction"}],"trialsShown":[{"nct":"NCT06108206","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Adaptive Radiotherapy and MRIs Based on Patients With Newly Diagnosed High-Grade Glioma"},{"nct":"NCT06816927","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Trial of Glioblastoma Immunotherapy Advancement With Nivolumab and Relatlimab"},{"nct":"NCT06860594","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Testing the Addition of an Anti-Cancer Drug, Triapine, to the Usual Radiation Therapy for Recurrent Glioblastoma or Astrocytoma"},{"nct":"NCT02977780","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"INdividualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT)"},{"nct":"NCT06556563","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"EF-41/KEYNOTE D58: Phase 3 Study of Optune Concomitant With Temozolomide Plus Pembrolizumab in Newly Diagnosed Glioblastoma"},{"nct":"NCT04047264","phase":"NA","status":"RECRUITING","isNew":false,"title":"Feasibility of Intra- and Post-operative Microdialysis During Neurosurgery for Central Nervous System Lesions"},{"nct":"NCT03212274","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations"},{"nct":"NCT06319027","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Identifying Findings on Brain Scans That Could Help Make Better Predictions About Brain Cancer Progression, The GABLE Trial"}],"usage":{"input":13581,"output":8901},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"MCT1\" OR \"MCT4\" OR SLC16A1 OR SLC16A3 OR LDHA) AND (glioma OR glioblastoma) AND (orthotopic OR xenograft OR \"in vivo\" OR radiotherapy) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(LONP1 OR \"Lon protease\") AND (inhibitor OR CDDO OR obtusilactone OR \"blood-brain barrier\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"evidenceIds":["PMID:38156441","PMID:40305312","PMID:40088962","PMID:41799416","PMID:41521420","PMID:41655698","PMID:42262932","PMID:42021123","PMID:41995675","PMID:41706678","NCT06108206","NCT06816927","NCT06860594","NCT02977780","NCT06556563","NCT04047264","NCT03212274","NCT06319027"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787160361777","cycle":58,"visit":1,"ts":"2026-08-19T17:26:01.777Z","cancer":{"key":"multiple endocrine neoplasia type 1","name":"multiple endocrine neoplasia type 1","mondo":{"id":"MONDO:0007540","name":"multiple endocrine neoplasia type 1"}},"control":false,"modelLabel":"SCIENCE","summary":"In MEN1-related metastatic NETs, c-MET protein is expressed in only ~20% of tumours (3/43 strongly), so cabozantinib-class therapy should be tested prospectively only in MET-IHC-selected patients, while the dominant untested dependency remains the menin-p27/p18 G1 axis (CDK4/6).","confidence":0.34,"notebook":"Programme opens with a thin pack: two abstracts carry real information, the rest are case reports (P2, P3, P4, P7, P10) and the trial set is off-target noise (T1 fezolinetant/ADT, T3 IPH4502 solid-tumour phase 1, T4 BNT116 NSCLC, T5–T7 care-delivery/newborn screening). T2 (NCT04969926, NIDDK parathyroid natural history) and T8 (NCT03050268) are the only recruiting studies plausibly enrolling MEN1 germline carriers — registry value, not therapeutic.\n\nMechanistic frame for the desk: MEN1 [GERMLINE, causal] is a tumour suppressor encoding menin, a scaffold for KMT2A/MLL H3K4 methyltransferase complexes; biallelic loss in duodenopancreatic, parathyroid and pituitary lineages is loss-of-function, hence not directly druggable — synthetic lethality or downstream-effector logic only [KNOWN]. CDKN1B/CDKN2B [SOMATIC-likely, KG-correlated] place the G1–S restriction point downstream of menin loss (menin normally supports p27/p18 transcription) [KNOWN], which is where I expect the strongest tractable dependency. Recorded so the desk never re-proposes it: menin–MLL inhibitors (revumenib-class) are conceptually inverted here — they antagonise a protein already lost in MEN1 tumours [KNOWN].\n\nP1 (PMID:41018051) is the only new target datum and it cuts both ways. In 43 MEN1-related metastatic NETs, 34/43 were c-MET–negative, 6 weak, 3 strong. The authors' conclusion (\"a role for c-MET inhibition\") is not supported by an unselected-use reading of their own numbers; the defensible hypothesis is MET IHC (H-score >50) as an enrichment biomarker for cabozantinib-class agents in the ~7% strongly positive subset — this is why the lead opens at low confidence rather than as a headline. Whether IHC tracks MET amplification/HGF autocrine signalling is unresolved from the abstract.\n\nP9 (PMID:42137458, review) reframes panNET as a co-evolving immune-excluded, CAF-rich niche — consistent with the near-uniform failure of checkpoint monotherapy in well-differentiated NET [KNOWN]; this argues for stroma/vascular-directed combination rather than IO monotherapy, and I log it as a hypothesis-generating lead only (review-level evidence).\n\nP8 (PMID:42140757) is actionable now: TriNetX, 129 vs 305, concomitant cervical thymectomy raised cure 96.9% vs 88.2% (RR persistent disease 0.26) at the cost of transient hypoparathyroidism (~38%) — mechanistically intrathymic supernumerary parathyroid tissue. Retrospective, surgeon-selection confounded.\n\nSafety notebook entry from P5 (PMID:42541759): GLP-1R is expressed on panNET lines and GLP-1RA is proliferative preclinically; clinical data conflict. Any MEN1 hypothesis involving incretin agents must be flagged, not assumed benign.","leadChanges":[{"id":"L1","title":"MET-IHC-selected c-MET inhibition (cabozantinib +/- anti-VEGF) in MEN1-related duodenopancreatic NET","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L2","title":"Menin-loss to p27/p18 G1 dysregulation as a CDK4/6-inhibitor dependency in MEN1 tumours","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L3","title":"Stroma/immune-exclusion-directed combination rather than checkpoint monotherapy in MEN1 panNET","level":"LEAD","status":"NEW","confidence":0.22},{"id":"L4","title":"Concomitant cervical thymectomy at parathyroidectomy to eradicate intrathymic supernumerary parathyroid tissue in MEN1 pHPT","level":"LEAD","status":"NEW","confidence":0.45}],"unverifiedCitations":0,"openQuestions":["Does c-MET IHC positivity in MEN1 NETs correspond to MET amplification/exon-14 events or HGF autocrine signalling, and does any MEN1 patient response to cabozantinib exist in published series?","Are MEN1-null endocrine tumour cells preferentially sensitive to CDK4/6 inhibition (via p27/p18 loss), and is there published isogenic or organoid evidence?","Beyond CDK4/6, what synthetic-lethal partners of menin loss are documented (EZH2/PRC2, PRMT5, ATR/replication stress, HDAC) in panNET or parathyroid models?","Do MEN1-germline panNETs share the immune-excluded, CAF-rich TME described for sporadic panNET, or do they differ in MHC-I and CD8 topology?","Is the cervical-thymectomy cure benefit reproducible when surgeon volume and extent of parathyroid resection are controlled, and what is the permanent hypoparathyroidism penalty?","How should GLP-1RA exposure be handled in MEN1 carriers with occult panNETs given preclinical GLP-1R-driven proliferation and conflicting clinical data?"],"nextQueries":["(MEN1 OR menin) AND (CDK4/6 OR palbociclib OR ribociclib OR CDKN1B OR p27 OR p18) AND SRC:MED AND PUB_YEAR:[2015 TO 2026]","(\"menin\" OR MEN1) AND (\"synthetic lethal\" OR EZH2 OR PRMT5 OR \"replication stress\" OR ATR OR HDAC) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","\"pancreatic neuroendocrine\" AND (MEN1 OR \"multiple endocrine neoplasia type 1\") AND (\"177Lu-DOTATATE\" OR PRRT OR everolimus OR sunitinib OR temozolomide) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"papersShown":[{"pmid":"41018051","doi":"10.1210/jendso/bvaf147","year":2025,"isNew":true,"title":"MEN1-Related Neuroendocrine Tumors Show c-MET Overexpression"},{"pmid":"42327516","doi":"10.1016/j.radcr.2026.05.056","year":2026,"isNew":true,"title":"Insulinomatosis: A case report of a multifocal insulin-secreting entity"},{"pmid":"42569418","doi":"10.7759/cureus.114115","year":2026,"isNew":true,"title":"Multidisciplinary Management of the Rare Coexistence of Multiple Endocrine Neoplasia Type 1 and Chronic Thromboembolic Pulmonary Hypertension: A Case Report"},{"pmid":"42557533","doi":"10.3760/cma.j.cn112147-20251215-00797","year":2026,"isNew":true,"title":"[Multiple endocrine neoplasia presenting initially as acute pulmonary thromboembolism: a case report]"},{"pmid":"42541759","doi":"10.1093/ejendo/lvag135","year":2026,"isNew":true,"title":"Safety of glucagon-like peptide-1 receptor agonists in neuroendocrine neoplasms"},{"pmid":"42338092","doi":"10.1111/jne.70219","year":2026,"isNew":true,"title":"Characteristics, management, and outcomes of patients with VIPoma-A retrospective analysis of the ENETS database"},{"pmid":"42245473","doi":"10.1210/jcemcr/luag136","year":2026,"isNew":true,"title":"Functioning gonadotroph macroadenoma associated with multiple endocrine neoplasia type 1"},{"pmid":"42140757","doi":"10.1016/j.surg.2026.110261","year":2026,"isNew":true,"title":"Impact of cervical thymectomy on multiple endocrine neoplasia type 1 patients undergoing parathyroidectomy for primary hyperparathyroidism"},{"pmid":"42137458","doi":"10.3892/ol.2026.15630","year":2026,"isNew":true,"title":"Multi-omics profiling of pancreatic neuroendocrine tumors: Interplay of genomic instability and the tumor microenvironment (Review)"},{"pmid":"42510114","doi":"10.3390/diagnostics16142251","year":2026,"isNew":true,"title":"Upregulation of Somatostatin Receptor Expression in Lactating Breast Shown in &lt;sup&gt;99m&lt;/sup&gt;Tc-HYNIC-TOC Scintigraphy"}],"trialsShown":[{"nct":"NCT06957691","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Proof-of-Concept Trial to Assess the Efficacy and Safety of Fezolinetant in Improving Vasomotor Symptoms in Men With Prostate Cancer Undergo"},{"nct":"NCT04969926","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Natural History Study of Parathyroid Disorders"},{"nct":"NCT06781983","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Safety and Tolerability of IPH4502 in Patients With Advanced Solid Tumors"},{"nct":"NCT05142189","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Clinical Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced No"},{"nct":"NCT05250284","phase":"n/a","status":"RECRUITING","isNew":true,"title":"The Intersection of Oncology Care and Worker Well-Being"},{"nct":"NCT06834204","phase":"NA","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Advancing Care Coordination Between Cancer and Primary Care Teams for Complex Cancer Survivors"},{"nct":"NCT03655223","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Early Check: Expanded Screening in Newborns"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":8092,"output":6117},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"multiple endocrine neoplasia type 1\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"multiple endocrine neoplasia type 1\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41018051","PMID:42327516","PMID:42569418","PMID:42557533","PMID:42541759","PMID:42338092","PMID:42245473","PMID:42140757","PMID:42137458","PMID:42510114","NCT06957691","NCT04969926","NCT06781983","NCT05142189","NCT05250284","NCT06834204","NCT03655223","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787160154823","cycle":57,"visit":1,"ts":"2026-08-19T17:22:34.823Z","cancer":{"key":"hereditary diffuse gastric cancer","name":"hereditary diffuse gastric cancer","mondo":{"id":"MONDO:0007648","name":"hereditary diffuse gastric adenocarcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"In HDGC, treat germline CDH1/CTNNA1 truncation as a haploinsufficiency-to-biallelic-loss adherens-junction defect and test mitotic-spindle-orientation dependencies as its synthetic-lethal handle, while excluding PD-1 monotherapy in signet-ring histology on immune-quiescence grounds.","confidence":0.45,"notebook":"Visit 1 establishes the programme from a pack that is genetically rich but therapeutically thin: HDGC remains a surgery-and-surveillance disease, and nothing in this pack reports a systemic agent tested in germline carriers. Two papers are load-bearing. P1 (PMID:40998418) resolves CTNNA1 mechanism: truncating transcripts are degraded by NMD, tumours lose αE-catenin protein, non-truncating transcripts remain functional in humanised Drosophila, and DGC risk is 8-fold higher in truncating carriers — i.e. haploinsufficiency-then-biallelic-loss, mirroring CDH1 [GERMLINE]. This makes the *functional* assay (NMD readout + fly complementation) the natural companion classifier for the VUS problem that drives over- and under-gastrectomy; T1 (NCT05126290) supplies the carrier cohort to anchor it. P2 (PMID:41517846) gives the only mechanistic handle for direct killing: E-cadherin loss produces mitotic spindle misorientation and displacement of dividing progenitors out of the epithelial plane, and pT1a SRCCs are indolent until they acquire invasive traits. That phenotype nominates mitosis/spindle-orientation dependencies (LGN-NuMA-dynein axis, KIF11, Aurora A, PLK1) as candidate synthetic-lethal partners of adherens-junction loss [INFERRED]; [KNOWN] the published CDH1-null synthetic lethalities (ROS1 inhibition, PI3K/AKT, mTOR) are not represented in this pack and must be verified before I lean on them.\n\nP4 (PMID:41902313) is the highest-value negative signal and I am recording it so the desk never re-proposes naked checkpoint blockade: the signet-ring TIM is \"quiescent\", Treg-high, CD8-effector-poor, with CXCL13-depleted exhausted CD8 cells and absent mature tertiary lymphoid structures. Any immunotherapy lead here must be a TLS-induction / Treg-depletion combination, not PD-1 monotherapy. P7 (PMID:42278208) opens a repurposing route independent of driver genetics — HER2-low ADC payload delivery in GC/GEJ — though diffuse-type tumours are classically HER2-negative [KNOWN], so the real question is surface-antigen density (CLDN18.2 [KNOWN]) in αE-catenin/E-cadherin-null cells. P9/P10 confirm early-onset gastroesophageal cancer is enriched for poorly cohesive histology and hereditary syndromes (4.3% of EO cases, PMID:41893978) but supply no target. P5, P6, P8 are off-target for this programme. MAP3K6, despite the KG anchor, has zero support in this pack — parked, not a lead.\n\nFour leads open. Next visit must (i) find or fail to find direct isogenic evidence for a druggable dependency in CDH1-null and CTNNA1-null gastric epithelium, (ii) test whether CTNNA1-null tumours share the spindle phenotype, and (iii) establish whether cfDNA/methylation (T2, NCT06726642) can detect intramucosal pT1a SRCC — I expect it cannot, and saying so would retire a tempting surveillance lead.","leadChanges":[{"id":"L1","title":"Spindle-orientation dependency as synthetic lethal partner of adherens-junction loss in CDH1/CTNNA1-null gastric epithelium","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L2","title":"NMD-based functional classification of CTNNA1 variants as the gate for risk-reducing decisions","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L3","title":"TLS-induction / Treg-depletion combination required for any immunotherapy in diffuse and signet-ring gastric cancer","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"Surface-antigen payload delivery (HER2-low ADC, CLDN18.2) as genotype-agnostic systemic option in diffuse gastric cancer","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Is there published isogenic evidence of a druggable synthetic-lethal dependency in CDH1-null or CTNNA1-null gastric epithelium (ROS1, PI3K/AKT, spindle/mitotic), and do CDH1- and CTNNA1-null cells converge on the same vulnerability?","Do CTNNA1-null DGCs show the same mitotic spindle misorientation and progenitor displacement that PMID:41517846 attributes to E-cadherin loss, or is the phenotype CDH1-specific?","What is the measured HER2-low and CLDN18.2 antigen prevalence specifically in poorly cohesive/signet-ring and HDGC-derived tumours, and does adherens-junction loss change ADC internalisation?","Can tertiary lymphoid structure maturation or CXCL13 be pharmacologically restored in signet-ring gastric models, and with which agent class?","Can cfDNA/methylation assays (NCT06726642) detect intramucosal pT1a SRCC in CDH1/CTNNA1 carriers, or is tumour burden below detection - i.e. should a cfDNA surveillance lead be opened or pre-emptively retired?","Is there any evidence at all supporting MAP3K6 as an HDGC predisposition or maintenance gene, or should the KG anchor be formally parked?"],"nextQueries":["(CDH1 OR \"E-cadherin\") AND (\"synthetic lethal\" OR ROS1 OR crizotinib OR entrectinib OR \"spindle orientation\") AND gastric AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(CLDN18.2 OR \"claudin 18.2\" OR \"HER2-low\") AND (\"diffuse gastric\" OR \"signet ring\" OR \"poorly cohesive\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"tertiary lymphoid structure\" OR CXCL13 OR CCR8) AND gastric AND (induction OR agonist OR \"Treg depletion\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"40998418","doi":"10.1136/gutjnl-2024-334601","year":2026,"isNew":true,"title":"Hereditary diffuse gastric cancer spectrum associated with germline &lt;i&gt;CTNNA1&lt;/i&gt; loss of function revealed by clinical and molecular data from 351 carrier families and"},{"pmid":"41517846","doi":"10.5230/jgc.2026.26.e5","year":2026,"isNew":true,"title":"The Changing Landscape of Hereditary Diffuse Gastric Cancer"},{"pmid":"42419310","doi":"10.1016/j.suc.2026.03.006","year":2026,"isNew":true,"title":"Role of Genetics in Gastric Malignancy: Screening, Prevention and Treatment"},{"pmid":"41902313","doi":"10.1002/ijc.70416","year":2026,"isNew":true,"title":"Immune, molecular and genetic profiles of gastric signet ring cell carcinoma: Recent progress and future challenges"},{"pmid":"42238721","doi":"10.14309/crj.0000000000002156","year":2026,"isNew":true,"title":"Multifocal Small Bowel Gastrointestinal Stromal Tumors and Concurrent Neuroendocrine Tumor in Neurofibromatosis Type 1"},{"pmid":"42136974","doi":"10.1515/almed-2025-0169","year":2026,"isNew":true,"title":"Carcinocythemia detection in peripheral blood smears: a literature review"},{"pmid":"42278208","doi":"10.3390/ijms27114673","year":2026,"isNew":true,"title":"HER2-Low Gastric and Gastroesophageal Junction Adenocarcinoma: From Assessment to Treatment Strategies"},{"pmid":"41969585","doi":"10.3892/ol.2026.15556","year":2026,"isNew":true,"title":"Whole-exome sequencing unveils novel potential gene mutations involved in primary renal small cell carcinoma"},{"pmid":"41950398","doi":"10.1093/jncics/pkag034","year":2026,"isNew":true,"title":"Molecular characteristics and clinical outcomes of patients with gastroesophageal cancer diagnosed at ages younger than 50 years"},{"pmid":"41893978","doi":"10.1007/s10120-026-01724-z","year":2026,"isNew":true,"title":"Early- versus late-onset gastroesophageal cancer: real-world outcomes from a 13-year central European cohort study"}],"trialsShown":[{"nct":"NCT05126290","phase":"n/a","status":"RECRUITING","isNew":true,"title":"CTNNA1 Familial Expansion Study"},{"nct":"NCT06726642","phase":"n/a","status":"RECRUITING","isNew":true,"title":"CfDNA in Hereditary And High-risk Malignancies 2"}],"usage":{"input":7467,"output":6097},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"hereditary diffuse gastric cancer\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"hereditary diffuse gastric cancer\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:40998418","PMID:41517846","PMID:42419310","PMID:41902313","PMID:42238721","PMID:42136974","PMID:42278208","PMID:41969585","PMID:41950398","PMID:41893978","NCT05126290","NCT06726642"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787159948230","cycle":56,"visit":1,"ts":"2026-08-19T17:19:08.230Z","cancer":{"key":"hereditary breast and ovarian cancer syndrome","name":"hereditary breast and ovarian cancer syndrome","mondo":{"id":"MONDO:0003582","name":"hereditary breast ovarian cancer syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Gate PARP inhibitor use in non-BRCA HBOC carriers (PALB2/RAD51C/RAD51D vs ATM/CHEK2) by a functional HR readout — RAD51 foci plus genomic HRD scar — rather than by germline gene label, and test ATR/WEE1 inhibition as the alternative for checkpoint-gene carriers.","confidence":0.45,"notebook":"**Visit 1 — programme initialisation.** The pack is, therapeutically, near-empty: seven of eight papers and eight of eight trials are genetics/screening/registry infrastructure, not intervention. P4 (PMID:40918841, breast-awareness education) has zero mechanistic content — recorded so the desk never mines it again. More usefully, the query term \"hereditary breast and ovarian cancer syndrome\" itself is the problem: therapy literature indexes under *BRCA1/2*, *HRD*, *PARP inhibitor*, not under the syndrome label. Next visit's queries are re-pointed accordingly.\n\nWhat does move. P6 (PMID:41528496) formalises HBOC as a gene *panel* syndrome — PALB2, ATM, BARD1, CHEK2, BRIP1, RAD51C, RAD51D alongside BRCA1/2 — and states germline status now steers treatment. Mechanistically these are not equivalent: PALB2, RAD51C, RAD51D sit in the BRCA-axis core (PALB2 as the BRCA1–BRCA2 bridge; RAD51 paralogues loading the filament), so biallelic loss should phenocopy BRCA-null synthetic lethality with PARP trapping [KNOWN], whereas ATM/CHEK2 act upstream in checkpoint signalling and are poor PARPi predictors [KNOWN] — plausibly better matched to ATR/WEE1 inhibition. The actionable inference: gene label is a weak surrogate; a functional HR readout (RAD51 nuclear foci in cycling tumour cells, HRD genomic scar) should gate PARPi in non-BRCA carriers. P5 (PMID:41899580) puts germline BRCA2 at up to 22-fold pancreatic risk with BRCA1/ATM moderate — the same lead extends across organs (platinum backbone then PARPi maintenance) [KNOWN]. P8 (PMID:42272637) nominally supports HRD prostate biology in Arab men, but 47.5% BRCA1 and 55% BRCA2 \"mutation\" rates with ~65% homozygosity from 40 FFPE blocks is not credible as pathogenic burden; I read those as common variants/FFPE deamination artefact and weight the paper near zero. Abstract-only, so this is an inference, not a refutation.\n\nTwo interception leads open. P2 (PMID:41620477) shows plasma metabolomes separate healthy heterozygous HRR carriers from non-carriers with gene-specific models >80% — implying monoallelic HRR loss has a systemic metabolic phenotype, i.e. haploinsufficiency is not silent. P3 (PMID:41876608) reaches AUC 0.98 for \"BRCAness\" from serum miRNA plus clinical data with an independent-cohort risk correlation of R=0.93; the AUC is high enough to suspect leakage/overfitting, but the second cohort is the interesting part. Together these are candidate enrichment tools for prevention trials and for timing risk-reducing surgery, which NCT02760849 is already testing as salpingectomy-first de-escalation. P7 (PMID:42016816) flags MINAS (BRCA2+MLH1, ~1.37% of hereditary cancer patients): therapy must follow each tumour's own deficiency (HRD→PARPi vs MMRd→checkpoint), not the germline list; n=1, so hypothesis only.\n\nNo promotions are possible on visit 1; four leads open at LEAD.","leadChanges":[{"id":"L1","title":"Functional-HRD gating, not gene label, for PARPi in non-BRCA1/2 HBOC genes","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"Circulating BRCAness signatures (metabolome + miRNA) to enrich and time interception in HBOC carriers","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L3","title":"MINAS: tumour-deficiency-matched rather than germline-list-matched therapy","level":"LEAD","status":"NEW","confidence":0.28},{"id":"L4","title":"Founder-allele cohorts as ready-made, genotype-uniform interception and pharmacodynamic populations","level":"LEAD","status":"NEW","confidence":0.22}],"unverifiedCitations":0,"openQuestions":["Does biallelic PALB2/RAD51C/RAD51D loss produce PARPi sensitivity equal to BRCA1/2 in prospective data, and do ATM/CHEK2 carriers genuinely fail PARPi while responding to ATR/WEE1 inhibition?","Is RAD51-foci immunofluorescence (or an HRD scar) validated as a treatment-gating assay in non-BRCA HBOC genes, and what is its concordance with germline gene label?","What are the dominant clinical resistance routes in germline-HBOC tumours progressing on PARPi — reversion alleles versus 53BP1/shieldin loss versus efflux — and are they detectable in ctDNA before radiographic progression?","Do the circulating BRCAness classifiers (metabolome, miRNA) survive strict independent-cohort validation, and is the metabolic shift in heterozygous carriers causal or epiphenomenal?","In MINAS patients, does lesion-directed therapy (MMRd->checkpoint, HRD->PARPi) outperform germline-list-directed therapy?","Which non-PARP synthetic-lethal partners of BRCA1/2 loss (POLQ/Pol-theta, USP1, ATR) have 2023-2026 clinical readouts worth opening as leads?"],"nextQueries":["(PALB2 OR RAD51C OR RAD51D OR BARD1) AND (\"PARP inhibitor\" OR olaparib OR niraparib OR talazoparib) AND (response OR sensitivity OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"BRCA1\" OR \"BRCA2\") AND (\"reversion mutation\" OR \"53BP1\" OR shieldin OR \"restored homologous recombination\") AND (\"PARP inhibitor resistance\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"polymerase theta\" OR POLQ OR novobiocin OR \"USP1 inhibitor\" OR \"ATR inhibitor\" OR ceralasertib) AND (\"homologous recombination deficient\" OR BRCA) AND (\"synthetic lethal\" OR trial) AND SRC:MED AND PUB_YEAR:[2023 TO 202"],"papersShown":[{"pmid":"41521709","doi":"10.1002/mgg3.70144","year":2026,"isNew":true,"title":"Identifying a Recurrent BRCA1 Variant in the Qatari Population With Unique Genotype-Phenotype Correlations"},{"pmid":"41620477","doi":"10.1038/s41598-026-35789-8","year":2026,"isNew":true,"title":"Metabolomic-driven prediction of the mutational status of healthy individuals with a family history of hereditary breast and ovarian cancer syndrome: the HRRmet study"},{"pmid":"41876608","doi":"10.1038/s41598-026-45020-3","year":2026,"isNew":true,"title":"A lasso-based model combining miRNA and clinical variables predicts future risk of breast and ovarian cancer"},{"pmid":"40918841","doi":"10.7759/cureus.89378","year":2025,"isNew":true,"title":"Evaluating the Effectiveness of an Educational Awareness Program Through Knowledge Change: A Cross-Sectional Study Promoting Breast Awareness"},{"pmid":"41899580","doi":"10.3390/cancers18060976","year":2026,"isNew":true,"title":"Genetic Predisposition to Pancreatic Cancer: A Systematic Review of Hereditary Syndromes and Familial Aggregation"},{"pmid":"41528496","doi":"10.1007/s00404-025-08270-6","year":2026,"isNew":true,"title":"Genetic tumor syndromes in female cancer: insights into inherited cancer predisposition and clinical implications"},{"pmid":"42016816","doi":"10.1155/crom/3353129","year":2026,"isNew":true,"title":"Multilocus Inherited Neoplasia Alleles Syndrome in a Patient With BRCA2-Associated Breast Cancer and MLH1-Related Lynch Syndrome"},{"pmid":"42272637","doi":"10.3389/fcell.2026.1737736","year":2026,"isNew":true,"title":"Comprehensive &lt;i&gt;BRCA1/2&lt;/i&gt; mutation landscape in prostate cancer in the UAE and Arab population"}],"trialsShown":[{"nct":"NCT02302742","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry"},{"nct":"NCT03246841","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes."},{"nct":"NCT02760849","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations"},{"nct":"NCT04494945","phase":"NA","status":"RECRUITING","isNew":true,"title":"Identifying and Caring for Individuals With Inherited Cancer Syndrome"},{"nct":"NCT06914726","phase":"NA","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Patient Centered Clinical Decision Support for Hereditary Cancer Syndromes"},{"nct":"NCT02012699","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Integrated Cancer Repository for Cancer Research"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT04009148","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Cascade Testing in Families With Newly Diagnosed Hereditary Breast and Ovarian Cancer Syndrome"}],"usage":{"input":7736,"output":6658},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"hereditary breast and ovarian cancer syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"hereditary breast and ovarian cancer syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41521709","PMID:41620477","PMID:41876608","PMID:40918841","PMID:41899580","PMID:41528496","PMID:42016816","PMID:42272637","NCT02302742","NCT03246841","NCT02760849","NCT04494945","NCT06914726","NCT02012699","NCT03050268","NCT04009148"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787159688389","cycle":55,"visit":1,"ts":"2026-08-19T17:14:48.389Z","cancer":{"key":"familial adenomatous polyposis","name":"familial adenomatous polyposis","mondo":{"id":"MONDO:0021055","name":"classic familial adenomatous polyposis"}},"control":false,"modelLabel":"SCIENCE","summary":"eRapa's phase II FAP data (PMID:42048421) missed its colorectal primary endpoint but showed a duodenal-specific, intermittent-dosing signal — so the programme should pursue duodenal polyp burden as the primary chemoprevention endpoint while tracking three mechanistically distinct FAP-directed agents","confidence":0.55,"notebook":"Programme initiated. The pack is unusually trial-rich for a chemoprevention indication, so the desk starts with four druggable nodes hanging off the single anchor APC [GERMLINE, causal; second-hit somatic in polyps].\n\nMost actionable: encapsulated rapamycin. The phase II (PMID:42048421) enrolled 30 FAP patients across three schedules; 97% completed, bioavailability predictable, but the primary colorectal polyp burden endpoint did **not** reach significance in any cohort (best −39.4%, P=0.28). The only nominally significant signal was duodenal polyp burden reduction with intermittent dosing (P=0.04), and toxicity clustered in the daily arm — i.e. an apparently non-monotonic schedule–effect relationship, which I read as feedback reactivation (S6K→IRS-1 relief, AKT rebound, incomplete 4E-BP1 suppression) under continuous low-dose mTORC1 inhibition [INFERRED; mTORC1 hyperactivation downstream of Wnt/β-catenin in Apc-mutant adenomas is [KNOWN]]. The duodenal signal matters disproportionately because duodenal and pancreatic cancer dominate residual mortality after prophylactic colectomy (PMID:42101961). eRapa is already in phase 3 (NCT06950385), so this is a LEAD whose fate is externally determined; the desk's value-add is the duodenum-first endpoint argument and the schedule question.\n\nSecond: direct pharmacology at the lesion itself. FOG-001 (NCT05919264) is a first-in-class β-catenin:TCF interaction blocker [KNOWN] — the only agent here that targets the exact node released by APC loss rather than a downstream branch. The therapeutic window IS the whole argument: canonical Wnt is obligatory for intestinal crypt stem cell renewal and bone homeostasis [KNOWN], so I expect crypt hypoplasia/diarrhoea as dose-limiting and predicted resistance via Wnt-independent β-catenin output (YAP/TAZ, or TCF-independent transcription). Third: REC-4881 (NCT05552755) is a FAP-dedicated placebo-controlled trial of an allosteric MEK1/2 inhibitor [KNOWN] — MAPK output is required for adenoma progression in Apc-mutant epithelium, but whether it lowers Wnt target output or acts on stroma is unresolved from the registry entry alone. Fourth, lower conviction: ONC201/dordaviprone as a prevention agent (NCT05630794), mechanism ClpP agonism/ISR induction [KNOWN], no efficacy data yet.\n\nRecorded for the notebook so it is not re-proposed naively: PRNP ablation cuts Apc^Min/+ tumour burden but *worsens* AOM/DSS colitis-associated carcinogenesis via sustained NF-κB and M1 macrophage persistence (PMID:42364787) — anti-PrP repurposing into an inflamed polyposis mucosa carries a directional hazard. Desmoid disease is now a listed primary indication for intestinal transplantation (PMID:42324901) with morbidity illustrated by ureteric obstruction (PMID:42577576): a pharmacological desmoid lead is the clearest unmet need in FAP, and I have no drug-level citation for it yet.\n\nNothing promotes above LEAD this visit; single evidence-bearing visit.","leadChanges":[{"id":"L1","title":"Intermittent-schedule mTORC1 inhibition (eRapa) targeted at duodenal rather than colorectal polyp burden in FAP","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"Direct beta-catenin:TCF interface blockade (FOG-001) as node-matched therapy for APC-null neoplasia","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"MEK1/2 inhibition (REC-4881) in FAP polyposis","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"ONC201/dordaviprone as a mechanistically orthogonal colorectal adenoma prevention agent","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L5","title":"FAP-associated intra-abdominal desmoid: pharmacological control to displace multivisceral/intestinal transplantation","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["Does the eRapa duodenal signal (P=0.04, intermittent dosing) replicate in NCT06950385, and is the apparent inferiority of daily dosing explained by feedback AKT/S6K reactivation measurable in crypt biopsies?","Is there any published tolerability or pharmacodynamic data for FOG-001 that defines a beta-catenin:TCF blockade window compatible with normal intestinal crypt and bone Wnt dependence?","For REC-4881 in FAP, does MEK1/2 inhibition reduce Wnt/beta-catenin target gene output in adenomatous epithelium, or is the effect stromal/immune?","What is the current pharmacological evidence base for FAP-associated intra-abdominal desmoid (nirogacestat, sorafenib, methotrexate/vinorelbine) that could pre-empt intestinal transplantation?","Do colibactin-producing pks+ E. coli, ETBF or F. nucleatum measurably accelerate adenoma progression specifically in APC-germline-mutant mucosa, and is decolonisation or fibre/polyphenol intervention testable as a prevention arm?","Are there modern combination chemoprevention data (COX-2 inhibitor or eicosapentaenoic acid plus mTOR or MEK inhibition) that beat single agents on duodenal endpoints?"],"nextQueries":["(\"familial adenomatous polyposis\" OR \"Apc(Min)\") AND (rapamycin OR sirolimus OR mTOR OR \"MEK inhibitor\" OR REC-4881) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"desmoid\" AND (\"familial adenomatous polyposis\" OR FAP)) AND (nirogacestat OR \"gamma-secretase\" OR sorafenib OR \"systemic therapy\") AND SRC:MED AND PUB_YEAR:[2021 TO 2026]","(\"beta-catenin\" AND (\"TCF\" OR \"transcription inhibitor\" OR tankyrase OR \"porcupine\")) AND (\"APC mutant\" OR \"colorectal\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42488318","doi":"10.1007/s40200-026-02016-0","year":2026,"isNew":true,"title":"APC alterations in papillary thyroid carcinoma: molecular mechanisms, clinical implications, and future perspective"},{"pmid":"42083308","doi":"10.1080/19490976.2026.2664684","year":2026,"isNew":true,"title":"Gut microbiota and diet in colorectal cancer: Converging determinants of carcinogenesis"},{"pmid":"42048609","doi":"10.1080/15592294.2026.2660022","year":2026,"isNew":true,"title":"&lt;i&gt;NOS1&lt;/i&gt; hypermethylation may participate in the colorectal cancer development and be associated with its prognosis"},{"pmid":"42364787","doi":"10.1016/j.bbadis.2026.168334","year":2026,"isNew":true,"title":"Cellular prion protein suppresses colitis and colorectal carcinogenesis via modulating inflammatory responses"},{"pmid":"42522924","doi":"10.1111/den.70250","year":2026,"isNew":true,"title":"Endoscopic Papillectomy for Ampullary Tumors in Older Patients: Balancing Oncologic Benefit and Geriatric Risk"},{"pmid":"42419310","doi":"10.1016/j.suc.2026.03.006","year":2026,"isNew":true,"title":"Role of Genetics in Gastric Malignancy: Screening, Prevention and Treatment"},{"pmid":"42324901","doi":"10.1097/mot.0000000000001298","year":2026,"isNew":true,"title":"Intestinal transplantation for tumors"},{"pmid":"42048421","doi":"10.1158/1078-0432.ccr-25-4126","year":2026,"isNew":true,"title":"Phase II Trial of Encapsulated Rapamycin to Reduce Polyp Burden Associated with Familial Adenomatous Polyposis"},{"pmid":"42577576","doi":"10.1002/ccr3.73328","year":2026,"isNew":true,"title":"Obstructive Pyelonephritis Secondary to Ureteral Compression by an Intra-Abdominal Desmoid Tumor in Familial Adenomatous Polyposis: A Case Report"},{"pmid":"42101961","doi":"10.1111/apm.70191","year":2026,"isNew":true,"title":"Familial Adenomatous Polyposis-Risk of Cancer, Cancer Prevention, and Long-Term Consequences: Learnings from Five Decades with the Danish Polyposis Register"}],"trialsShown":[{"nct":"NCT05919264","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"FOG-001 in Locally Advanced or Metastatic Solid Tumors"},{"nct":"NCT07726771","phase":"NA","status":"RECRUITING","isNew":true,"title":"Evaluation of the Ileo-anal Pouch in FAP (ENDOPOL)"},{"nct":"NCT02012699","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Integrated Cancer Repository for Cancer Research"},{"nct":"NCT07066046","phase":"NA","status":"RECRUITING","isNew":true,"title":"Artificial Intelligence-assisted Colonoscopy in the Detection and Characterization of Colorectal Lesions"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT05630794","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Testing for Safety and Colorectal Cancer Preventive Effects of ONC201"},{"nct":"NCT05552755","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Evaluate REC-4881 in Participants With Familial Adenomatous Polyposis (FAP)"},{"nct":"NCT06950385","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Phase 3 Trial of eRapa in Patients With Familial Adenomatous Polyposis"}],"usage":{"input":7874,"output":6160},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"familial adenomatous polyposis\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"familial adenomatous polyposis\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42488318","PMID:42083308","PMID:42048609","PMID:42364787","PMID:42522924","PMID:42419310","PMID:42324901","PMID:42048421","PMID:42577576","PMID:42101961","NCT05919264","NCT07726771","NCT02012699","NCT07066046","NCT03050268","NCT05630794","NCT05552755","NCT06950385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787159478152","cycle":54,"visit":1,"ts":"2026-08-19T17:11:18.152Z","cancer":{"key":"lynch syndrome","name":"Lynch syndrome","mondo":{"id":"MONDO:0005835","name":"Lynch syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise low-dose aspirin chemoprevention (CaPP3) and genotype-agnostic neoadjuvant/organ-sparing checkpoint blockade in germline MMR carriers, and interrogate the TGFBR2-frameshift asymmetry as a cell-therapy engineering handle.","confidence":0.58,"notebook":"Visit 1 opens the programme. The pack is mostly noise for this target (P2–P5 are endometrial biomarker, fertility-preservation, bladder and pancreatic-EV reviews with only incidental Lynch mentions; P10 is a single unconfirmed Amsterdam-II case). Four things are usable.\n\nFirst, chemoprevention. CaPP3 (PMID:42425127) is the first randomised dose-de-escalation trial in carriers, comparing 100 mg and 300 mg against the CAPP2-validated 600 mg daily, primary endpoint new primary dMMR cancers. The abstract in the pack is truncated before results — I cannot state whether non-inferiority was met, and I will not infer it. Mechanistically aspirin plausibly acts through platelet COX-1/PGE2–EP2/EP4 suppression and reduced WNT–β-catenin output in crypt stem cells [KNOWN], with a possible immune-surveillance component specific to frameshift-neoantigen-bearing clones [SPECULATIVE]. This is the highest-value lead because the agent is approved, cheap, and the population is defined by [GERMLINE] MLH1/MSH2/MSH6/PMS2/EPCAM status.\n\nSecond, organ-sparing immunotherapy. P8 frames neoadjuvant/immuno-ablative ICI in MSI-H/dMMR disease as a surgery-sparing paradigm, directly relevant to the extended-versus-segmental resection dilemma reviewed in P6; ATOMIC (NCT02912559) anchors the adjuvant dMMR question. P9 is the important discipline point: across 93 Lynch patients with MSI-H digestive cancers, PFS at 24 months was 81.5% (MLH1), 67.2% (MSH2/EPCAM), 78.6% (MSH6), with no significant gene or variant-class effect; only ECOG ≥2 mattered. Record this as a closed door — do not propose germline-genotype-stratified ICI trials. Small single-centre cohort, so it excludes large effects only.\n\nThird, frameshift-peptide vaccination for primary prevention is flagged as promising in P6 but with no data in this pack; it stays a low-confidence LEAD.\n\nFourth, a genuinely new mechanistic hook: NCT07411599 puts TROP2-directed CAR-NK cells with TGFBR2 knockout into CRC peritoneal carcinomatosis. TGFBR2 is the Monarch [SOMATIC] correlate here, and its A10 coding microsatellite is a canonical frameshift target in MSI tumours [KNOWN] — so the tumour is already TGF-β-blind while effector cells are not. TGFBR2-KO effectors exploit exactly that asymmetry [INFERRED]. Normal-tissue caveat: TGFBR2 loss in the lymphoid compartment risks autoimmunity/lymphoproliferation, so the window depends on transient, dose-controlled cell products.\n\nNext I need CaPP3 effect sizes, dMMR-specific neoadjuvant ICI organ-preservation durability with ctDNA/stool surveillance (NCT05410977), and resistance genetics (B2M, JAK1/2, HLA LOH) in Lynch versus sporadic MLH1-methylated tumours.","leadChanges":[{"id":"L1","title":"Low-dose aspirin (100-300 mg) for chemoprevention of dMMR cancers in germline MMR carriers","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"Genotype-agnostic neoadjuvant / immuno-ablative PD-1 blockade as an organ-sparing strategy in Lynch-associated MSI-H tumours","level":"LEAD","status":"NEW","confidence":0.62},{"id":"L3","title":"Frameshift-peptide neoantigen vaccination for primary/secondary prevention in MMR carriers","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L4","title":"Exploit the TGFBR2-frameshift asymmetry: TGFBR2-knockout effector cell therapy in MSI-H/dMMR colorectal disease","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["What were the actual per-dose dMMR cancer incidence rates, non-inferiority margin and bleeding harms in CaPP3, and does the effect differ by MMR gene or BMI?","In dMMR/Lynch colorectal and endometrial cancer, what fraction of neoadjuvant ICI patients achieve durable organ preservation, and what is the ctDNA/stool-negative recurrence rate that would license watch-and-wait?","How frequent are B2M, JAK1/2 and HLA-LOH escape events in Lynch-associated versus sporadic MLH1-hypermethylated MSI-H tumours, and is there a salvage strategy (IL-2/NK-based, oncolytic) for MHC-I-null escape?","Is there any human immunogenicity or adenoma-incidence data for frameshift-peptide vaccines in unaffected MMR carriers, and can it be combined with aspirin?","Does tumour TGFBR2 A10 frameshift status predict benefit from TGF-beta-pathway-edited cell therapy or TGF-beta blockade in MSI-H disease?","Are colibactin-producing pks+ E. coli or F. nucleatum enriched in MMR-carrier adenomas specifically, making microbiome/diet modification a carrier-directed prevention lever rather than a general CRC one?"],"nextQueries":["(\"Lynch syndrome\" OR \"mismatch repair deficient\") AND (\"frameshift peptide\" OR \"neoantigen vaccine\" OR Nous-209) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"MSI-H\" OR dMMR) AND (\"neoadjuvant\" OR \"organ preservation\" OR \"watch and wait\") AND (pembrolizumab OR dostarlimab OR nivolumab) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"MSI-H\" OR dMMR) AND (resistance) AND (B2M OR JAK1 OR \"HLA loss of heterozygosity\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42083308","doi":"10.1080/19490976.2026.2664684","year":2026,"isNew":true,"title":"Gut microbiota and diet in colorectal cancer: Converging determinants of carcinogenesis"},{"pmid":"42033293","doi":"10.1080/20565623.2026.2658215","year":2026,"isNew":true,"title":"Serum HE4 and polymorphisms in MMP9 and MMP13 associated with survival outcome in patients with endometrial carcinoma: a retrospective cohort study and nomogram development"},{"pmid":"41985078","doi":"10.1080/07853890.2026.2650869","year":2026,"isNew":true,"title":"Advances in the application of assisted reproductive technology in fertility preservation for female patients with malignant tumours of the reproductive systems"},{"pmid":"41661092","doi":"10.1080/20565623.2026.2622297","year":2026,"isNew":true,"title":"Diagnosis, evaluation, and management of patients with non-muscle invasive bladder cancer"},{"pmid":"42398175","doi":"10.1016/j.intimp.2026.117102","year":2026,"isNew":true,"title":"The immunopharmacological role of B-cell and neutrophil-derived extracellular vesicles in pancreatic cancer: Mechanisms of inflammation, tumor progression, and potential therapeuti"},{"pmid":"42553833","doi":"10.1055/a-2760-7548","year":2026,"isNew":true,"title":"Extent of Surgery in Lynch Syndrome Associated Colorectal Cancer and Endometrial Cancer Risk Reduction: Seeing the Forest for the Trees"},{"pmid":"42425127","doi":"10.1016/s2468-1253(26)00114-7","year":2026,"isNew":true,"title":"Aspirin for cancer prevention in individuals with Lynch syndrome: first results from the CaPP3 multicentre, randomised, double-blind, non-inferiority trial"},{"pmid":"41460162","doi":"10.1002/ijc.70307","year":2026,"isNew":true,"title":"Organ-sparing strategies in patients with MSI/dMMR tumors including Lynch syndrome: Current state of the art and future perspectives for clinical decision-making"},{"pmid":"42001099","doi":"10.1186/s13053-026-00339-w","year":2026,"isNew":true,"title":"Impact of germline MMR gene variants on immune checkpoint inhibitors response in patients with MSI-H/dMMR digestive cancers: a retrospective cohort analysis"},{"pmid":"42181344","doi":"10.7759/cureus.107546","year":2026,"isNew":true,"title":"Complete Radiotherapy Response of Chemoresistant Para-Aortic Lymph Node Metastases in an Endometrial Cancer Patient Meeting the Amsterdam II Criteria for Lynch Syndrome"}],"trialsShown":[{"nct":"NCT05410977","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Collecting Blood and Stool Samples to Detect Colorectal Cancer or Advanced Neoplasia in Lynch Syndrome Patients"},{"nct":"NCT03805919","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Men at High Genetic Risk for Prostate Cancer"},{"nct":"NCT02978625","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers"},{"nct":"NCT02912559","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair"},{"nct":"NCT07411599","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Dual Administration Of Intraperitoneal And Intravenous TROP2-Directed CAR-NK With TGF-Beta Receptor 2 (TGFBR2) Knock Out (KO) Therapy For Co"},{"nct":"NCT07106359","phase":"NA","status":"RECRUITING","isNew":true,"title":"Initial Testing of a Behavioral Intervention About Genetic Services for Families at Risk of Lynch Syndrome"},{"nct":"NCT02359565","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas,"},{"nct":"NCT04494945","phase":"NA","status":"RECRUITING","isNew":true,"title":"Identifying and Caring for Individuals With Inherited Cancer Syndrome"}],"usage":{"input":8668,"output":5653},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Lynch syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Lynch syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42083308","PMID:42033293","PMID:41985078","PMID:41661092","PMID:42398175","PMID:42553833","PMID:42425127","PMID:41460162","PMID:42001099","PMID:42181344","NCT05410977","NCT03805919","NCT02978625","NCT02912559","NCT07411599","NCT07106359","NCT02359565","NCT04494945"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787159279346","cycle":53,"visit":1,"ts":"2026-08-19T17:07:59.346Z","cancer":{"key":"li-fraumeni syndrome","name":"Li-Fraumeni syndrome","mondo":{"id":"MONDO:0018875","name":"Li-Fraumeni syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"In germline TP53 breast cancer ERBB2 amplification is the sole recurrent co-driver and the apoptotic arm (BAX/TP53I3) is transcriptionally dead, so HER2-directed antibody backbones plus p53-independent death induction — not genotoxic therapy — are the priority leads for Li-Fraumeni syndrome.","confidence":0.5,"notebook":"Visit 1 opens the programme with one genuinely informative dataset and one allele-specific mechanism; the rest of the pack is surveillance infrastructure and off-target case reports.\n\nThe anchor is P4 (PMID:42168203). Germline TP53 breast cancers are near-uniformly biallelic at TP53 and, crucially, carry **no recurrent oncogenic co-driver except ERBB2 amplification** — so HER2 is the only conventional direct target the disease offers, and it is actionable today with trastuzumab/pertuzumab, T-DXd or tucatinib. That matters more in LFS than elsewhere because P7 (PMID:42546295) documents deliberate deferral of radiotherapy in a germline TP53 p.R196* carrier, and P2 (PMID:41652616) frames syndrome-driven osteosarcoma as partly a therapy-induced problem: every lead in this programme must be scored on genotoxic burden, since ionizing radiation and alkylators/anthracyclines carry second-malignancy cost in carriers [KNOWN]. HER2-directed antibody backbones are the rare cytotoxic-sparing option.\n\nSecond, P4's phenotype is mechanistically specific: a high burden of *short amplified aneuploid segments*, present already in situ, escalating with invasion. That is a breakage-fusion-bridge/replication-stress signature [INFERRED], which nominates CIN-tolerance and replication-checkpoint nodes (ATR, WEE1, PKMYT1, KIF18A) as synthetic-lethal handles in a tumour whose driver is tumour-suppressor loss and therefore undruggable directly [SPECULATIVE for the specific node]. P4 also shows BAX and TP53I3 fail to be induced — the apoptotic arm is transcriptionally dead, so p53-independent death routes (BH3 mimetics, MCL-1 inhibition, SMAC mimetics) and redox collapse via the thioredoxin/TrxR1 axis reviewed in P1 (PMID:42155152) become the rational way to restore priming rather than trying to re-engage p53 targets.\n\nThird, P8 (PMID:41854379) establishes proof-of-principle for allele-stratified therapy in germline TP53: the African-centric P47S variant binds PIN1 excessively, depletes PIN1–cyclin D1 complexes, and sensitises liver cancer cells to colchicine-binding-site tubulin agents (lexibulin, colchicine, combretastatin A-4). Repurposing-first, and it argues the whole germline TP53 allele spectrum should be screened variant-by-variant rather than treated as one disease — consistent with P3 (PMID:41917811), which separates reactivators/refolders, mutant-p53 degraders and synthetic lethality as non-interchangeable strategies keyed to mutation class.\n\nThe decisive unknown: whether the second hit in LFS tumours preserves a missense protein (LOH retaining mutant) or eliminates it (nonsense/deletion). Reactivators such as Y220C-selective agents need retained protein [KNOWN]; degraders need GOF protein; neither works on p.R196*-type null tumours. Trial pack contains **zero interventional systemic-therapy studies** — only registries and whole-body MRI surveillance (NCT01443468, NCT04541654, NCT02950987, NCT03176836), which are nonetheless the biospecimen route to test these hypotheses. Recorded as a gap, not a lead.","leadChanges":[{"id":"L1","title":"ERBB2 amplification as the only recurrent actionable co-driver in germline TP53 breast cancer","level":"LEAD","status":"NEW","confidence":0.58},{"id":"L2","title":"Short-amplicon chromosomal instability as a synthetic-lethal handle (ATR/WEE1/PKMYT1/KIF18A) in TP53-null LFS tumours","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"Allele-specific vulnerability of germline TP53 variants: P47S-PIN1 axis and colchicine-site tubulin agents","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L4","title":"Restoring apoptotic priming p53-independently: BH3 mimetics and thioredoxin-system collapse in LFS tumours","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["In germline TP53 tumours, does the somatic second hit preserve a missense protein (LOH with retained mutant allele) or eliminate it (nonsense/frameshift/deletion) — i.e. what fraction of LFS tumours are even eligible for p53 reactivators (Y","Is ERBB2 amplification genuinely enriched in germline-TP53 breast cancer relative to sporadic premenopausal HER2+ rates, and can antibody-drug-conjugate-based, radiation- and anthracycline-sparing regimens achieve comparable control in carr","Which CIN-tolerance node (KIF18A, PKMYT1, WEE1, ATR) is selectively lethal in TP53-null models bearing the short-amplified-segment signature, and does the signature predict response better than TP53 status alone?","Does the P47S-PIN1 vulnerability generalise to canonical LFS alleles, and does direct PIN1 inhibition phenocopy the tubulin-agent sensitivity?","What is the normal-tissue window in carriers whose somatic cells are TP53-heterozygous — do ATR/WEE1 inhibitors, tubulin agents or TrxR1 inhibitors carry excess toxicity or mutagenic second-cancer risk in a haploinsufficient host?","Does the LFS-BC immune phenotype (low CD8 infiltration but higher proliferating cytotoxic T cells, declining with invasion) identify a checkpoint-blockade-responsive or STING-agonist-responsive window, particularly at the in situ stage?"],"nextQueries":["(\"germline TP53\" OR \"Li-Fraumeni\") AND (\"loss of heterozygosity\" OR \"second hit\" OR \"biallelic\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"TP53\" AND (\"KIF18A\" OR \"PKMYT1\" OR \"WEE1\" OR \"ATR inhibitor\") AND (\"chromosomal instability\" OR \"synthetic lethal\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"germline TP53\" OR \"Li-Fraumeni\") AND (\"HER2\" OR ERBB2 OR trastuzumab OR \"radiation-induced\" OR \"second malignancy\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"papersShown":[{"pmid":"42155152","doi":"10.1016/j.redox.2026.104209","year":2026,"isNew":true,"title":"Crosstalk of thioredoxin system and programmed cell death: from pathophysiology to novel therapy"},{"pmid":"41652616","doi":"10.1186/s13023-026-04243-3","year":2026,"isNew":true,"title":"Unraveling syndrome-driven osteosarcoma: genetic insights and therapeutic frontiers"},{"pmid":"41917811","doi":"10.1186/s11658-026-00907-x","year":2026,"isNew":true,"title":"Targeting mutant p53 in cancer: from mechanistic insights to therapeutic strategies"},{"pmid":"42168203","doi":"10.1038/s41467-026-73163-4","year":2026,"isNew":true,"title":"Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers"},{"pmid":"41877551","doi":"10.1080/20450907.2026.2641996","year":2026,"isNew":true,"title":"Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass C with &lt;i&gt;SYN2&lt;/i&gt;::&lt;i&gt;PPARG&lt;/i&gt; fusion in an older adult"},{"pmid":"41674328","doi":"10.1080/20450907.2026.2626299","year":2026,"isNew":true,"title":"Synchronous diagnosis of multicentric glioma with distinct isocitrate dehydrogenase molecular profiles: a case report"},{"pmid":"42546295","doi":"10.1097/dad.0000000000003398","year":2026,"isNew":true,"title":"Primary Cutaneous Anaplastic Large Cell Lymphoma in a Patient With Li Fraumeni Syndrome"},{"pmid":"41854379","doi":"10.1158/1541-7786.mcr-25-1297","year":2026,"isNew":true,"title":"A Personalized Therapeutic Approach for Liver Cancers Expressing the African-Centric P47S Variant of TP53"},{"pmid":"41762262","doi":"10.1007/s00330-026-12382-1","year":2026,"isNew":true,"title":"Prevalence of venous extension in malignant adrenal neoplasia: beyond primary tumors and identification of a novel imaging sign"},{"pmid":"41373161","doi":"10.1111/ijd.70206","year":2026,"isNew":true,"title":"Skin Cancer Predisposition Genes, Full-Body Skin Examinations, Familial Disclosure, and Genetic Testing Among High-Risk Individuals"}],"trialsShown":[{"nct":"NCT06888388","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Long-term Safety of Nipple Sparing Mastectomy in Women With High Penetrance Breast Cancer Susceptibility Genes in Breast Cancer"},{"nct":"NCT01143454","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Characterization of Patients With Uncommon Presentations and/or Uncommon Diseases Associated With the Cardiovascular System"},{"nct":"NCT01443468","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Clinical and Genetic Studies of Li-Fraumeni Syndrome"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"},{"nct":"NCT03176836","phase":"NA","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Li-Fraumeni Syndrome Imaging Study"},{"nct":"NCT05126810","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Willingness to Participate in a Trial Comparing Standard Genetic Counseling Versus Personalized Genetic Counseling"},{"nct":"NCT04541654","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress"},{"nct":"NCT02950987","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Screening With Whole Body MRI For Detection Of Primary Tumors In Children And Adults With Li-Fraumeni Syndrome (LFS) And Other Cancer Predis"}],"usage":{"input":8284,"output":7310},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Li-Fraumeni syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Li-Fraumeni syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42155152","PMID:41652616","PMID:41917811","PMID:42168203","PMID:41877551","PMID:41674328","PMID:42546295","PMID:41854379","PMID:41762262","PMID:41373161","NCT06888388","NCT01143454","NCT01443468","NCT03050268","NCT03176836","NCT05126810","NCT04541654","NCT02950987"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787159058791","cycle":52,"visit":1,"ts":"2026-08-19T17:04:18.791Z","cancer":{"key":"systemic mastocytosis","name":"systemic mastocytosis","mondo":{"id":"MONDO:0016586","name":"systemic mastocytosis"}},"control":false,"modelLabel":"SCIENCE","summary":"Anchor the SM programme on KIT D816V-selective, CNS-sparing inhibition (elenestinib, bezuclastinib) with KIT VAF as the pharmacodynamic endpoint, while treating SRSF2/ASXL1/RUNX1/TET2/CBL co-mutations as a separate, non-KIT-addicted compartment requiring clone-directed combination logic.","confidence":0.62,"notebook":"Visit 1 opens the programme on a pack that is largely retrieval noise: P1 (microneedles), P2 (rituximab in IgA nephropathy), P3 (gut–lung axis), P4 (neem), P5–P7 (behavioural/nursing), P8 (thyroid exosomal SPP1) carry no inferential weight for mast cell neoplasia and are logged as off-target so they are not re-mined. Two papers and five trials are usable.\n\nMechanistic spine (P9, PMID:42512272): SM is a monogenic-driver clonal MC neoplasm — KIT D816V [SOMATIC] in >95%, ligand-independent autophosphorylation driving constitutive KIT signalling, survival and apoptosis resistance; the Monarch anchor set (TET2, SRSF2, ASXL1, CBL, RUNX1) is confirmed as co-occurring [SOMATIC] CHIP-context lesions conferring aggressive phenotype and independent adverse prognosis, not germline predisposition. This gives the desk a clean two-compartment model: the KIT-addicted MC compartment (directly druggable oncogene → type I inhibition) versus the myeloid co-mutant compartment (tumour-suppressor/spliceosome loss → not directly druggable, requires clone-directed or synthetic-lethal logic). Do not conflate the two: a KIT inhibitor should debulk MCs and mediator burden without clearing an SRSF2/ASXL1/RUNX1 clone. [INFERRED]\n\nTherapeutic landscape from trials: two independent sponsors are running randomised placebo-controlled programmes in *indolent* SM — elenestinib/BLU-263 (NCT04910685, ph2/3) and bezuclastinib/CGT9486 (NCT05186753, ph2) — plus bezuclastinib in advanced SM (NCT04996875) and a Blueprint ISM natural-history study (NCT07264959). The interesting design hypothesis is therapeutic-window engineering rather than novel target: KIT is required in normal haematopoietic progenitors, germ cells, melanocytes and interstitial cells of Cajal [KNOWN], and CNS-penetrant KIT inhibition carries cognitive/intracranial-haemorrhage liability [KNOWN]; both next-generation agents are positioned as more selective/peripherally restricted. Lead L1 is therefore about D816V selectivity + CNS exclusion enabling treatment of indolent disease, with molecular (VAF) response as the pharmacodynamic readout.\n\nL2 (co-mutation-directed combination) and L3 (surface antigen targeting: CD25/CD2/CD30 aberrancy is diagnostic per P9, so CD30 ADC and CD123×CD3 engagers such as MGD024, NCT05362773, are testable) are lower-confidence and explicitly flagged: I hold background knowledge that single-agent brentuximab vedotin was underwhelming in CD30+ mastocytosis [KNOWN] and MGD024's SM eligibility is inferred from retrieval, not stated in the record shown — both must be verified before any promotion.\n\nP10 (PMID:42326297) is a single case of non-cirrhotic portal hypertension with variceal bleeding from hepatic MC infiltration — anecdotal, but it defines an unmet endpoint: whether infiltrative organ damage/fibrosis is reversible under KIT blockade, which no pack trial answers.\n\nNo lead earns CANDIDATE this visit; all are first-touch.","leadChanges":[{"id":"L1","title":"D816V-selective, CNS-restricted KIT inhibition to extend targeted therapy into indolent SM","level":"LEAD","status":"NEW","confidence":0.8},{"id":"L2","title":"Co-mutant myeloid clone (SRSF2/ASXL1/RUNX1/TET2/CBL) as a KIT-independent compartment in advanced SM and SM-AHN","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L3","title":"Surface-antigen (CD30 / CD123) targeting of neoplastic mast cells","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Do elenestinib and bezuclastinib achieve deeper KIT D816V VAF reduction and tryptase normalisation than avapritinib in indolent SM, and does peripheral restriction actually eliminate cognitive/intracranial-haemorrhage signals?","What are the documented acquired resistance mechanisms to type I KIT D816V inhibitors in SM (secondary KIT substitutions vs RAS-MAPK reactivation vs BCL2/MCL1 dependence), and are any pharmacologically addressable?","In advanced SM and SM-AHN, does KIT inhibition reduce SRSF2/ASXL1/RUNX1/TET2/CBL clone VAF, or only the KIT-mutant mast cell fraction?","Is there any published evidence for CD30-ADC or CD123-directed T-cell engager activity in mast cell neoplasia, and is SM an eligible cohort in NCT05362773?","Is infiltrative organ damage (hepatic fibrosis, non-cirrhotic portal hypertension as in PMID:42326297, ascites, osteolysis) reversible under sustained KIT blockade, and which endpoint captures that?","Which negative or failed SM interventions (interferon, cladribine, midostaurin discontinuation drivers, CD30 ADC) should be permanently retired from the desk's proposal space?"],"nextQueries":["(\"systemic mastocytosis\" OR \"mast cell leukemia\") AND (avapritinib OR elenestinib OR bezuclastinib OR midostaurin) AND (resistance OR \"variant allele frequency\" OR \"molecular response\") AND SRC:MED","\"systemic mastocytosis\" AND (SRSF2 OR ASXL1 OR RUNX1 OR TET2 OR CBL) AND (prognosis OR clone OR \"associated hematologic neoplasm\" OR azacitidine OR venetoclax) AND SRC:MED","(\"mast cell\" AND (CD30 OR CD25 OR CD123)) AND (brentuximab OR \"antibody-drug conjugate\" OR \"bispecific\" OR \"CAR T\") AND SRC:MED"],"papersShown":[{"pmid":"42499529","doi":"10.1016/j.bioactmat.2026.07.013","year":2026,"isNew":true,"title":"Emerging bioactive microneedle platforms for disease management: From cutaneous disorders to systemic therapeutics"},{"pmid":"42336628","doi":"10.1080/0886022x.2026.2662109","year":2026,"isNew":true,"title":"The successful use of rituximab in children with IgA nephropathy and minimal change-like lesions: a case series"},{"pmid":"42324603","doi":"10.1080/19490976.2026.2689168","year":2026,"isNew":true,"title":"Cross-kingdom microbiome interactions along the gut-lung axis: immune-microecological coordination, shared mechanisms, and disease-context dependence in respiratory disorders"},{"pmid":"42320775","doi":"10.1016/j.jep.2026.122088","year":2026,"isNew":true,"title":"Ethnopharmacological landscape of Azadirachta indica (Neem): Phytochemical diversity bridging traditional heritage and modern medicine"},{"pmid":"42305636","doi":"10.1016/j.pecinn.2026.100480","year":2026,"isNew":true,"title":"Development and Piloting of a Web-based Adaptation of Motivational Interviewing to Promote Oral Health"},{"pmid":"42230124","doi":"10.1080/0886022x.2026.2673605","year":2026,"isNew":true,"title":"Influencing factors of oral frailty in Chinese maintenance hemodialysis patients: a Bayesian network analysis"},{"pmid":"42212117","doi":"10.1016/j.apjon.2026.100963","year":2026,"isNew":true,"title":"Patient personas of delayed healthcare-seeking behavior among patients with breast cancer-related lymphedema: A qualitative study"},{"pmid":"42153613","doi":"10.1080/15476278.2026.2670152","year":2026,"isNew":true,"title":"Thyroid cancer-derived exosomal SPP1 promotes tumor progression by driving macrophage M2 polarization through the CD44/JAK2/STAT3 signaling pathway"},{"pmid":"42512272","doi":"10.3390/cancers18142205","year":2026,"isNew":true,"title":"Systemic Mastocytosis: Molecular Pathophysiology, WHO Diagnostic Framework, and &lt;i&gt;KIT&lt;/i&gt;-Directed Targeted Therapies"},{"pmid":"42326297","doi":"10.7759/cureus.109267","year":2026,"isNew":true,"title":"Systemic Mastocytosis Presenting as Non-cirrhotic Portal Hypertension With Upper Gastrointestinal Bleeding in a Young Female Patient: A Case Report"}],"trialsShown":[{"nct":"NCT00935090","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"3'-Deoxy-3'-[18F] Fluorothymidine PET Imaging in Patients With Cancer"},{"nct":"NCT07264959","phase":"n/a","status":"RECRUITING","isNew":true,"title":"An Observational Study in Participants With Indolent Systemic Mastocytosis (ISM)"},{"nct":"NCT04910685","phase":"phase 2/phase 3","status":"RECRUITING","isNew":true,"title":"(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis"},{"nct":"NCT04996875","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"(Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis"},{"nct":"NCT03779854","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Naive T Cell Depletion for Preventing Chronic Graft-versus-Host Disease in Children and Young Adults With Blood Cancers Undergoing Donor Ste"},{"nct":"NCT05362773","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study of MGD024 in Patients With Relapsed or Refractory Hematologic Malignancies"},{"nct":"NCT01137825","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Registry of Older Patients With Cancer"},{"nct":"NCT05186753","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"(Summit) A Study to Evaluate the Efficacy and Safety of CGT9486 Versus Placebo in Patients With Indolent or Smoldering Systemic Mastocytosis"}],"usage":{"input":8697,"output":5322},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"systemic mastocytosis\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"systemic mastocytosis\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42499529","PMID:42336628","PMID:42324603","PMID:42320775","PMID:42305636","PMID:42230124","PMID:42212117","PMID:42153613","PMID:42512272","PMID:42326297","NCT00935090","NCT07264959","NCT04910685","NCT04996875","NCT03779854","NCT05362773","NCT01137825","NCT05186753"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787158853387","cycle":51,"visit":1,"ts":"2026-08-19T17:00:53.387Z","cancer":{"key":"primary myelofibrosis","name":"primary myelofibrosis","mondo":{"id":"MONDO:0009692","name":"primary myelofibrosis"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise mutant-CALR neoepitope-directed immunotherapy (bispecific/CAR-T/vaccine) as the only clonally selective PMF strategy in the pack, with BET (pelabresib) and XPO1 (selinexor) ruxolitinib combinations as near-term disease-modification tests and the HO-1/NLRP3 stromal axis as a new anti-fibro","confidence":0.5,"notebook":"Programme opens with a real asymmetry: JAK inhibition is entrenched but non-disease-modifying, so every lead this visit is judged by whether it plausibly touches clone or stroma rather than spleen volume alone (P7 PMID:42324204, P6 PMID:42324205 confirm guideline standard-of-care framing; ~50% discontinue ruxolitinib within a year per P8 PMID:42522770).\n\nGermline/somatic correction to the KG anchor first: JAK2 V617F, CALR exon 9 del52/ins5, and MPL W515 are [SOMATIC] disease-initiating lesions in PMF, not germline predisposition; SH2B3/LNK and the JAK2 46/1 haplotype are the genuine [GERMLINE] risk contributors, and TET2/ASXL1/SF3B1/U2AF1 are [SOMATIC] co-mutations (P3 PMID:42237068 confirms ASXL1 first, then spliceosome genes; ~1/3 PMF triple-negative) [KNOWN for the germline assignment]. Any clone-directed strategy must therefore be stratified by driver, and a third of PMF will have no neoepitope at all.\n\nStrongest new lead: mutant CALR as a cell-surface, tumour-restricted neoepitope for mAbs, bispecific engagers, CAR-T, ADCs and vaccines, with reported molecular remissions and sparing of normal haematopoiesis (P9 PMID:42001411). Normal-tissue argument is the best in the pack — wild-type CALR is ER-resident/eat-me signal on stressed cells, whereas the mutant C-terminus is trafficked to the surface only in mutant clones [INFERRED from P9]. Expected resistance: subclonal CALR (JAK2/triple-negative escape), neoepitope shedding, T-cell tolerance/exhaustion, and outgrowth of ASXL1-mutant CALR-negative subclones [SPECULATIVE].\n\nSecond tier: rux-combination signals from the meta-analysis (P1 PMID:41761659) — selinexor (SVR35 92%), BET inhibitor BMS-986158 (90%) in JAKi-naïve, siremadlin (MDM2/p53 reactivation, 45%) after JAKi. These are single-arm pooled estimates across 19 heterogeneous studies, so treat effect sizes as hypothesis-generating only; pelabresib now has a fresh phase 3 (NCT07357727), which is the practical read-out to watch given prior mixed MANIFEST-2 haemoglobin/SVR-vs-symptom discordance [KNOWN]. Siremadlin logged as a watchlist item; P4 (PMID:42078583) independently nominates p53/p21 activation plus STAT3/NF-κB suppression in MPN models, mechanistically convergent though the agent itself (herbal formula) is not translatable.\n\nStroma/inflammation lead is new and non-redundant: HO-1 loss with nuclear BACH1 in MF megakaryocytes and NLRP3/caspase-1/IL-1β-driven collagen deposition, reversed by CORM-A1 or MCC950 (P10 PMID:42476324) — points to IL-1β blockade or HO-1 induction as anti-fibrotic add-ons; window concern is NLRP3's role in host defence.\n\nAlso new: LSD1 inhibition (iadademstat) with ASTX727 in advanced MPN (NCT06661915), and ropeginterferon in early/low-risk PMF (NCT06468033) as an interception question.\n\nNotebook negatives: P2 (PV thrombosis) and P5 (sepsis neutrophils) are off-target for PMF and yielded no lead; gecacitinib MAIC (P8) is indirect, unmatched-population evidence and must not be read as head-to-head superiority.","leadChanges":[{"id":"L1","title":"Mutant CALR neoepitope-directed immunotherapy in CALR-mutant PMF","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"BET bromodomain inhibition (pelabresib) added to ruxolitinib","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L3","title":"XPO1 inhibition (selinexor) with ruxolitinib in JAKi-naive MF","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L4","title":"HO-1/BACH1-NLRP3-IL-1beta axis as anti-fibrotic stromal target","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L5","title":"LSD1 inhibition plus oral hypomethylation in advanced/accelerated-phase MPN","level":"LEAD","status":"NEW","confidence":0.33}],"unverifiedCitations":0,"openQuestions":["Does mutant-CALR-directed immunotherapy reduce CALR VAF and marrow fibrosis in humans, and what fraction of PMF (given ~33% triple-negative, JAK2 dominance) is even eligible?","In the pelabresib phase 3 (NCT07357727), does SVR35/TSS benefit come with fibrosis-grade or VAF reduction, or is the anaemia/haemoglobin penalty reproducing earlier BET-combination signals?","Is the selinexor+ruxolitinib 92% SVR35 signal an artefact of small single-arm cohorts, and does response track TP53 wild-type status?","Does MDM2 inhibition (siremadlin) after JAK-inhibitor failure act via p53 reactivation in TP53-wild-type clones, and does it select TP53-mutant escape?","Can IL-1beta/NLRP3 blockade or HO-1 induction reverse established marrow fibrosis in a mammalian PMF model without unacceptable infection risk?","Does early intervention with ropeginterferon alfa-2b in low/intermediate-1-risk or pre-fibrotic PMF (NCT06468033) alter fibrosis progression rather than just counts?"],"nextQueries":["(\"calreticulin\" OR CALR) AND (neoantigen OR neoepitope OR \"bispecific\" OR \"CAR-T\" OR vaccine OR antibody) AND (myelofibrosis OR \"myeloproliferative\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","myelofibrosis AND (pelabresib OR selinexor OR siremadlin OR navitoclax OR bomedemstat) AND (\"bone marrow fibrosis\" OR \"allele burden\" OR \"disease modification\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","myelofibrosis AND (NLRP3 OR \"IL-1\" OR inflammasome OR \"heme oxygenase\" OR BACH1 OR \"TGF-beta\") AND (fibrosis OR stroma OR megakaryocyte) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41761659","doi":"10.1080/07853890.2026.2634532","year":2026,"isNew":true,"title":"Efficacy and safety of Ruxolitinib-based combination therapy in the patients with Myelofibrosis (MF): a systematic review and meta-analysis"},{"pmid":"42262970","doi":"10.1080/07853890.2026.2682982","year":2026,"isNew":true,"title":"Thrombotic burden and longitudinal outcomes in Thai patients with polycythemia vera"},{"pmid":"42237068","doi":"10.1080/16078454.2026.2682015","year":2026,"isNew":true,"title":"Distinct clinical, molecular, and treatment response profiles in primary and secondary myelofibrosis: a single-center retrospective study"},{"pmid":"42078583","doi":"10.1016/j.pscia.2026.100121","year":2026,"isNew":true,"title":"Fufang Huangbo Formula mitigates myeloproliferative neoplasms by activating p53/p21 signaling axis and inhibiting STAT3 and NF-κB signaling pathways"},{"pmid":"41814716","doi":"10.1080/07853890.2026.2640268","year":2026,"isNew":true,"title":"Exploring the mechanism of polymorphonuclear neutrophils against sepsis based on immune model"},{"pmid":"42324205","doi":"10.1002/ijc.70595","year":2026,"isNew":true,"title":"The German ONKOPEDIA Guideline for Myelofibrosis in 2025-Recommendations of an MPN Expert Panel of the German Society for Hematology and Oncology (DGHO)"},{"pmid":"42324204","doi":"10.1002/ijc.70596","year":2026,"isNew":true,"title":"Primary Myelofibrosis (PMF)-The German ONKOPEDIA Guideline 2025"},{"pmid":"42522770","doi":"10.1002/hon.70230","year":2026,"isNew":true,"title":"Matching-Adjusted Indirect Comparison of Gecacitinib, Fedratinib, Pacritinib, and Momelotinib in Second-Line Myelofibrosis Therapy"},{"pmid":"42001411","doi":"10.1080/10428194.2026.2658135","year":2026,"isNew":true,"title":"From JAK to CALR: redefining therapeutic targets in myeloproliferative neoplasms"},{"pmid":"42476324","doi":"10.1016/j.freeradbiomed.2026.07.030","year":2026,"isNew":true,"title":"Heme oxygenase-1/CO signaling suppresses NLRP3 inflammasome-mediated stromal fibrosis in primary myelofibrosis"}],"trialsShown":[{"nct":"NCT06661915","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)"},{"nct":"NCT07228624","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Ruxolitinib Before, During and After Hematopoietic Cell Transplant in Older Patients With Myelofibrosis and Myelodysplastic Syndrome/Myelopr"},{"nct":"NCT07357727","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF)"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"},{"nct":"NCT07302776","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"TACrolimus Targeted Immunosuppression Cessation in ALlogeneic HCT"},{"nct":"NCT07443306","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Clinical Trial of Flonoltinib Maleate Tablets in the Treatment of JAK Inhibitor Refractory/Relapsed/Intolerant Patients With Intermediate "},{"nct":"NCT07317700","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Clinical Trial of Flonoltinib Maleate for Intermediate or High-Risk Myelofibrosis"},{"nct":"NCT06468033","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"P1101 in Treating Patients With Early PMF or Overt PMF at Low or Intermediate-1 Risk"}],"usage":{"input":8955,"output":5959},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"primary myelofibrosis\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"primary myelofibrosis\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41761659","PMID:42262970","PMID:42237068","PMID:42078583","PMID:41814716","PMID:42324205","PMID:42324204","PMID:42522770","PMID:42001411","PMID:42476324","NCT06661915","NCT07228624","NCT07357727","NCT06001385","NCT07302776","NCT07443306","NCT07317700","NCT06468033"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787158654501","cycle":50,"visit":1,"ts":"2026-08-19T16:57:34.502Z","cancer":{"key":"essential thrombocythemia","name":"essential thrombocythemia","mondo":{"id":"MONDO:0005029","name":"essential thrombocythemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise mutant-CALR-directed immunotherapy (INCA033989 class) as ET's first plausibly clone-eradicating strategy, with LSD1 inhibition and ropeginterferon as driver-agnostic comparators and MDM2/p53 reactivation as the repurposing hedge.","confidence":0.55,"notebook":"Programme opens with a usable spine: three mechanistically distinct routes to clone-directed therapy in ET, plus one repurposing route.\n\nThe strongest new signal is mutant-CALR [SOMATIC] as a surface neoepitope. P10 (PMID:42001411) argues that frameshift CALR generates a disease-specific, cell-surface-accessible epitope that drives ligand-independent MPL activation, and catalogues mAbs, TCEs, CAR-T, ADCs and peptide vaccines with selective activity against mutant clones and reported molecular responses; T6 (NCT05936359) is the corresponding first-in-human agent (INCA033989 ± ruxolitinib). This is the only route in the pack with a plausible route to clonal eradication rather than count control. Therapeutic window argument: wild-type CALR is an essential ER chaperone but the mutant C-terminus is neomorphic and only mutant protein traffics to the surface with MPL, so on-target normal-tissue exposure should be low [INFERRED]. Expected resistance: epitope-negative subclone outgrowth (JAK2- or MPL-mutant subclones, triple-negative clones), MPL downregulation, T-cell exhaustion/tolerance for the T-cell-engaging formats.\n\nSecond, epigenetic megakaryopoiesis dependency: bomedemstat (LSD1/KDM1A) has reached randomised phase 3 in HU-resistant/intolerant ET against BAT (T4, NCT06079879), and iadademstat is being randomised with ASTX727 in advanced MPN (T1). LSD1 acts in a GFI1B/RCOR complex required for megakaryocyte maturation [KNOWN]; the window is the argument here and needs quantifying (thrombocytopenia, neutropenia).\n\nThird, ropeginterferon is now positive in a North American, driver-mutation-agnostic ET cohort: 60.2% durable modified-ELN response, treatment-naïve and HU-pretreated (P8, PMID:42306077, NCT05482971). Key unanswered question from the abstract: whether molecular/allele-burden response differs by JAK2 vs CALR vs MPL — that stratification determines whether interferon or CALR-directed immunotherapy is the backbone for CALR-mutant ET.\n\nFourth, a repurposing lead: p53 reactivation. P4 (PMID:42078583) shows a herbal formula alleviating an MPL-W515L-driven ET model via p53/p21-driven senescence with STAT3/NF-κB suppression — mechanistically consistent with P2 (PMID:41761659), where ruxolitinib+siremadlin (MDM2 inhibitor) gave SVR35 45% in JAK-inhibitor-exposed MF. TP53 is usually wild-type in chronic-phase ET [KNOWN], so MDM2 inhibition is a rational clone-stressing strategy; the herbal agent itself is not a tractable lead.\n\nRecorded negatives/noise so the desk does not re-tread: JAK inhibition alone is explicitly non-clonally-specific and does not alter natural history (P10, P2); T3 (Ruxo-BEAT) is the only ET-specific JAK-inhibitor readout in the pack and remains unreported. P5 is a dialysis catheter-lock RCT with no MPN content — retrieval noise. P3/P6/P7/P9 are descriptive/MF-guideline material; they define post-ET-MF as the endpoint any disease-modifying claim must move.","leadChanges":[{"id":"L1","title":"Mutant-CALR neoepitope-directed immunotherapy in CALR-mutant ET","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"LSD1/KDM1A inhibition to dismantle the megakaryocytic dependency in ET","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L3","title":"Ropeginterferon alfa-2b as driver-agnostic clonal control backbone in ET","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L4","title":"MDM2 inhibition to reactivate wild-type p53 in chronic-phase MPN","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":1,"openQuestions":["Does mutant-CALR-directed antibody therapy reduce CALR allele burden in humans, and at what dose/exposure does epitope-negative or triple-negative subclone escape appear?","In EXCEED-ET and SURPASS-ET, does molecular/allele-burden response to ropeginterferon differ between JAK2 V617F, CALR and MPL ET, and does that justify genotype-specific backbones?","What are the reported bomedemstat phase 3 efficacy and cytopenia rates versus BAT, and does LSD1 inhibition alter allele burden or only platelet count?","Is there any ET-specific (not MF) evidence that any agent delays progression to post-ET myelofibrosis or leukemic transformation?","Do TP53 wild-type chronic-phase ET progenitors show selective sensitivity to MDM2 inhibition, and does treatment enrich TP53-mutant subclones?","Which non-driver co-mutations (ASXL1, SF3B1/U2AF1, TET2, SH2B3) predict resistance to interferon or LSD1 inhibition in ET specifically?"],"nextQueries":["(\"calreticulin\" OR CALR) AND (neoepitope OR antibody OR \"CAR-T\" OR \"bispecific\" OR vaccine) AND (myeloproliferative OR thrombocythemia) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"essential thrombocythemia\") AND (\"allele burden\" OR \"molecular response\" OR clonal) AND (interferon OR ropeginterferon OR bomedemstat OR LSD1) AND SRC:MED","(\"essential thrombocythemia\" OR \"pre-fibrotic\") AND (progression OR \"post-ET myelofibrosis\" OR transformation) AND (ASXL1 OR SF3B1 OR TP53 OR TET2) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41907306","doi":"10.1016/j.pscia.2026.100116","year":2026,"isNew":true,"title":"Next-generation Janus kinase inhibitors: Integrating synthetic innovation, structural biology, and computational design for precision drug discovery"},{"pmid":"41761659","doi":"10.1080/07853890.2026.2634532","year":2026,"isNew":true,"title":"Efficacy and safety of Ruxolitinib-based combination therapy in the patients with Myelofibrosis (MF): a systematic review and meta-analysis"},{"pmid":"42237068","doi":"10.1080/16078454.2026.2682015","year":2026,"isNew":true,"title":"Distinct clinical, molecular, and treatment response profiles in primary and secondary myelofibrosis: a single-center retrospective study"},{"pmid":"42078583","doi":"10.1016/j.pscia.2026.100121","year":2026,"isNew":true,"title":"Fufang Huangbo Formula mitigates myeloproliferative neoplasms by activating p53/p21 signaling axis and inhibiting STAT3 and NF-κB signaling pathways"},{"pmid":"41820022","doi":"10.1080/0886022x.2026.2641842","year":2026,"isNew":true,"title":"Comparative efficacy of low-concentration trisodium citrate and low-concentration heparin for locking central venous hemodialysis catheters: a randomized controlled study"},{"pmid":"42324204","doi":"10.1002/ijc.70596","year":2026,"isNew":true,"title":"Primary Myelofibrosis (PMF)-The German ONKOPEDIA Guideline 2025"},{"pmid":"42340052","doi":"10.1002/ajh.70417","year":2026,"isNew":true,"title":"Impact of Atrial Fibrillation on the Risk of Thrombosis and Bleeding for Patients With Polycythemia Vera and Essential Thrombocytosis in the Real World"},{"pmid":"42306077","doi":"10.1016/j.lana.2026.101529","year":2026,"isNew":true,"title":"Ropeginterferon alfa-2b-njft treatment in essential thrombocythemia across different driver mutations: results from a North American, single-arm, multicentre study (EXCEED-ET)"},{"pmid":"42554550","doi":"10.1016/j.jaccas.2026.109575","year":2026,"isNew":true,"title":"Transient Coronary Thrombosis Mimicking Myopericarditis Revealing JAK2-Positive Essential Thrombocythemia"},{"pmid":"42001411","doi":"10.1080/10428194.2026.2658135","year":2026,"isNew":true,"title":"From JAK to CALR: redefining therapeutic targets in myeloproliferative neoplasms"}],"trialsShown":[{"nct":"NCT06661915","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)"},{"nct":"NCT07357727","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF)"},{"nct":"NCT02577926","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"The Ruxo-BEAT Trial in Patients With High-risk Polycythemia Vera or High-risk Essential Thrombocythemia"},{"nct":"NCT06079879","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study of Bomedemstat (IMG-7289/MK-3543) Compared to Best Available Therapy (BAT) in Participants With Essential Thrombocythemia and an Ina"},{"nct":"NCT05320198","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Study of DISC-0974 (RALLY-MF) in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia"},{"nct":"NCT05936359","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neop"},{"nct":"NCT06361641","phase":"NA","status":"RECRUITING","isNew":true,"title":"Functional and Phenotypic Characterization of Monocytes in Myeloproliferative Syndromes"},{"nct":"NCT00935090","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"3'-Deoxy-3'-[18F] Fluorothymidine PET Imaging in Patients With Cancer"}],"usage":{"input":8545,"output":4420},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"essential thrombocythemia\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"essential thrombocythemia\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41907306","PMID:41761659","PMID:42237068","PMID:42078583","PMID:41820022","PMID:42324204","PMID:42340052","PMID:42306077","PMID:42554550","PMID:42001411","NCT06661915","NCT07357727","NCT02577926","NCT06079879","NCT05320198","NCT05936359","NCT06361641","NCT00935090"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787158469941","cycle":49,"visit":1,"ts":"2026-08-19T16:54:29.941Z","cancer":{"key":"polycythemia vera","name":"polycythemia vera","mondo":{"id":"MONDO:0009891","name":"acquired polycythemia vera"}},"control":false,"modelLabel":"SCIENCE","summary":"PV drug development in the fresh pack has shifted from hematocrit control to clone-directed therapy — two PV-specific JAK-axis agents (flonoltinib NCT07232290, BEBT-507 NCT07012109) plus randomized LSD1+HMA (NCT06661915) — so the desk's priority question is whether any of these reduce JAK2 V617F all","confidence":0.42,"notebook":"Visit 1 opens with no literature — the Europe PMC pull returned nothing, so every claim here rests on trial registrations plus explicitly tagged background. That constrains how far leads can climb: all four below stay at LEAD.\n\nFirst a KG correction for the record. Monarch flags JAK2 as causal/germline-likely for MONDO:0009891, but acquired PV is driven by somatic JAK2 V617F (or exon 12 indels) in the HSC compartment [SOMATIC][KNOWN]; germline JAK2 contributions are the 46/1 haplotype risk allele and, separately, germline V617I/hereditary thrombocytosis — a different disease [GERMLINE][KNOWN]. The desk should not treat JAK2 here as a predisposition gene.\n\nWhat the pack actually adds is a picture of where PV drug development has moved: away from hematocrit control toward clone-directed therapy. Two first-in-class JAK-axis agents are now in PV-specific trials — flonoltinib maleate (NCT07232290, phase IIa, four dose levels) and BEBT-507 (NCT07012109, phase 1). Flonoltinib is a JAK2/FLT3-biased inhibitor [KNOWN]; BEBT-507's class is not disclosed in the pack, so I will not assign a mechanism [SPECULATIVE that it is a JAK2-selective or dual-target agent]. The interesting question these raise is whether increased JAK2 selectivity translates into V617F allele-burden reduction rather than the cytokine-mediated symptom benefit that type I pan-JAK1/2 inhibition delivers; Ruxo-BEAT (NCT02577926) in high-risk PV/ET is the comparator dataset that should answer whether ruxolitinib does more than control counts. Expected resistance: JAK2 heterodimer-mediated inhibitor persistence, acquired TET2/DNMT3A/ASXL1 subclones, TP53 evolution to post-PV MF [KNOWN]. Window argument: JAK2 is obligate for EPO/TPO/G-CSF signalling, so on-target anemia/thrombocytopenia and reactivation-on-withdrawal cap the achievable depth [KNOWN].\n\nSecond axis is epigenetic. NCI's randomized ASTX727 ± iadademstat (NCT06661915) tests LSD1/KDM1A inhibition on a hypomethylating backbone in advanced MPN — mechanistically aimed at the GFI1B–LSD1 differentiation block in the MPN stem cell [KNOWN]. Pelabresib + ruxolitinib entering a new phase 3 (NCT07357727) keeps BET/NF-κB cytokine circuit inhibition alive in MF; extending it to PV is an inference, not a tested claim.\n\nThird, an inverse-direction observation worth banking so the desk never mis-signs it: DISC-0974 (NCT05320198) is an anti-hemojuvelin agent that *lowers* hepcidin to relieve MF anemia — the opposite pharmacology to iron-restrictive hepcidin agonism in PV. It nonetheless demonstrates the HJV–hepcidin axis is drug-tractable in humans, which is the argument for hepcidin-mimetic phlebotomy replacement in PV.\n\nNext visit must retrieve actual literature: BEBT-507's target, MAJIC-PV/rusfertide readouts, and allele-burden endpoints.","leadChanges":[{"id":"L1","title":"Selectivity-optimized JAK2 inhibition for molecular (allele-burden) response in JAK2 V617F PV","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"LSD1/KDM1A inhibition on a hypomethylating backbone to break the MPN stem-cell differentiation block","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"BET/NF-kB inhibition added to JAK inhibition — test extension from myelofibrosis into high-risk PV","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L4","title":"Hepcidin/hemojuvelin axis as a pharmacologic lever on PV erythrocytosis","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["What is BEBT-507's molecular target/class, and is NCT07012109 a JAK2-selective, mutant-selective, or multi-kinase program?","Do any JAK-axis agents in PV (flonoltinib, ruxolitinib per Ruxo-BEAT/MAJIC-PV) reduce JAK2 V617F allele burden, or only counts and symptoms?","Does hepcidin-mimetic iron restriction in PV reduce thrombotic events, or only replace phlebotomy?","In advanced MPN, is LSD1 inhibition's benefit differentiation-driven clone reduction or cytoreductive myelosuppression — and what is the platelet-toxicity ceiling?","Which non-JAK2 co-mutations (TET2, DNMT3A, ASXL1, TP53) predict failure of interferon vs JAK inhibitor vs epigenetic therapy in PV?","Is the monocyte/inflammatory phenotype at PV diagnosis (NCT06361641) a tractable target axis or only a biomarker?"],"nextQueries":["(\"polycythemia vera\") AND (\"allele burden\" OR \"molecular response\" OR \"JAK2 V617F\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"polycythemia vera\") AND (rusfertide OR hepcidin OR \"iron restriction\" OR ropeginterferon) AND SRC:MED","(\"myeloproliferative neoplasm\") AND (LSD1 OR KDM1A OR iadademstat OR bomedemstat OR \"BET inhibitor\" OR pelabresib) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[],"trialsShown":[{"nct":"NCT06661915","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)"},{"nct":"NCT07357727","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF)"},{"nct":"NCT07012109","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Study of BEBT-507 Injection in Subjects With Polycythemia Vera (PV)"},{"nct":"NCT07232290","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Phase IIa Study of Flonoltinib Maleate Tablets in the Treatment of Patients With Polycythemia Vera"},{"nct":"NCT02577926","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"The Ruxo-BEAT Trial in Patients With High-risk Polycythemia Vera or High-risk Essential Thrombocythemia"},{"nct":"NCT05320198","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Study of DISC-0974 (RALLY-MF) in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia"},{"nct":"NCT06361641","phase":"NA","status":"RECRUITING","isNew":true,"title":"Functional and Phenotypic Characterization of Monocytes in Myeloproliferative Syndromes"},{"nct":"NCT00935090","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"3'-Deoxy-3'-[18F] Fluorothymidine PET Imaging in Patients With Cancer"}],"usage":{"input":2904,"output":5756},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"polycythemia vera\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"polycythemia vera\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["NCT06661915","NCT07357727","NCT07012109","NCT07232290","NCT02577926","NCT05320198","NCT06361641","NCT00935090"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787158271593","cycle":48,"visit":5,"ts":"2026-08-19T16:51:11.593Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Asciminib 200 mg BID is now prospectively validated as durable salvage in T315I CML-CP (MMR 53.3%, 86% maintaining MMR >=144 weeks), promoting the sequential ATP-site-to-allosteric switch to CANDIDATE, while three independent dose-reduction/potency-downgrading cohorts promote risk-stratified de-esca","confidence":0.62,"notebook":"This visit's pack is dominated by exposure/dose biology and by asciminib's T315I endgame; it produced nothing on the dual-occupancy hypothesis for a fourth consecutive visit.\n\nThe important new datum is the phase 1 final analysis in T315I-mutated CML-CP: asciminib 200 mg BID, n=48, MMR 53.3% of evaluable patients, 86% maintaining first MMR ≥144 weeks, grade ≥3 AEs 60.4% but only 8.3% AE discontinuations and arterial occlusive events 4.4/100 patient-years (PMID:42463944). This partly closes open question 3 — the T315I activity is real, prospective, and dose-anchored at 200 mg BID in a resistance-selected (not intolerance-selected) population, so the Turkish registry signal (PMID:42090741) is unlikely to be pure tolerance-selection artefact. L8 therefore rises to CANDIDATE. Two boundaries recorded: no kinase-domain sequencing at asciminib failure is reported in the abstract, and ~47% of T315I patients never reached MMR — that residual is where dual myristoyl+ATP-site blockade has an actual rationale, whereas frontline dual therapy remains unsupported. L1 is accordingly weakened (held at CANDIDATE) and its scope narrowed to high-risk/T315I disease; the fresh asciminib evidence is again monotherapy-only and again reports EMR/MMR rather than MR4.5 or TFR (PMID:42463944; MAIC vs flumatinib, PMID:42591375 — indirect, imatinib-anchored, low-tier).\n\nDose optimisation moves substantially. Low-dose dasatinib in second line or beyond re-induced depth in patients who had failed to reach MMR (27.0% MMR, 32.4% MR4, 29.7% MR4.5; 81.8% of baseline-MMR patients deepened) with a single MR4 loss (PMID:42394986); D-IMPACT shows that downgrading potency — usually to imatinib, mostly for toxicity — improved molecular response in 52.6% and permitted 21 TFR attempts of which 17 remained treatment-free at median 22 months (PMID:42193014); a systematic dose-optimisation review covers all seven approved agents including pre-TFR reduction (PMID:40761712). Mechanistically this favours the coverage-plateau/adherence reading over dose-proportional efficacy [INFERRED]. L7 promotes to CANDIDATE. But flumatinib TDM contradicts naive halving: efficacy tracked concentration with floors (Cmax2h >87.75 ng/mL for MMR, >132.0 for DMR) while toxicity tracked trough >49 ng/mL (PMID:42338759), and a haemodialysis patient reached MMR on asciminib 40 mg QD with delayed Tmax, 30.9% CV and negligible dialyzability (PMID:42412118). New lead L9: de-escalate to a measured concentration floor, not a fraction of label dose.\n\nL2 retired: NCT02689440 silent for a third evidence-bearing visit, no CML BCL2/MCL1 data in any pack.","leadChanges":[{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"WEAKENED","confidence":0.68},{"id":"L8","title":"Sequential ATP-site to allosteric switch: asciminib as non-cross-resistant salvage after ponatinib and in T315I disease","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.58},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.6},{"id":"L9","title":"Concentration-floor (TDM-anchored) de-escalation: reduce exposure to a measured pharmacokinetic threshold, not to a fraction of label dose","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L2","title":"BCL2 co-dependence of the TKI-persistent CML clone: dasatinib + venetoclax","level":"LEAD","status":"RETIRED","confidence":0.15}],"unverifiedCitations":0,"openQuestions":["What is the kinase-domain mutation spectrum at asciminib failure - specifically in the ~21 T315I patients from NCT02081378 who never reached MMR - and do myristoyl-pocket variants (A337V, P465S, F359) or T315I-containing compound mutants ap","Do any ASC4FIRST or NCT03906292 publications report MR4.5 and subsequent TFR-attempt/TFR-success rates by prerandomisation stratum, or does the asciminib advantage remain confined to EMR/MMR and tolerability?","In the D-IMPACT and low-dose dasatinib cohorts, how do re-escalation and TFR-success rates stratify by ELTS, transcript type (e13a2 vs e14a2) and ASXL1 status, and were any patients downgraded while still ASXL1-mutated?","Are there agent-specific exposure thresholds (trough or Cmax) for maintaining MR4/MR4.5 during dasatinib, nilotinib-tablet or asciminib de-escalation, analogous to the flumatinib Cmax_2h floors, and how much of the observed deepening after ","Is there any published low-dose asciminib (40-80 mg QD) efficacy series beyond case reports, and does the exposure-response curve for asciminib differ between native and T315I-mutated BCR-ABL1?","Has any CML dataset reported BH3 profiling or MCL1/BCL-xL switching in TKI-persistent CD34+CD38- cells that would justify reopening the BCL2 lead?"],"nextQueries":["\"chronic myeloid leukemia\" AND asciminib AND (\"mutation\" OR \"A337V\" OR \"P465S\" OR \"F359\" OR \"compound mutation\") AND (resistance OR failure) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","\"chronic myeloid leukemia\" AND (\"treatment-free remission\" OR TFR) AND (\"dose reduction\" OR de-escalation OR downgrading) AND (ASXL1 OR ELTS OR \"transcript type\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic myeloid leukemia\" AND (\"therapeutic drug monitoring\" OR trough OR \"plasma concentration\") AND (asciminib OR dasatinib OR nilotinib) AND (\"molecular response\" OR MR4) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"42591375","doi":"10.21037/tcr-2026-1659","year":2026,"isNew":true,"title":"Matching-adjusted indirect comparison between asciminib and flumatinib as first-line treatment for chronic myeloid leukemia in China"},{"pmid":"42463944","doi":"10.1038/s41375-026-02972-9","year":2026,"isNew":true,"title":"Asciminib monotherapy in patients with BCR::ABL1 T315I-mutated chronic-phase chronic myeloid leukemia: phase 1 trial final results"},{"pmid":"42412118","doi":"10.1007/s00280-026-04919-4","year":2026,"isNew":true,"title":"Pharmacokinetics of asciminib in a patient with chronic myeloid leukemia undergoing maintenance hemodialysis"},{"pmid":"42394986","doi":"10.3389/fphar.2026.1734319","year":2026,"isNew":true,"title":"Low-dose dasatinib in second-line therapy or beyond for the treatment of chronic-phase chronic myeloid leukemia: a real-world cohort study"},{"pmid":"42193014","doi":"10.3390/cancers18101656","year":2026,"isNew":true,"title":"Assessment of Transitioning from High-Potency to Low-Potency Inhibitors in Chronic Myeloid Leukemia (CML) Patients: The Downgrading-Impact (D-IMPACT) Project"},{"pmid":"42338759","doi":"10.2147/dddt.s612207","year":2026,"isNew":true,"title":"Optimizing Flumatinib Therapy in Chinese Chronic-Phase Chronic Myeloid Leukemia Based on Therapeutic Drug Monitoring"},{"pmid":"42037644","doi":"10.1177/11795476261436608","year":2026,"isNew":true,"title":"Successful Management of Tyrosine Kinase Inhibitor-Induced Bone Marrow Aplasia in Chronic Phase Chronic Myeloid Leukemia with Ponatinib: A Case Report and Literature Review"},{"pmid":"40761712","doi":"10.2147/cpaa.s532263","year":2025,"isNew":true,"title":"Dose Optimization of Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia"},{"pmid":"42238029","doi":"10.15586/jkc.v13i2.437","year":2026,"isNew":true,"title":"Concurrent Chronic Myeloid Leukemia and Metastatic Renal Cell Carcinoma in a 61-year-old Female: Successful Treatment with Low-Dose Immunotherapy and Combination Targeted Therapy"},{"pmid":"42584922","doi":"10.1080/17474086.2026.2715450","year":2026,"isNew":false,"title":"Nilotinib in chronic myeloid leukemia: clinical value, real-world challenges, and the potential of nilotinib tablets to improve therapeutic outcomes"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":14463,"output":9358},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic myeloid leukemia\" AND asciminib AND (\"MR4.5\" OR \"treatment-free remission\" OR \"resistance mutation\" OR \"myristoyl\" OR A337V OR P465S) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","\"chronic myeloid leukemia\" AND (\"dose reduction\" OR \"de-escalation\" OR \"low-dose\") AND (dasatinib OR nilotinib OR imatinib) AND (\"molecular response\" OR pharmacokinetic) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:42591375","PMID:42463944","PMID:42412118","PMID:42394986","PMID:42193014","PMID:42338759","PMID:42037644","PMID:40761712","PMID:42238029","PMID:42584922","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787158026195","cycle":47,"visit":1,"ts":"2026-08-19T16:47:06.195Z","cancer":{"key":"hodgkin lymphoma","name":"Hodgkin lymphoma","mondo":{"id":"MONDO:0004952","name":"Hodgkins lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Open the Hodgkin programme on CD30-ADC plus PD-1 blockade (brentuximab vedotin + nivolumab, NCT01896999/NCT05675410) with spatial TME topology as the companion selection biomarker, while formally excluding BCR/BTK-axis agents from HL consideration.","confidence":0.55,"notebook":"Visit 1 opens the programme with a pack that is mostly off-target: shikonin/ferroptosis in DLBCL (PMID:42295078), BKPyV genomics (PMID:42223211), paediatric executive function (PMID:42094776), engineered bacteria (PMID:42240055) carry no Hodgkin-specific signal. Trials T2–T6 and T8 are likewise non-HL; note explicitly that the non-covalent BTK inhibitors and BTK degraders in the pack (pirtobrutinib in PMID:42355593, BGB-16673 in NCT05006716) are not HL leads — HRS cells have crippled B-cell receptor/BTK programmes with loss of B-cell identity transcription factors, so BCR-axis kinase inhibition has no mechanistic footing here [KNOWN]. Recording that now so the desk does not re-propose it.\n\nTwo HL-specific threads are worth opening. First, CD30 ADC plus PD-1 blockade. Brentuximab vedotin remains the anchor CD30-directed ADC (PMID:42355593, PMID:42070121), and the NCI programme is testing it with nivolumab ± ipilimumab in R/R disease (NCT01896999) and against standard chemo-immunotherapy in frontline (NCT05675410). Mechanistically this is a coupling argument, not additivity: MMAE-driven immunogenic cell death and HRS-cell depletion inside a rosette of exhausted CD4 T cells, layered onto near-universal 9p24.1 gain that drives PD-L1/PD-L2 and JAK2 in HRS cells [KNOWN]. Tempering this, the Saudi multicentre cohort (PMID:42432844) found BV-containing regimens gave only numerically higher ORR (82.5% vs 76.9%), identical CR (~60%), and an EFS advantage (22.5 vs 11.2 months) that lost significance on adjustment — real-world effect size is smaller than registration data imply, so the lead enters at moderate confidence and the interesting question becomes patient selection, not universal use.\n\nSecond, TME topology as the selection instrument. PMID:42358815 argues that spatial/topological arrangement of immune cells in cHL — quantified by digital image analysis, spatial transcriptomics, scRNAseq, ctDNA — outperforms clinical variables for the 10–20% who fail to achieve CR. This is a testable correlative programme grafted onto NCT05675410/NCT01896999 biopsies.\n\nThird, an NK-directed hypothesis: HRS cells frequently lose B2M/MHC-I, which should blunt CD8 killing while leaving them missing-self vulnerable [KNOWN]; NK engagers and CAR-NK platforms are maturing (PMID:42033215). Weakest of the three; needs HL-specific data.\n\nOn the KG anchor: KLHDC8B is a germline familial HL susceptibility gene affecting cytokinesis/midbody function [KNOWN] — Monarch's \"correlated/somatic-likely\" tag is misleading. No pack citation supports it, so no lead; it is an open question, not a target.","leadChanges":[{"id":"L1","title":"CD30 ADC + PD-1 (± CTLA-4) blockade as chemotherapy-sparing backbone in classical Hodgkin lymphoma","level":"LEAD","status":"NEW","confidence":0.68},{"id":"L2","title":"Spatial/topological TME architecture as the assignment biomarker for the 10-20% of cHL that fails to reach CR","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L3","title":"NK-directed targeting of MHC-I-deficient HRS cells (CD30 NK engagers / CAR-NK)","level":"LEAD","status":"NEW","confidence":0.32}],"unverifiedCitations":0,"openQuestions":["Does CD30 IHC intensity, 9p24.1 copy number, or B2M/HLA-I status predict benefit from BV+nivolumab over ABVD-type chemotherapy in NCT05675410 and NCT01896999?","Is the real-world attenuation of BV benefit in R/R cHL (PMID:42432844) explained by prior-line heterogeneity/transplant access, or by genuine CD30-axis resistance (antigen loss, MDR1 efflux)?","Which specific spatial TME features (HRS-macrophage distance, PD-L1+ niche density, CD8 exclusion) reproducibly separate CR from non-CR patients across independent cHL cohorts?","Is KLHDC8B in Hodgkin lymphoma strictly germline predisposition (cytokinesis/midbody defect, Reed-Sternberg binucleation) with no somatic maintenance role — i.e. should it be excluded as a target?","Do B2M/HLA class I-null cHL cases exist as a defined subgroup, and are they enriched among checkpoint-inhibitor failures (the entry criterion for any NK-directed strategy)?","What are the documented mechanisms of acquired resistance to PD-1 blockade in cHL specifically (JAK/STAT, IFN-gamma pathway, antigen presentation), and which are pharmacologically re-addressable?"],"nextQueries":["(\"Hodgkin lymphoma\" AND (\"9p24.1\" OR PD-L1 OR \"JAK2\") AND (resistance OR \"acquired resistance\" OR biomarker)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"Hodgkin lymphoma\" AND (B2M OR \"beta-2 microglobulin\" OR \"HLA class I\" OR \"antigen presentation\" OR \"natural killer\")) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"Hodgkin lymphoma\" AND (KLHDC8B OR \"familial Hodgkin\" OR germline OR predisposition)) AND SRC:MED"],"papersShown":[{"pmid":"42355593","doi":"10.3390/jcm15124425","year":2026,"isNew":true,"title":"Precision Medicine in Non-Hodgkin Lymphoma: Advances in BTK Inhibition, CD30-Directed Antibody-Drug Conjugates, and HDAC-Mediated Epigenetic Therapy with Pirtobrutinib, Brentuximab"},{"pmid":"42432844","doi":"10.1080/16078454.2026.2700811","year":2026,"isNew":true,"title":"Effectiveness and safety of brentuximab vedotin-containing regimen versus standard chemotherapy in relapsed or refractory Hodgkin lymphoma: a multicenter cohort study"},{"pmid":"42295078","doi":"10.1080/14756366.2026.2674446","year":2026,"isNew":true,"title":"Shikonin suppresses diffuse large B-cell lymphoma progression by inducing ferritinophagy and ferroptosis &lt;i&gt;via&lt;/i&gt; lncRNA ADPGK-AS1 downregulation"},{"pmid":"42240055","doi":"10.1080/15384047.2026.2683171","year":2026,"isNew":true,"title":"Leveraging the bacteria for enhanced cancer immunotherapy: from a perspective of synthetic biology"},{"pmid":"42223211","doi":"10.1080/21505594.2026.2679815","year":2026,"isNew":true,"title":"Do BKPyV genomic features underlie clinical divergence between kidney and hematopoietic transplant recipients?"},{"pmid":"42094776","doi":"10.1016/j.apjon.2026.100958","year":2026,"isNew":true,"title":"Factors associated with executive function in children with lymphoma undergoing chemotherapy: A cross-sectional study based on the theory of unpleasant symptoms"},{"pmid":"42088834","doi":"10.1016/j.synbio.2026.04.012","year":2026,"isNew":true,"title":"Remodeling memory T cells with chemotherapy and immune checkpoint inhibitors as host pre-conditioning to empower in vivo CAR-T therapy"},{"pmid":"42070121","doi":"10.1080/2162402x.2026.2667160","year":2026,"isNew":true,"title":"Trial watch: antibody-drug conjugates in cancer therapy"},{"pmid":"42033215","doi":"10.1080/15384047.2026.2658896","year":2026,"isNew":true,"title":"Advances in natural killer cell immunotherapy for hematologic malignancies"},{"pmid":"42358815","doi":"10.32604/or.2026.079403","year":2026,"isNew":true,"title":"Prognostic Value of Spatial and Topological Features of Tumor Microenvironment in Classic Hodgkin Lymphoma"}],"trialsShown":[{"nct":"NCT01896999","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma"},{"nct":"NCT06724237","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Testing Whether High Dose Chemotherapy and Infusion of the Patients' Own Stem Cells Improves Survival in Patients With Peripheral T-cell Lym"},{"nct":"NCT00740805","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Veliparib, Cyclophosphamide, and Doxorubicin Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Non-Hodgkin "},{"nct":"NCT07630545","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"A Phase I Study in Healthy Volunteers and Parkinson's Disease (PD) Patients."},{"nct":"NCT03876769","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients"},{"nct":"NCT06549595","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Study of Surovatamig (AZD0486) Plus Rituximab in Previously Untreated Follicular Lymphoma Patients"},{"nct":"NCT05675410","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Study to Compare Standard Therapy to Treat Hodgkin Lymphoma to the Use of Two Drugs, Brentuximab Vedotin and Nivolumab"},{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"}],"usage":{"input":8384,"output":4880},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Hodgkin lymphoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Hodgkin lymphoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42355593","PMID:42432844","PMID:42295078","PMID:42240055","PMID:42223211","PMID:42094776","PMID:42088834","PMID:42070121","PMID:42033215","PMID:42358815","NCT01896999","NCT06724237","NCT00740805","NCT07630545","NCT03876769","NCT06549595","NCT05675410","NCT05006716"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787157833164","cycle":46,"visit":1,"ts":"2026-08-19T16:43:53.164Z","cancer":{"key":"mantle cell lymphoma","name":"mantle cell lymphoma","mondo":{"id":"MONDO:0018876","name":"mantle cell lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Loss of miR-146a-5p with MAPK-ERK/PI3K-AKT hyperactivation is a reversible, non-genetic ibrutinib-resistance axis in MCL that should be tested as hypomethylating-agent or dual pathway-inhibitor add-back to BTKi in resistant PDX models.","confidence":0.5,"notebook":"Visit 1 opens the programme. The pack is review-heavy, but three items carry real mechanistic weight and two are noise to be logged and never re-mined: P1 (paraneoplastic FSGS in blastoid MCL, PMID:42264686) and P2 (zanubrutinib-associated ocular surface disease, PMID:42574588) are single cases — safety/phenomenology only, no target. P3 is a generic lymphoproliferative review; no MCL-specific claim to build on.\n\nThe highest-value paper is PMID:42335205: three independently derived ibrutinib-resistant MCL lines, PDX and patient biopsies converge on loss of miRNAs restraining MAPK-ERK and PI3K-AKT, with miR-146a-5p reproducibly lost and its re-expression re-sensitising cells; promoter hypermethylation is offered as the mechanism of loss. This is a *non-genetic*, potentially reversible resistance axis distinct from BTK C481S/L528W and PLCG2 [KNOWN], and it names two actionable, already-approved pathway classes plus an epigenetic re-activation strategy. Caveat from the abstract alone: hypermethylation is \"a potential\" mechanism, not demonstrated causally; and miR-146a's canonical targets are IRAK1/TRAF6/NF-κB [KNOWN], so the ERK/AKT link may be indirect. Therapeutic window is the weak point — MEK/ERK and PI3K/AKT inhibition is broadly toxic (rash, colitis, hyperglycaemia) [KNOWN], so intermittent dosing or PI3Kδ-selective agents are the rational framing.\n\nSecond axis: escape from BTK dependence rather than pathway bypass. BGB-16673 (NCT05006716) degrades rather than occupies BTK, which should survive kinase-domain and scaffold mutations [INFERRED]; sonrotoclax+zanubrutinib in a randomised phase 3 (NCT06742996) tests whether BCL2 co-dependence — plausible given CCND1 [SOMATIC]-driven proliferative stress — converts BTKi response into deeper remission. Expected escape: BCL2 G101V/D103Y, MCL1 upregulation [KNOWN].\n\nThird axis: antigen sequencing after CD19 CAR-T failure, where prognosis is dismal (PMID:42564502). One durable >20-month CR on Pola-R-Benda (CD79b ADC) plus NCCN-level support for mosunetuzumab+polatuzumab post-BTKi (PMID:42532836), ROR1 ADC ± nemtabrutinib (NCT05458297), and CD19xCD3 surovatamig (NCT06564038) make \"switch the antigen, not the modality\" a testable programme. ROR1 is oncofetal with minimal adult expression — the cleanest window here.\n\nFourth: moving cellular therapy first-line for TP53-altered/p53-overexpressing MCL (CARMAN, PMID:42581349; Window-3, NCT05495464) — a chemo-refractory subgroup by biology, not fitness.\n\nNothing earns CANDIDATE this visit; all five entries are new LEADs. Next visit I need: whether hypomethylating agents actually restore miR-146a in MCL; ATM [SOMATIC] loss as an ATR-inhibitor synthetic-lethal handle (KG anchor, zero pack support); and CDK4/6 or CCND1-degrader data.","leadChanges":[{"id":"L1","title":"Restore miR-146a-5p / block MAPK-ERK+PI3K-AKT to reverse non-genetic ibrutinib resistance","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L2","title":"BTK degradation (BGB-16673) for MCL progressing on covalent and non-covalent BTK inhibitors","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"BCL2 co-targeting with BTK inhibition: sonrotoclax + zanubrutinib in R/R MCL","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L4","title":"Antigen-switch salvage after CD19 CAR-T failure: CD79b ADC, CD20xCD3, ROR1 ADC","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L5","title":"First-line cellular therapy for TP53-altered / p53-overexpressing high-risk MCL","level":"LEAD","status":"NEW","confidence":0.45}],"unverifiedCitations":0,"openQuestions":["Is miR-146a promoter hypermethylation causal for its loss in ibrutinib-resistant MCL, and do azacitidine/decitabine restore miR-146a-5p and ibrutinib sensitivity in PDX?","Does ATM [SOMATIC] loss, the second KG anchor, create exploitable ATR/PARP synthetic lethality in MCL, and is there any MCL-specific ATR-inhibitor data?","Does CCND1 [SOMATIC] overexpression confer actionable CDK4/6 or cyclin D1-degrader dependence, and does palbociclib potentiate BTKi/venetoclax in MCL?","In post-CD19 CAR-T relapse, how often is CD19 truly lost vs retained - i.e. which salvage antigen should be chosen by biopsy?","Do BTK degraders retain activity in models with the miR-146a-low ERK/AKT-hyperactive resistance state, or is that state degrader-agnostic?","What are the mechanisms of BCL2-inhibitor resistance specific to MCL (G101V vs MCL1 upregulation) and can they be predicted before sonrotoclax exposure?"],"nextQueries":["\"mantle cell lymphoma\" AND (\"miR-146a\" OR \"microRNA\" OR \"DNA methylation\" OR azacitidine OR decitabine) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"mantle cell lymphoma\" AND (ATM OR \"ATR inhibitor\" OR ceralasertib OR elimusertib OR \"synthetic lethality\") AND SRC:MED","\"mantle cell lymphoma\" AND (\"CDK4\" OR palbociclib OR \"cyclin D1\" OR \"BTK degrader\" OR \"BGB-16673\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42264686","doi":"10.1016/j.nefroe.2026.501512","year":2026,"isNew":true,"title":"Reversible podocytopathy in a patient with blastoid-variant mantle cell lymphoma: A case of paraneoplastic FSGS and a literature review"},{"pmid":"42574588","doi":"10.1097/icl.0000000000001303","year":2026,"isNew":true,"title":"Moraxella nonliquefaciens Keratitis Due to Ocular Surface Disease in a Patient Treated with Zanubrutinib for Mantle Cell Lymphoma"},{"pmid":"42278551","doi":"10.3390/ijms27115026","year":2026,"isNew":true,"title":"Molecular Insights and Novel Therapies for Lymphoproliferative Disorders"},{"pmid":"42564502","doi":"10.1177/17588359261472319","year":2026,"isNew":true,"title":"Long-term complete remission following treatment with polatuzumab vedotin, rituximab, and bendamustine in a patient with mantle cell lymphoma relapsing after CAR-T cell therapy: a "},{"pmid":"42340653","doi":"10.1007/s12094-026-04474-7","year":2026,"isNew":true,"title":"Advances in targeted and cellular therapies for relapsed/refractory mantle cell lymphoma: immunotherapeutic strategies and challenges"},{"pmid":"42581349","doi":"10.1186/s12885-026-16602-1","year":2026,"isNew":true,"title":"Trials in progress: CARMAN - study protocol of a randomized controlled, international, multicenter, open-label phase II trial evaluating early treatment intensification in patients"},{"pmid":"42532836","doi":"10.1080/21645515.2026.2712177","year":2026,"isNew":true,"title":"Mosunetuzumab: A bispecific CD20 × CD3 antibody for follicular lymphoma with promising evidence in other B-NHL subtypes"},{"pmid":"42505228","doi":"10.3390/curroncol33070426","year":2026,"isNew":true,"title":"First-Line Bruton's Tyrosine Kinase Inhibitor-Based Regimens for Mantle Cell Lymphoma"},{"pmid":"42555305","doi":"10.1080/17474086.2026.2715445","year":2026,"isNew":true,"title":"Refining risk stratification for mantle cell lymphoma: integrating novel combination treatments and personalized approaches"},{"pmid":"42335205","doi":"10.1182/bloodadvances.2025016640","year":2026,"isNew":true,"title":"Loss of miR-146a-5p contributes to ibrutinib resistance in mantle cell lymphoma"}],"trialsShown":[{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06742996","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Study to Investigate the Efficacy and Safety of Sonrotoclax Plus Zanubrutinib Compared With Placebo Plus Zanubrutinib in Adults With Relap"},{"nct":"NCT07673367","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Nemtabrutinib With CAR T Therapy in Relapsed/Refractory Mantle Cell Lymphoma"},{"nct":"NCT06667687","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study to Evaluate Adverse Events, Change in Disease Activity, and How Intravenously Infused ABBV-291 Moves Through the Body in Adult Partici"},{"nct":"NCT05458297","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study of Zilovertamab Vedotin (MK-2140) as Monotherapy and in Combination in Participants With Aggressive and Indolent B-cell Malignancies"},{"nct":"NCT06980116","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Dose Determining Study of EXS73565 in Participants With Relapsed or Refractory B-Cell Malignancies"},{"nct":"NCT05495464","phase":"EARLY_phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Pilot \"Window-3\" Study of Acalabrutinib Plus Rituximab Followed by Brexucabtagene Autoleucel Therapy in Patients With Previously Untreated"},{"nct":"NCT06564038","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study of AZD0486 Monotherapy or in Combination With Other Anti-Cancer Agents for Mature B-Cell Malignancies"}],"usage":{"input":8659,"output":6495},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"mantle cell lymphoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"mantle cell lymphoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42264686","PMID:42574588","PMID:42278551","PMID:42564502","PMID:42340653","PMID:42581349","PMID:42532836","PMID:42505228","PMID:42555305","PMID:42335205","NCT05006716","NCT06742996","NCT07673367","NCT06667687","NCT05458297","NCT06980116","NCT05495464","NCT06564038"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787157591620","cycle":45,"visit":1,"ts":"2026-08-19T16:39:51.620Z","cancer":{"key":"follicular lymphoma","name":"follicular lymphoma","mondo":{"id":"MONDO:0018906","name":"follicular lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"FL's frontline is being contested by CD3 engagers (mosunetuzumab, surovatamig/AZD0486) in low-burden and untreated disease, giving a BCL2-translocation-agnostic killing mechanism; next visit must test whether antigen loss, T-cell fitness, or MHC-II (CREBBP/EZH2) status governs response.","confidence":0.45,"notebook":"No papers retrieved this visit, so the programme is built entirely from the trial slate plus the Monarch anchor. Three of eight trials are noise (T1 peripheral T-cell lymphoma, T2 Parkinson's, T5 glioblastoma) and are logged as irrelevant so the desk does not re-read them.\n\nWhat the trial pack actually says: the therapeutic centre of gravity in FL has shifted from anti-CD20 monotherapy toward CD3-engaging bispecifics, and — importantly — that shift is now being tested in the *earliest*, lowest-risk settings, not just late relapse. NCT06337318 randomises mosunetuzumab (CD20xCD3) against rituximab in low tumour burden FL, and NCT06549595 puts surovatamig/AZD0486 (CD19xCD3) plus rituximab against R-CHOP/R-CVP/BR in previously untreated FL. Mechanistically this matters because the defining FL lesion in the anchor set — t(14;18) IGH::BCL2 [SOMATIC], with BCL6 as the second recurrent partner — confers an apoptotic block downstream of intrinsic mitochondrial priming, which chemotherapy and rituximab-mediated ADCC both depend on to varying degrees [KNOWN]. Redirected T-cell cytotoxicity kills largely via granzyme/perforin and is less dependent on the BCL2-guarded intrinsic pathway [INFERRED], which is the cleanest rationale for engagers displacing chemoimmunotherapy in a BCL2-translocated disease. Using a CD19 engager (surovatamig) alongside rituximab also decouples the killing antigen from the antigen most likely lost under anti-CD20 pressure [INFERRED].\n\nSecond thread: BTK. NCT05100862 tests zanubrutinib + anti-CD20 against lenalidomide/rituximab in R/R FL/MZL, while NCT05006716 escalates BGB-16673, a BTK-directed chimeric degrader, in B-cell malignancies. Degradation rather than occupancy is the stated route around kinase-domain escape (C481S under covalent, T474I/L528W under non-covalent inhibitors) [KNOWN]; FL is a less BTK-addicted disease than CLL/MCL, so the honest question is whether chronic active BCR signalling is a maintenance dependency in FL at all, or only in a GCB-like subset.\n\nThird thread, weaker but worth carrying: HLA-DRB1 in the anchor set points at MHC class II. CREBBP and EZH2 loss-of-function reduce MHC-II expression and blunt CD4 T-cell surveillance in FL [KNOWN]; if true, MHC-II-low tumours should retain sensitivity to CD3 engagers (MHC-independent) while being resistant to lenalidomide-driven immune synapse restoration — a testable stratifier across NCT02390869/NCT05100862 versus NCT06337318.\n\nNothing to retire yet. Next visit I need actual literature: engager efficacy and resistance data (CD19/CD20 antigen loss, T-cell exhaustion, prior-CAR-T sequencing), BTK dependency in FL specifically, and whether MHC-II status predicts immunotherapy benefit. All leads sit at LEAD; no promotion is earned on trial registrations alone.","leadChanges":[{"id":"L1","title":"CD3 bispecific engagers displace chemoimmunotherapy in t(14;18)/BCL2-driven FL","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L2","title":"BTK degradation vs occupancy: is chronic active BCR signalling a maintenance dependency in FL?","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"MHC class II (HLA-DRB1 anchor) status as the stratifier splitting immunomodulatory from MHC-independent immunotherapy in FL","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["What are the reported resistance mechanisms to mosunetuzumab and other CD20xCD3 engagers in FL — CD20 antigen loss/mutation, trogocytosis, or T-cell exhaustion — and does prior CAR-T or prior engager exposure cross-resist?","Does CD19 targeting (surovatamig/AZD0486) preserve activity after anti-CD20 failure, and conversely does it compromise later CD19 CAR-T?","Is there FL-specific evidence that BTK degradation (BGB-16673) outperforms covalent/non-covalent BTK inhibition, and is BCR signalling a genuine maintenance dependency in FL or only in a molecular subset?","Do CREBBP/EZH2 mutations and low MHC class II expression predict failure of lenalidomide-based regimens while sparing CD3-engager efficacy in FL?","Why has venetoclax monotherapy underperformed in t(14;18)-positive FL, and which co-dependency (MCL1, BCL-XL, BFL1) explains it — is there a rational engager or degrader combination?","What defines POD24 biology molecularly (m7-FLIPI components, TP53, 1p36/TNFRSF14) and can any of the above leads be aimed specifically at that high-risk group?"],"nextQueries":["(\"follicular lymphoma\" AND (mosunetuzumab OR epcoritamab OR glofitamab OR \"bispecific antibody\") AND (resistance OR \"antigen loss\" OR \"CD20 mutation\" OR exhaustion)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"follicular lymphoma\" AND (CREBBP OR EZH2 OR \"MHC class II\" OR HLA-DR) AND (immune OR \"antigen presentation\" OR microenvironment)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"follicular lymphoma\" AND (\"BTK degrader\" OR BGB-16673 OR NX-5948 OR zanubrutinib OR venetoclax) AND (efficacy OR resistance OR dependency)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[],"trialsShown":[{"nct":"NCT06724237","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Testing Whether High Dose Chemotherapy and Infusion of the Patients' Own Stem Cells Improves Survival in Patients With Peripheral T-cell Lym"},{"nct":"NCT07630545","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"A Phase I Study in Healthy Volunteers and Parkinson's Disease (PD) Patients."},{"nct":"NCT06549595","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Study of Surovatamig (AZD0486) Plus Rituximab in Previously Untreated Follicular Lymphoma Patients"},{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06860594","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Testing the Addition of an Anti-Cancer Drug, Triapine, to the Usual Radiation Therapy for Recurrent Glioblastoma or Astrocytoma"},{"nct":"NCT02390869","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Rituximab and Lenalidomide vs Rituximab Alone as Maintenance After R-chemoterapy for Relapsed/Refractory FL Patients"},{"nct":"NCT05100862","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study of Zanubrutinib Plus Anti-CD20 Versus Lenalidomide Plus Rituximab in Participants With Relapsed/Refractory Follicular or Marginal Zo"},{"nct":"NCT06337318","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Comparing Rituximab and Mosunetuzumab Drug Treatments for People With Low Tumor Burden Follicular Lymphoma"}],"usage":{"input":3094,"output":5036},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"follicular lymphoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"follicular lymphoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["NCT06724237","NCT07630545","NCT06549595","NCT05006716","NCT06860594","NCT02390869","NCT05100862","NCT06337318"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787157356409","cycle":44,"visit":1,"ts":"2026-08-19T16:35:56.409Z","cancer":{"key":"diffuse large b-cell lymphoma","name":"diffuse large B-cell lymphoma","mondo":{"id":"MONDO:0018905","name":"diffuse large B-cell lymphoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise METTL3 (STM2457) inhibition to dismantle the m6A-β-catenin-MYC/BCL2 axis underlying rituximab resistance in double-expressor DLBCL, and test it against venetoclax/BTK-degrader backbones now in trial.","confidence":0.42,"notebook":"Programme opened. Pack is clinically broad but mechanistically thin; I take four mechanistic leads plus one biomarker-strategy lead, and log two dead ends.\n\nMechanistic gains. PMID:42242087 gives the first fresh resistance axis: METTL3 → m6A of CTNNB1 (YTHDF2-dependent) → β-catenin → MYC transactivation of BCL2, driving rituximab resistance in double-expressor DLBCL (U-2932), with STM2457 + RTX active in xenograft. This connects a druggable writer enzyme to the two KG anchors that matter ([SOMATIC] BCL2, and MYC by co-expression). Caveat: the abstract asserts YTHDF2 *stabilises* CTNNB1 mRNA, whereas YTHDF2 canonically accelerates decay [KNOWN] — either a non-canonical readout or a mislabelled reader; single cell line, no isogenic RTX-resistant panel. Lead, not candidate.\n\nPMID:42593144 nominates OGT/O-GlcNAcylation as a prognostic and functional dependency across 2,090 array-profiled cases with knockdown/inhibitor effects in OCI-LY3 (ABC/MYD88-driven [KNOWN]) and SU-DHL-4 (GCB), implicating O-GlcNAc cross-talk with phospho-signalling and anti-apoptotic factors. Therapeutic window is the weak point: OGT is essential in essentially all nucleated cells [KNOWN], so the argument must be a synthetic-lethal one (OGT/OGA modulation + venetoclax or BTKi) rather than monotherapy.\n\nClinical scaffolding. NCT05006716 (BGB-16673, BTK chimeric degrader) and NCT03223610 (ViPOR: venetoclax+ibrutinib+prednisone+obinutuzumab+lenalidomide) together define the non-chemotherapy NF-κB/BCL2 co-targeting axis for ABC/MCD-like DLBCL; degradation should survive C481S and non-covalent-inhibitor resistance, with expected escape via PLCG2, CARD11, and BCL2 or NF-κB-independent bypass [KNOWN/INFERRED]. NCT06792253 is a phase 3 of dual PI3K/HDAC inhibition (BEBT-908/ifupinostat + rituximab) — a genuinely testable epigenetic-plus-survival-signalling hypothesis at pivotal stage, worth tracking for readout rather than novel proposal.\n\nBiomarker-adaptive frontline: interim PET after 3× Pola-R-CHP separated CD5+ DLBCL outcomes with implausibly wide HRs in 32 patients (PMID:42482660, retrospective, hypothesis-generating only), and NCT04980222 tests ctDNA-high-risk selection for glofitamab+R-CHP; mosunetuzumab activity across B-NHL (PMID:42532836) and axi-cel population modelling (PMID:42596901) support early T-cell redirection in high-risk biology. The open question is whether ctDNA or interim PET better selects for engager intensification.\n\nLogged as low priority / not pursued: shikonin-induced ferritinophagy via ADPGK-AS1/MT2A (PMID:42295078) — natural product, no DLBCL-relevant PK argument; opaganib/SphK2 (PMID:42256552) — review with no DLBCL data. Watch item, not a lead: CD3⁺ malignant B cells driving M2/TGF-β immunosuppression via FLI1/NFATC2 (PMID:42247321) — could explain engager/CAR-T failure but needs orthogonal confirmation. eQTL-MR \"risk gene\" signature (PMID:42420780) conflates germline eQTL inference with somatic maintenance; not actionable.","leadChanges":[{"id":"L1","title":"METTL3 inhibition to reverse rituximab resistance in double-expressor DLBCL","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L2","title":"OGT/O-GlcNAc dependency as a synthetic-lethal partner in DLBCL","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L3","title":"BTK degradation plus BCL2/NF-κB co-targeting in ABC/MCD-like DLBCL","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L4","title":"Dual PI3K/HDAC inhibition (BEBT-908/ifupinostat) + rituximab in R/R DLBCL","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L5","title":"Biomarker-adaptive early T-cell redirection in high-risk frontline DLBCL","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["Does STM2457 + rituximab (or + venetoclax) reproduce in isogenic rituximab-resistant DE-DLBCL lines beyond U-2932, and is the CTNNB1 m6A site truly YTHDF2-dependent given canonical YTHDF2 decay function?","Is there any DLBCL-selective therapeutic window for OGT inhibition, i.e. does O-GlcNAc loss kill lymphoma cells at doses sparing normal B and myeloid progenitors?","What DLBCL-specific response and resistance data exist for BTK degraders (BGB-16673) — do responses occur in BTKi-refractory ABC-DLBCL, and what are the emergent mutations?","Which selector — interim PET, ctDNA MRD, or both — identifies patients who benefit from frontline engager intensification, and do CD3+ malignant B cells / TGF-β-driven M2 macrophages predict engager failure?","In the EZB/GCB genotypes, does dual PI3K/HDAC inhibition (BEBT-908) show genotype-restricted benefit, and does it phenocopy EZH2 inhibition (tulmimetostat, NCT04104776)?"],"nextQueries":["\"diffuse large B-cell lymphoma\" AND (METTL3 OR m6A OR STM2457) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"diffuse large B-cell lymphoma\" AND (\"BTK degrader\" OR BGB-16673 OR NX-5948 OR \"pirtobrutinib\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"large B-cell lymphoma\" AND (\"circulating tumor DNA\" OR ctDNA OR \"minimal residual disease\") AND (glofitamab OR epcoritamab OR mosunetuzumab OR \"CAR T\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"42596901","doi":"10.1080/13696998.2026.2714649","year":2026,"isNew":true,"title":"Impact on health outcomes of treating all eligible large B-cell lymphoma patients with axicabtagene ciloleucel in Portugal - A modeling approach"},{"pmid":"42532836","doi":"10.1080/21645515.2026.2712177","year":2026,"isNew":true,"title":"Mosunetuzumab: A bispecific CD20 × CD3 antibody for follicular lymphoma with promising evidence in other B-NHL subtypes"},{"pmid":"42482660","doi":"10.1080/07853890.2026.2697132","year":2026,"isNew":true,"title":"Interim PET response of Pola-R-CHP predicts outcome in previously untreated CD5-positive diffuse large B-cell lymphoma: a multicenter retrospective study"},{"pmid":"42420780","doi":"10.1080/16078454.2026.2700818","year":2026,"isNew":true,"title":"Integrated multi-omics analysis identifies prognostic risk genes and constructs a predictive signature in diffuse large B-cell lymphoma"},{"pmid":"42295078","doi":"10.1080/14756366.2026.2674446","year":2026,"isNew":true,"title":"Shikonin suppresses diffuse large B-cell lymphoma progression by inducing ferritinophagy and ferroptosis &lt;i&gt;via&lt;/i&gt; lncRNA ADPGK-AS1 downregulation"},{"pmid":"42256552","doi":"10.1016/j.pscia.2026.100125","year":2026,"isNew":true,"title":"Therapeutic potential of the sphingosine kinase 2 inhibitor opaganib"},{"pmid":"42247321","doi":"10.1080/15384047.2026.2684140","year":2026,"isNew":true,"title":"Neoplastic CD3⁺ B cells remodel the DLBCL tumor microenvironment via single-cell and spatial transcriptomics"},{"pmid":"42070121","doi":"10.1080/2162402x.2026.2667160","year":2026,"isNew":true,"title":"Trial watch: antibody-drug conjugates in cancer therapy"},{"pmid":"42242087","doi":"10.1016/j.prp.2026.156559","year":2026,"isNew":true,"title":"Mechanism of METTL3 promoting rituximab resistance via β-catenin/MYC axis in double-expressor diffuse large B cell lymphoma"},{"pmid":"42593144","doi":"10.1080/10428194.2026.2712107","year":2026,"isNew":true,"title":"Effects of O-GlcNAc glycosylated modified transferase on prognosis of diffuse large B-cell lymphoma and analysis of downstream targets"}],"trialsShown":[{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06792253","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Study Comparing BEBT-908 Combined With R to SOC for the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma"},{"nct":"NCT04104776","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas"},{"nct":"NCT06781359","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Study on Plasmablastic Lymphoma Patients"},{"nct":"NCT03226704","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Leukapheresis for CAR or Adoptive Cell Therapy Manufacturing"},{"nct":"NCT03223610","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (ViPOR) in Relapsed/Refractory B-cell Lymphoma"},{"nct":"NCT04980222","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Evaluate the Safety and Efficacy of Glofitamab in Combination With Rituximab (R) Plus Cyclophosphamide, Doxorubicin, Vincristine,"},{"nct":"NCT02203526","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (TEDDI-R) in Pri"}],"usage":{"input":8710,"output":5915},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"diffuse large B-cell lymphoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"diffuse large B-cell lymphoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42596901","PMID:42532836","PMID:42482660","PMID:42420780","PMID:42295078","PMID:42256552","PMID:42247321","PMID:42070121","PMID:42242087","PMID:42593144","NCT05006716","NCT06792253","NCT04104776","NCT06781359","NCT03226704","NCT03223610","NCT04980222","NCT02203526"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787157154833","cycle":43,"visit":1,"ts":"2026-08-19T16:32:34.833Z","cancer":{"key":"waldenstrom macroglobulinemia","name":"Waldenstrom macroglobulinemia","mondo":{"id":"MONDO:0100280","name":"Waldenstrom macroglobulinemia"}},"control":false,"modelLabel":"SCIENCE","summary":"In BTKi-treated WM, ⁶⁸Ga-pentixafor PET/CT response dissociates from IgM-based IWWM response, nominating CXCR4-high residual clones as the tractable BTKi-resistance compartment and motivating imaging-guided CXCR4-antagonist/BTKi combinations alongside BTK degrader (BGB-16673) and MYD88-downstream (M","confidence":0.55,"notebook":"Programme opens on MYD88-mutant lymphoplasmacytic lymphoma. First correction: the KG anchor labels MYD88 \"causal/germline-likely\" — in WM the actionable event is MYD88 L265P, a **somatic** gain-of-function allele present in ~90–95% of cases that assembles a myddosome with IRAK1/4 and drives NF-κB via BTK/HCK [KNOWN]; germline MYD88 variants (immunodeficiency) are a different biology and must not be conflated. Familial WM predisposition exists but is not MYD88-anchored [SPECULATIVE]; the natural-history/high-risk-family registries here (NCT00923507, NCT00039676) are the only route to that question. P9 (PMID:42352898) corroborates the MYD88/CXCR4 dyad, BTKi-centred therapy, and BTKi resistance as the central unmet need.\n\nFour leads open. (1) CXCR4 axis. P10 (PMID:42113823) is the most mechanistically interesting item: in 33 WM/LPL patients, ⁶⁸Ga-pentixafor PET/CT response diverged from IgM/M-protein IWWM response specifically in the BTKi arm (18/33) while chemoimmunotherapy showed 93% concordance. [INFERRED] CXCR4-high clones persist anatomically under BTKi while IgM falls — consistent with WHIM-like CXCR4^S338X conferring BTKi resistance and AKT/ERK-mediated marrow retention [KNOWN]. Testable: pentixafor-guided addition of a CXCR4 antagonist (mavorixafor, ulocuplumab) to zanubrutinib; ¹⁷⁷Lu-pentixather theranostics [SPECULATIVE]. Normal-tissue caveat: CXCR4 is essential for HSC niche retention and neutrophil homeostasis — expect mobilisation/leukocytosis as the window-limiting toxicity.\n\n(2) BTK protein degradation/non-covalent occupancy to defeat C481S and the kinase-dead/non-covalent-resistant L528W and T474 alleles: BGB-16673 (NCT05006716) and nemtabrutinib (NCT04728893) both accrue B-cell malignancies including WM. Degradation should be genotype-agnostic where scaffolding-only mutant BTK persists [INFERRED]. (3) Node-shifting below BTK: EXS73565 (NCT06980116) is, to my knowledge, a MALT1-directed agent [KNOWN, low confidence — the pack does not state mechanism]; MALT1/IRAK4 inhibition would bypass all BTK-binding-site resistance in MYD88 L265P disease. Must verify mechanism before promoting. (4) Transformed WM: P4 (PMID:41797694) — 15 transformations, 86.7% non-GCB DLBCL, 33% CNS/testis, median OS 26 months, BTKi-based salvage associated with longer OS (p=0.007). Small, retrospective, selection-biased, but mechanistically coherent with MYD88/CD79B non-GCB biology and CNS-penetrant BTKi.\n\nNotebook negatives/low-yield to avoid re-proposing: P3 (PROTAC review) covers GPX4/PARP/epigenetic degraders only — no WM relevance; P5 (Raman serum spectroscopy), P8 (IgM myeloma, MYD88/CXCR4 wild-type — a diagnostic exclusion, not a WM lead), P1 (DFPP safety; hyperviscosity supportive care) are not therapeutic hypotheses. P2 (ibrutinib gut microbiome) is hypothesis-generating for diarrhoea toxicity only. P6 flags that anti-MAG neuropathy disability persists despite clone eradication — a clone-independent effector problem worth a future lead. P7 (MBD1/BCL6) is GC-derived biology, off-target for LPL.","leadChanges":[{"id":"L1","title":"Pentixafor-guided CXCR4 antagonism to eradicate BTKi-persistent WM clones","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L2","title":"BTK degradation and non-covalent BTK occupancy for BTKi-resistant MYD88-mutant WM","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L3","title":"Bypassing BTK entirely: MALT1/IRAK4 blockade downstream of the L265P myddosome","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L4","title":"BTKi-based salvage for histologic transformation of WM to non-GCB DLBCL, including immune-privileged sites","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["Does ⁶⁸Ga-pentixafor uptake in BTKi-treated WM track CXCR4^WHIM genotype and marrow MYD88 L265P MRD, or merely tumour bulk?","Which BTK/PLCG2 resistance alleles actually emerge in WM (vs CLL) on zanubrutinib, and does BGB-16673 clear L528W-bearing clones?","What is the disclosed molecular target of EXS73565, and is MALT1 or IRAK4 the superior MYD88-L265P-downstream node in WM models?","Is the BTKi survival signal in transformed WM (PMID:41797694) reproducible in a larger, genotyped, immortal-time-corrected cohort?","Which agents have WM-specific post-BTKi activity — venetoclax, CD19/CD22 CAR-T (NCT06340737), BCMA-directed therapy — and what response criteria should be used given IgM/imaging discordance?","Why does anti-MAG neuropathy disability persist after clone-directed therapy, and is a complement- or antibody-clearance strategy needed rather than deeper clone suppression?"],"nextQueries":["(\"Waldenstrom\" OR \"lymphoplasmacytic lymphoma\") AND (CXCR4 OR pentixafor OR mavorixafor OR ulocuplumab) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"Waldenstrom\" OR \"MYD88 L265P\") AND (\"BTK degrader\" OR BGB-16673 OR NX-5948 OR pirtobrutinib OR \"L528W\" OR \"C481S\") AND SRC:MED","(\"Waldenstrom\" OR \"lymphoplasmacytic\") AND (MALT1 OR IRAK4 OR HCK OR venetoclax OR \"CAR-T\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42226480","doi":"10.1080/0886022x.2026.2667592","year":2026,"isNew":true,"title":"Risk factors for hypotension and technical complications during single-session double-filtration plasmapheresis: a 15-year retrospective study of 1,022 procedures"},{"pmid":"42002835","doi":"10.1080/19490976.2026.2659397","year":2026,"isNew":true,"title":"Longitudinal gut microbiome dynamics are associated with clinical outcome and toxicity during ibrutinib therapy"},{"pmid":"41885448","doi":"10.1080/14756366.2026.2636394","year":2026,"isNew":true,"title":"PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators"},{"pmid":"41797694","doi":"10.1080/07853890.2026.2624909","year":2026,"isNew":true,"title":"A single-center retrospective study suggests a potential benefit of BTK inhibitor-based therapy in patients with histologic transformation of Waldenström macroglobulinemia"},{"pmid":"42085818","doi":"10.1016/j.saa.2026.127980","year":2026,"isNew":true,"title":"Laser Raman spectroscopy-based characterization of metabolic heterogeneity in lymphoplasmacytic lymphoma and diffuse large B-cell lymphoma"},{"pmid":"42570342","doi":"10.1097/cco.0000000000001260","year":2026,"isNew":true,"title":"Peripheral neuropathies associated with immunoglobulin M monoclonal gammopathies and low-grade B-cell lymphomas: diagnostic and therapeutic approach"},{"pmid":"42563211","doi":"10.1002/hon.70227","year":2026,"isNew":true,"title":"DNA Replication Stress-Induced Transcriptome of Human Burkitt's Lymphoma Identifies Reciprocal Regulation Between MBD1 and BCL6 During Germinal Center-Derived B-Lymphomagenesis"},{"pmid":"41424304","doi":"10.4103/aam.aam_356_25","year":2026,"isNew":true,"title":"Immunoglobulin M Multiple Myeloma: Case Report of a Rare Variant of Multiple Myeloma with Diagnostic and Treatment Challenges"},{"pmid":"42352898","doi":"10.3390/ijms27125173","year":2026,"isNew":true,"title":"Decoding Waldenström Macroglobulinemia Through Genomics, Epigenomics and Cellular Interactions"},{"pmid":"42113823","doi":"10.1097/rlu.0000000000006518","year":2026,"isNew":true,"title":"68 Ga-pentixafor PET/CT Indicates Inconsistent Response With Monoclonal Protein-based Response Criteria in Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma Patients Treated"}],"trialsShown":[{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT00923507","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphopla"},{"nct":"NCT04728893","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)"},{"nct":"NCT06980116","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Dose Determining Study of EXS73565 in Participants With Relapsed or Refractory B-Cell Malignancies"},{"nct":"NCT00039676","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Clinical, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Hematologic Cancer"},{"nct":"NCT06340737","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"AutologousCD22 Chimeric Antigen Receptor (CAR)T Cells in w/Recurrent/Refractory B Cell Lymphomas"},{"nct":"NCT07426484","phase":"phase 4","status":"RECRUITING","isNew":true,"title":"Cosibelimab for CSCC in Patients With Kidney Transplant or Hematologic Malignancy"},{"nct":"NCT07169331","phase":"phase 4","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Evaluate the Efficacy and Safety of Zanubrutinib in Chinese Adults With Treatment-Naive Waldenström Macroglobulinemia"}],"usage":{"input":8828,"output":6214},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Waldenstrom macroglobulinemia\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Waldenstrom macroglobulinemia\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42226480","PMID:42002835","PMID:41885448","PMID:41797694","PMID:42085818","PMID:42570342","PMID:42563211","PMID:41424304","PMID:42352898","PMID:42113823","NCT05006716","NCT00923507","NCT04728893","NCT06980116","NCT00039676","NCT06340737","NCT07426484","NCT07169331"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787156950034","cycle":42,"visit":1,"ts":"2026-08-19T16:29:10.034Z","cancer":{"key":"multiple myeloma","name":"multiple myeloma","mondo":{"id":"MONDO:0009693","name":"plasma cell myeloma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise antigen-escape-aware BCMA sequencing (γ-secretase/antigen-density biomarkers, multi-antigen switch) and test the 1q21-amplification hypothesis for isatuximab-versus-daratumumab selection, while tracking p300/CBP inhibition (inobrodib) as the leading mechanistically orthogonal new class.","confidence":0.55,"notebook":"Visit 1 opens the myeloma programme. The KG anchor is thin: CCND1 [SOMATIC] (t(11;14) IGH-CCND1 juxtaposition, the venetoclax-sensitive subgroup [KNOWN]) and LIG4 [SOMATIC-likely, NHEJ ligase] — neither has any supporting citation in this pack, so I bank them as open questions rather than leads. Five pack items (P2 bortezomib LC-MS/MS bioanalysis, P4 gynaecological ferroptosis, P5 iMCD-TAFRO, P6 shikonin in DLBCL, P8 GSH/H2S review) carry no myeloma-specific therapeutic hypothesis; logged as non-actionable so the desk does not re-mine ferroptosis/redox reviews for this disease.\n\nMechanistically the highest-value input is P9: resistance to BCMA-directed therapy is modality-partitioned — antigen escape (TNFRSF17 biallelic loss, non-truncating BCMA extracellular-domain mutations, γ-secretase shedding, transcriptional silencing) dominates after bispecifics, whereas T-cell exhaustion/trogocytosis dominates post-CAR-T, and a \"plasma cell identity escape\" state (proliferative, lineage-divergent, BCMA-low) predicts primary refractoriness across modalities. That reframes elranatamab (P3) not as an endpoint but as a scaffold whose failure mode is predictable and pre-specifiable — hence T1 (AZD0305 ± elranatamab/Pd; AZD0305 mechanism not disclosed in the record, flagged) and T2 (belantamab mafodotin combinations, an ADC that is antigen-density-dependent and therefore vulnerable to the same shedding axis) [INFERRED].\n\nP10 gives the second lead: daratumumab and isatuximab are mechanistically non-interchangeable — isatuximab binds near the CD38 catalytic site (enzyme inhibition, internalisation, FOXM1 suppression, ROS) with proposed preferential activity in 1q21-amplified disease, while daratumumab's Fc-dependent trogocytosis strips CD38 and VLA-4, blunting cell-adhesion-mediated drug resistance and possibly priming subsequent T-cell redirection. This is a genotype-directed sequencing hypothesis testable retrospectively in existing dara-containing phase 3 cohorts (T3, T4, T8).\n\nT6 (inobrodib, p300/CBP bromodomain inhibition, phase 3 vs standard therapy with Pd) is a first-in-class epigenetic lead: p300/CBP sustains the IRF4–MYC plasma-cell transcriptional programme [KNOWN], mechanistically orthogonal to proteasome, IMiD and BCMA pressure. P1 (XVRd, XPO1 inhibition) is the weakest clinical lead — ORR 93.3% in 30 patients, 80% with extramedullary/PCL disease, but only 16.7% MRD-negative post-induction, single-arm and observational; I record the depth-of-response shortfall now so a future visit cannot over-read the ORR. P7 (RBMS1 stabilising PDPK1 mRNA → β-catenin, CCL2-driven M2 TAM polarisation) is preclinical single-paper biology but nominates a druggable node (PDPK1/PDK1; CCR2 axis) in the myeloma macrophage niche.\n\nNext visit I need: BCMA antigen-density biomarker data, GPRC5D/FcRH5 sequencing outcomes, 1q21-stratified CD38-mAb data, and any t(11;14)/CCND1 or NHEJ/LIG4 synthetic-lethality evidence.","leadChanges":[{"id":"L1","title":"Antigen-escape-adapted BCMA immunotherapy: pre-specify BCMA density/shedding and switch antigen rather than re-treat","level":"LEAD","status":"NEW","confidence":0.62},{"id":"L2","title":"Genotype-directed choice of anti-CD38 antibody: isatuximab for 1q21-amplified myeloma, daratumumab as immune primer before T-cell redirection","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L3","title":"p300/CBP bromodomain inhibition (inobrodib) as a transcription-addiction attack orthogonal to proteasome, IMiD and BCMA pressure","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L4","title":"XPO1 inhibition (selinexor) added to VRd for high-risk NDMM with extramedullary/plasma-cell-leukaemia biology — depth of response is the limiting problem","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L5","title":"RBMS1-PDPK1-beta-catenin axis and CCL2-driven M2 macrophage polarisation as a stromal-immune target in the myeloma niche","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does adding a gamma-secretase inhibitor to a BCMA bispecific raise surface BCMA density and salvage antigen-low relapse, and at what Notch-related toxicity cost?","Is the 1q21-amplification/FOXM1 hypothesis for preferential isatuximab activity supported by any stratified randomised or real-world outcome data, or only by mechanism?","What is the mechanism and target of AZD0305 (NCT06106945), and how does its elranatamab combination differ from existing BCMA doublets?","Does t(11;14)/CCND1 [SOMATIC] status predict response to any agent in this programme (venetoclax, inobrodib), and is there myeloma-specific evidence for CCND1-directed vulnerability?","Is LIG4 [SOMATIC-likely] alteration in myeloma an NHEJ-deficiency state exploitable by PARP inhibition, ATM/ATR or POLQ inhibition, or merely a correlate of genomic instability?","Do inobrodib phase 3 data or supporting mechanistic literature confirm IRF4/MYC collapse as the on-target pharmacodynamic readout in myeloma?"],"nextQueries":["(\"multiple myeloma\") AND (\"BCMA\" OR \"TNFRSF17\") AND (\"antigen loss\" OR \"gamma-secretase\" OR \"GPRC5D\" OR \"FcRH5\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"multiple myeloma\") AND (\"1q21\" OR \"CKS1B\" OR \"gain(1q)\") AND (isatuximab OR daratumumab OR CD38) AND SRC:MED","(\"multiple myeloma\") AND (\"t(11;14)\" OR CCND1 OR venetoclax OR LIG4 OR \"non-homologous end joining\") AND (resistance OR \"synthetic lethality\" OR biomarker) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42544613","doi":"10.1080/07853890.2026.2703403","year":2026,"isNew":true,"title":"Selinexor combined bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma with high-risk factors: a single-arm, multi-center, prospective observational cl"},{"pmid":"42526316","doi":"10.1016/j.jpba.2026.117686","year":2026,"isNew":true,"title":"A fast method for the quantification of bortezomib in serum and rat nervous tissue by liquid chromatography tandem mass spectrometry"},{"pmid":"42415463","doi":"10.1080/21645515.2026.2694852","year":2026,"isNew":true,"title":"Elranatamab: A novel B-cell maturation T-cell engager"},{"pmid":"42318797","doi":"10.1080/07853890.2026.2688328","year":2026,"isNew":true,"title":"Research progress of ferroptosis in gynecological diseases"},{"pmid":"42310940","doi":"10.1080/0886022x.2026.2671463","year":2026,"isNew":true,"title":"Successful treatment of idiopathic multicentric Castleman disease with TAFRO and kidney involvement: case report and literature review"},{"pmid":"42295078","doi":"10.1080/14756366.2026.2674446","year":2026,"isNew":true,"title":"Shikonin suppresses diffuse large B-cell lymphoma progression by inducing ferritinophagy and ferroptosis &lt;i&gt;via&lt;/i&gt; lncRNA ADPGK-AS1 downregulation"},{"pmid":"42277590","doi":"10.1080/15384101.2026.2686804","year":2026,"isNew":true,"title":"RBMS1 enhances PDPK1 mRNA stability to promote multiple myeloma malignancy and M2 macrophage polarization"},{"pmid":"42275298","doi":"10.1080/13510002.2026.2687238","year":2026,"isNew":true,"title":"Significance of GSH and H&lt;sub&gt;2&lt;/sub&gt;S regulation for cancer: an intricate interplay between diet, microbiota, metabolic reprogramming, and immune health"},{"pmid":"42434875","doi":"10.1080/14712598.2026.2703858","year":2026,"isNew":true,"title":"Potential of new BCMA-targeting therapies in overcoming resistance in multiple myeloma"},{"pmid":"42587741","doi":"10.3390/cells15151331","year":2026,"isNew":true,"title":"Mechanistic and Clinical Differences Between Daratumumab and Isatuximab in Multiple Myeloma: Emerging Roles of 1q Gain and Immune Remodeling"}],"trialsShown":[{"nct":"NCT06106945","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"AZD0305 as Monotherapy or in Combination With Anticancer Agents in Participants With Multiple Myeloma"},{"nct":"NCT05714839","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study to Investigate the Safety and Efficacy of Belantamab for the Treatment of Multiple Myeloma When Used as Monotherapy and in Combinati"},{"nct":"NCT03937635","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Lenalidomide, and Dexamethasone With or Without Daratumumab in Treating Patients With High-Risk Smoldering Myeloma"},{"nct":"NCT04566328","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Testing the Use of Combination Therapy in Adult Patients With Newly Diagnosed Multiple Myeloma, the EQUATE Trial"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT07772024","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Inobrodib, Pomalidomide and Dexamethasone Versus Standard Available Therapy in Relapsed or Refractory Multiple Myeloma"},{"nct":"NCT04898790","phase":"NA","status":"RECRUITING","isNew":true,"title":"Improving Cognitive Function in Older Adults Undergoing Stem Cell Transplant"},{"nct":"NCT07485647","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Identifying Effective and Cost-Conscious Maintenance Daratumumab Dosing"}],"usage":{"input":8522,"output":6318},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"multiple myeloma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"multiple myeloma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42544613","PMID:42526316","PMID:42415463","PMID:42318797","PMID:42310940","PMID:42295078","PMID:42277590","PMID:42275298","PMID:42434875","PMID:42587741","NCT06106945","NCT05714839","NCT03937635","NCT04566328","NCT06904066","NCT07772024","NCT04898790","NCT07485647"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787156740930","cycle":41,"visit":1,"ts":"2026-08-19T16:25:40.930Z","cancer":{"key":"myelodysplastic syndrome","name":"myelodysplastic syndrome","mondo":{"id":"MONDO:0018881","name":"myelodysplastic syndrome"}},"control":false,"modelLabel":"SCIENCE","summary":"Two independent 2026 signals — clinical BCL-xL co-dependence in venetoclax/HMA-refractory MDS (PMID:42189880) and preclinical XPO1 inhibition restoring nuclear p53 with venetoclax synergy (PMID:42007609, NCT06399640) — make TP53-wild-type, HMA-failure MDS the priority setting for combinatorial mitoc","confidence":0.5,"notebook":"Visit 1 opens the MDS programme. The pack is mostly noise (BKPyV virology, HPV vaccination, osteosarcoma KIF18A, pHGG case report, sterilisation cohort — no MDS relevance; logged so the desk does not re-mine them). Four signals are usable, and two of them converge on the same mitochondrial-apoptosis axis.\n\nConvergence 1 — apoptotic priming in HMA-failure MDS. P1 (PMID:42189880, NCT05455294) is the first clinical read-out here: BCL-xL co-dependence is proposed as the mechanism of venetoclax/HMA failure in MDS-EB, MDS/MPN overlap and secondary AML, and dual inhibition with navitoclax + venetoclax + decitabine was dose-escalated at only 25–50 mg navitoclax with grade ≥3 thrombocytopenia in 69%. [KNOWN] BCL-xL is the survival factor of the megakaryocyte/platelet lineage, so in a disease defined by cytopenias the therapeutic window is the whole argument — [INFERRED] this predicts that unselective BCL-xL antagonism is window-limited in MDS and that platelet-sparing strategies (lineage-restricted degraders, intermittent dosing) are the real path. Truncated abstract: efficacy data not visible, so I record this as mechanistically informative, clinically unproven.\n\nConvergence 2 — XPO1. P10 (PMID:42007609) reports XPO1 overexpression across MDS risk strata and selinexor-induced apoptosis via blocked nuclear export of p53, synergising with venetoclax through ROS/mitochondrial priming (preclinical, GEO + cell lines only). NCT06399640 independently puts eltanexor + venetoclax into R/R MDS/AML in the clinic. [INFERRED] If the mechanism is p53 nuclear retention, then TP53-mutant MDS — the anchor gene with the worst prognosis, reconfirmed exploratorily in P7 (PMID:41972336) — should be intrinsically resistant, and the trial must be read TP53-stratified. That is the sharpest falsifiable prediction I can set this visit.\n\nThird lead: pacritinib (NCT06303193, plus NCT06782373 in VEXAS) as a multi-kinase IRAK1/CSF1R/JAK2/FLT3 inhibitor. [KNOWN] IRAK1/4 hyperactivation downstream of TRAF6 and, in spliceosome-mutant MDS, the IRAK4-long isoform generated by U2AF1/SF3B1 [SOMATIC] missplicing, makes innate-immune signalling a maintenance dependency distinct from clonal cytotoxicity; CSF1R blockade additionally targets the inflammatory monocyte compartment. Peri-transplant ruxolitinib (NCT07228624) is adjacent evidence that JAK inhibition is tolerable in this population.\n\nFourth: olutasidenib in IDH1-mutant CCUS/lower-risk MDS/CMML (NCT06566742) — clonal interception before blast escalation; a differentiation-agent hypothesis, not cytoreduction.\n\nI decline to open a lead on NK/CAR-NK therapy (PMID:42033215) — a generic review with no MDS-specific antigen (no CD123/TIM-3 data in the pack).","leadChanges":[{"id":"L1","title":"XPO1 inhibition (selinexor/eltanexor) plus venetoclax in HMA-refractory MDS, restricted to TP53-wild-type disease","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"BCL-xL co-dependence as the venetoclax-resistance node in MDS with excess blasts — pursue platelet-sparing BCL-xL antagonism","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L3","title":"Innate-immune kinase blockade (pacritinib: IRAK1/CSF1R/JAK2/FLT3) in MDS and MDS/MPN overlap","level":"LEAD","status":"NEW","confidence":0.38},{"id":"L4","title":"IDH1 inhibition (olutasidenib) as clonal interception in IDH1-mutant CCUS and lower-risk MDS/CMML","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["Does XPO1-inhibitor/venetoclax activity in MDS segregate by TP53 status, and is there any published response data (not just synergy indices) in TP53-mutant MDS?","Are there platelet-sparing ways to drug BCL-xL in MDS (lineage-directed degraders, intermittent schedules), and does a BCL2:BCL2L1 or BH3-profiling biomarker prospectively identify the co-dependent patients?","Is the IRAK4-long isoform / TRAF6 inflammatory axis validated as a dependency specifically in SF3B1- and U2AF1-mutant MDS, and does pacritinib or an IRAK4-selective agent reduce IRAK4-L signalling in patient marrow?","For germline predisposition anchors (SAMD9/SAMD9L, GATA2, ASXL1 [GERMLINE]), is there any therapeutic or transplant-timing hypothesis distinct from somatic-clone targeting?","Which MDS-specific surface antigens (CD123, TIM-3, CD70, WT1 neoantigen) have actual MDS data supporting NK-engager, CAR or TCR approaches such as NCT06904066?","Does iron overload (ferritin >=500) act as a modifiable driver of oxidative stress/HMA resistance in MDS, or is it only a prognostic marker (PMID:41972336)?"],"nextQueries":["(\"myelodysplastic syndrome\" OR \"MDS\") AND (venetoclax OR \"BCL-2\" OR \"BCL-xL\" OR MCL1) AND (resistance OR \"BH3 profiling\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"myelodysplastic\" AND (SF3B1 OR U2AF1 OR SRSF2) AND (IRAK4 OR TRAF6 OR \"splicing modulator\" OR \"synthetic lethal\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"myelodysplastic syndrome\" AND (TP53 OR \"del(5q)\" OR TET2) AND (\"targeted therapy\" OR CAR OR \"NK cell\" OR CD123 OR TIM-3)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"42189880","doi":"10.1158/1078-0432.ccr-25-4905","year":2026,"isNew":true,"title":"Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A Phase I Dose-Escalation Study of Navitoclax, Venetoclax, and Decitabine"},{"pmid":"42328720","doi":"10.1080/15384047.2026.2689181","year":2026,"isNew":true,"title":"KIF18A inhibitor prevents chromosomally unstable osteosarcoma growth by activating spindle assembly checkpoint"},{"pmid":"42223211","doi":"10.1080/21505594.2026.2679815","year":2026,"isNew":true,"title":"Do BKPyV genomic features underlie clinical divergence between kidney and hematopoietic transplant recipients?"},{"pmid":"42148544","doi":"10.1080/07853890.2026.2654287","year":2026,"isNew":true,"title":"A cohort study on inflammatory response and coagulation function changes in women with silver clip or silk ligation sterilisation"},{"pmid":"42047045","doi":"10.1080/21645515.2026.2664310","year":2026,"isNew":true,"title":"The use of the HPV vaccine in a group of primarily unvaccinated HPV-positive patients"},{"pmid":"42033215","doi":"10.1080/15384047.2026.2658896","year":2026,"isNew":true,"title":"Advances in natural killer cell immunotherapy for hematologic malignancies"},{"pmid":"41972336","doi":"10.1080/16078454.2026.2657628","year":2026,"isNew":true,"title":"A survival prognostic model for high-risk myelodysplastic syndrome patients treated with decitabine"},{"pmid":"41877551","doi":"10.1080/20450907.2026.2641996","year":2026,"isNew":true,"title":"Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass C with &lt;i&gt;SYN2&lt;/i&gt;::&lt;i&gt;PPARG&lt;/i&gt; fusion in an older adult"},{"pmid":"41840938","doi":"10.1080/07853890.2026.2635832","year":2026,"isNew":true,"title":"Cord blood transfusion added matched unrelated donor transplantation as a preferable choice for aplastic anaemia: a comparative study from a single centre"},{"pmid":"42007609","doi":"10.1002/jcla.70229","year":2026,"isNew":true,"title":"Exportin 1 Inhibitor Combined With Venetoclax Induces Apoptosis in Myelodysplastic Syndrome by Mitochondria-Induced Apoptosis Pathway"}],"trialsShown":[{"nct":"NCT07228624","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Ruxolitinib Before, During and After Hematopoietic Cell Transplant in Older Patients With Myelofibrosis and Myelodysplastic Syndrome/Myelopr"},{"nct":"NCT06399640","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Eltanexor and Venetoclax in Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT06782373","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Assess the Effectiveness and Safety of Pacritinib in Patients With VEXAS Syndrome (PAXIS)"},{"nct":"NCT06303193","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysp"},{"nct":"NCT04898790","phase":"NA","status":"RECRUITING","isNew":true,"title":"Improving Cognitive Function in Older Adults Undergoing Stem Cell Transplant"},{"nct":"NCT02521493","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syn"}],"usage":{"input":9331,"output":5317},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"myelodysplastic syndrome\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"myelodysplastic syndrome\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42189880","PMID:42328720","PMID:42223211","PMID:42148544","PMID:42047045","PMID:42033215","PMID:41972336","PMID:41877551","PMID:41840938","PMID:42007609","NCT07228624","NCT06399640","NCT06904066","NCT06566742","NCT06782373","NCT06303193","NCT04898790","NCT02521493"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787156547148","cycle":40,"visit":1,"ts":"2026-08-19T16:22:27.148Z","cancer":{"key":"chronic lymphocytic leukemia","name":"chronic lymphocytic leukemia","mondo":{"id":"MONDO:0004948","name":"B-cell chronic lymphocytic leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritize BTK degraders (BGB-16673/bexobrutideg, NX-5948) as the mechanism-matched strategy for kinase-impaired BTK mutants (L528W/T474) after covalent and non-covalent BTKi failure, and define their resistance routes before promotion.","confidence":0.55,"notebook":"Programme opens with a pack that is heavily BCR-axis weighted and otherwise noisy. Discard as non-informative for CLL: P3 (CDK2 carboxamides, tested only in HepG2/MCF-7/MDA-MB-231, no lymphoid data), P4 (vaccine autoantibodyome, irrelevant), P5/P6/P7 (generic TPD, CAR-T preconditioning, NK reviews with no CLL-specific data), P2 (ibrutinib polymer-lipid nanoparticles assayed in K562 — a CML erythroleukemia line with no BTK dependence, so the cytotoxicity readout does not support a CLL claim; oral bioavailability of ibrutinib is not the clinical bottleneck anyway). T5, T7, T8 are non-CLL diseases. Recorded so the desk does not re-propose them.\n\nWhat is real: the resistance cascade after covalent BTKi → non-covalent BTKi → BCL2i is now the organizing problem. Covalent-BTKi escape via BTK C481S is answered by pirtobrutinib, but non-covalent escape via kinase-impaired/scaffold BTK mutants (L528W, T474I/L, A428D) [SOMATIC][KNOWN] cannot be solved by occupancy-based inhibition, because the mutant protein still nucleates BCR signalling. Degradation is the mechanistically correct answer, and the pack gives convergent clinical support: BGB-16673 (bexobrutideg) and NX-5948 produce rapid deep responses including in high-risk molecular subgroups with RP2Ds set (PMID:42252468), with medicinal-chemistry rationale for selective BTK PROTACs over the 500-kinase kinome reviewed in PMID:42587792, and two active trials (NCT07221500 in double-exposed BTKi/BCL2i patients; NCT05005716-adjacent dose expansion NCT05006716). This is Lead 1 — strongest of the visit, but still LEAD at level: the evidence is single-visit and largely conference-abstract grade. Window argument: BTK is confined to B cells, myeloid cells and platelets; complete degradation should mimic XLA — hypogammaglobulinaemia and infection risk, plus possible platelet/ITAM effects, deeper than inhibition [INFERRED].\n\nLead 2: dual LYN/BTK inhibition (birletinib) reported high ORR after BTKi, BCL2i *and* degrader exposure (PMID:42252468) — implies proximal Src-family redundancy sustains BCR signalling once BTK is removed; LYN is also myeloid/platelet-expressed, so haematotoxicity is the window question.\n\nLead 3: preemptive dual-pathway fixed duration — sonrotoclax+zanubrutinib head-to-head vs venetoclax+acalabrutinib (NCT07277231), against the venetoclax-monotherapy and ibrutinib+venetoclax long-term benchmarks (NCT02966756, NCT07774390). Hypothesis: a more potent BCL2 inhibitor lowers residual disease enough to suppress emergence of BCL2 G101V/D103Y [SOMATIC][KNOWN].\n\nLead 4 (weak, exploratory): gut microbiome as modifiable covariate of ibrutinib response/diarrhoea — SCFA-saccharolytic recovery in responders vs bile-acid-modifying/proteolytic expansion in non-responders across 291 longitudinal samples, n=30 mixed haematologic malignancies (PMID:42002835). Association only; confounding by disease burden and antibiotics unaddressed.\n\nNotably, no lead yet exploits the KG anchors TP53, ATM, POT1, RPS15 — the pack contains nothing on synthetic lethality in ATM/TP53-disrupted CLL. That gap drives next visit.","leadChanges":[{"id":"L1","title":"BTK protein degradation for BTKi-resistant CLL/SLL with scaffold or kinase-impaired BTK mutants","level":"LEAD","status":"NEW","confidence":0.62},{"id":"L2","title":"Dual LYN/BTK inhibition to close Src-family redundancy after BTK degrader failure","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L3","title":"Preemptive dual BCL2/BTK blockade with next-generation agents to suppress BCL2 resistance mutations","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L4","title":"Gut microbiome remodelling as a modifiable determinant of ibrutinib response and diarrhoea","level":"LEAD","status":"NEW","confidence":0.22}],"unverifiedCitations":0,"openQuestions":["What are the resistance mechanisms at progression on BTK degraders — BTK downregulation/loss, PLCG2 gain-of-function, CRBN/E3-ligase machinery loss, or BCR-independent NF-kB — and are they degrader-specific?","Does dual LYN/BTK inhibition add clinical benefit beyond BTK degradation, and at what cost in neutropenia/thrombocytopenia given LYN's myeloid and platelet roles?","Do BCL2 mutations (G101V/D103Y) and MCL1/BCL-xL upregulation still emerge under sonrotoclax, or does potency-driven deeper MRD clearance genuinely suppress them?","Is there a synthetic-lethal strategy for ATM- and TP53-disrupted CLL [SOMATIC] (ATR, WEE1, PARP) and any actionable consequence of RPS15 or POT1 lesions — the KG anchors currently unaddressed by any lead?","How should germline POT1/ATM-associated familial CLL [GERMLINE] be separated from somatic 11q/17p loss when nominating targets, and does germline status change tolerability of DNA-damage-directed agents?","What is the mechanistic basis of Richter transformation on BTK degraders, and does deep BTK loss select for it?"],"nextQueries":["\"chronic lymphocytic leukemia\" AND (\"BTK degrader\" OR PROTAC OR bexobrutideg OR \"BGB-16673\" OR \"NX-5948\") AND resistance AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic lymphocytic leukemia\" AND (ATM OR TP53 OR POT1 OR RPS15) AND (\"synthetic lethality\" OR ATR OR WEE1 OR PARP) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"Richter transformation\" AND (mechanism OR genomic OR treatment) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42252468","doi":"10.1186/s13045-026-01810-w","year":2026,"isNew":true,"title":"Novel BTK inhibitors and degraders for relapsed/refractory CLL/SLL: latest updates from ASH 2025 annual meeting"},{"pmid":"42436867","doi":"10.1016/j.ijpx.2026.100593","year":2026,"isNew":true,"title":"Quality by design-based development of ibrutinib polymer-lipid hybrid nanoparticles for enhanced lymphatic absorption and anticancer efficacy"},{"pmid":"42210722","doi":"10.1080/14756366.2026.2656826","year":2026,"isNew":true,"title":"Design, synthesis, anticancer activity, and mechanistic investigation of 4,5,6,7-tetrahydrobenzo[&lt;i&gt;b&lt;/i&gt;]thiophene carboxamides as CDK-2 inhibitors: &lt;i&gt;in vitro&"},{"pmid":"42118165","doi":"10.1080/21645515.2026.2661499","year":2026,"isNew":true,"title":"Absence of autoantibodies linked to cancer and autoimmune disorders 26 weeks after BNT162b2 boosting in CoronaVac- primed individuals"},{"pmid":"42092750","doi":"10.1080/10717544.2026.2665871","year":2026,"isNew":true,"title":"Targeted proteoform degradation for precision drug design, delivery, and therapy"},{"pmid":"42088834","doi":"10.1016/j.synbio.2026.04.012","year":2026,"isNew":true,"title":"Remodeling memory T cells with chemotherapy and immune checkpoint inhibitors as host pre-conditioning to empower in vivo CAR-T therapy"},{"pmid":"42033215","doi":"10.1080/15384047.2026.2658896","year":2026,"isNew":true,"title":"Advances in natural killer cell immunotherapy for hematologic malignancies"},{"pmid":"42002835","doi":"10.1080/19490976.2026.2659397","year":2026,"isNew":true,"title":"Longitudinal gut microbiome dynamics are associated with clinical outcome and toxicity during ibrutinib therapy"},{"pmid":"41972453","doi":"10.1080/19420862.2026.2657099","year":2026,"isNew":true,"title":"Impact of afucosylation strategy on antibody function: a comparative study of glycoengineered anti-CD20 antibodies Obinutuzumab and Obinutuzumab beta"},{"pmid":"42587792","doi":"10.3390/cells15151383","year":2026,"isNew":true,"title":"Targeting Bruton's Tyrosine Kinase in CLL: Selectivity, Resistance Mechanisms, and Emerging Therapeutic Strategies"}],"trialsShown":[{"nct":"NCT02966756","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study of Venetoclax in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma"},{"nct":"NCT07221500","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Study of NX-5948 in Adults With CLL/SLL Previously Treated With a Bruton's Tyrosine Kinase Inhibitor and a B-cell Lymphoma-2 Inhibitor (DA"},{"nct":"NCT07774390","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Ibrutinib Plus Venetoclax Long-Term Outcomes in CLL"},{"nct":"NCT05006716","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT07277231","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Study to Investigate Sonrotoclax (BGB-11417) Plus Zanubrutinib (BGB-3111) Compared With Venetoclax Plus Acalabrutinib in Adults With Previ"},{"nct":"NCT05082519","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Caloric Restriction and Activity to Reduce Chemoresistance in B-ALL"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"}],"usage":{"input":8781,"output":5528},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic lymphocytic leukemia\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic lymphocytic leukemia\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42252468","PMID:42436867","PMID:42210722","PMID:42118165","PMID:42092750","PMID:42088834","PMID:42033215","PMID:42002835","PMID:41972453","PMID:42587792","NCT02966756","NCT07221500","NCT07774390","NCT05006716","NCT06904066","NCT07277231","NCT05082519","NCT03147612"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787156350416","cycle":39,"visit":1,"ts":"2026-08-19T16:19:10.416Z","cancer":{"key":"acute lymphoblastic leukemia","name":"acute lymphoblastic leukemia","mondo":{"id":"MONDO:0004967","name":"acute lymphoblastic leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"In ETV6-rearranged ALL, super-enhancer disruption lowers CDKN1B and drives NF-κB-dependent BCL-2/BCL-XL expression, so venetoclax plus dexamethasone should be tested prospectively in this genotype with BH3 profiling and MCL1 escape as the primary resistance readout.","confidence":0.55,"notebook":"Visit 1. The pack is largely off-target (quinoa tellurium stress, BKPyV genotyping, two bibliometric surveys, dietary-management consensus) — logged as non-evidence so the desk does not re-query bibliometrics. Two mechanistic papers and four trials carry all the signal.\n\nThe strongest new object is the ETV6-SE→CDKN1B axis (PMID:42525958). ETV6 rearrangement [SOMATIC] does not merely delete a repressor; it physically disrupts an intragenic super-enhancer whose long-range loop sustains CDKN1B transcription, and p27 loss activates NF-κB with induction of BCL-2/BCL-XL. That converts an undruggable fusion/tumour-suppressor lesion into a stated apoptotic dependency, and the paper already reports additivity of venetoclax or navitoclax with dexamethasone in PDX. Mechanistically satisfying because glucocorticoid killing is BIM-dependent [KNOWN], so lowering the BCL-2/BCL-XL buffer should be epistatically additive rather than merely convergent. Caveats from the abstract: \"additive,\" not synergistic; no MRD or survival endpoint stated; whether CDKN1B re-expression (CDK4/6 inhibition as surrogate) reproduces the effect is untested. Window argument: BCL-2 inhibition spares most normal tissue but depletes B/T lymphocytes; BCL-XL inhibition causes dose-limiting thrombocytopenia [KNOWN], so venetoclax is the translatable arm and navitoclax only if BCL-XL is the dominant node. Expected resistance: MCL1 upregulation, BAX/BAK loss, and NF-κB-driven rebound — all assayable by BH3 profiling.\n\nSecond new lead is antigen-directed: AZD0486/surovatamig monotherapy in B-ALL (NCT06137118) alongside tisagenlecleucel for EOC-MRD-positive HR B-ALL (NCT03876769) and NGS-MRD/B-cell-recovery-guided management post-CAR (NCT05621291). The programme-level hypothesis is sequencing, not novelty: a CD19xCD3 engager [KNOWN] as salvage where CD19 is retained after CAR exhaustion, with B-cell recovery/NGS-MRD as the trigger. Resistance routes: CD19 exon-2 skipping, lineage switch, T-cell fitness loss.\n\nT-ALL remains the programme's hole. The KG anchor is dominated by T-ALL lesions (TAL1, TLX1/TLX3, STIL::TAL1, NUP214::ABL1, MLLT10, MYB) and the only new asset is CTD402 CAR-T (NCT07070219); ABL1-fusion T-ALL is an [INFERRED] TKI-addressable subset by analogy to the BCR::ABL1 imatinib+chemotherapy backbone (NCT03007147).\n\nThe MALAT1/METTL14/exosome→TRIM27→HMGB1 NK-axis paper (PMID:42390539) is recorded as a low-confidence lead only: single laboratory, nude-mouse xenografts (NK-competent but T-deficient, weak support for an immune-communication claim), NK92-MI as the sole effector model, and no in vivo pharmacology.","leadChanges":[{"id":"L1","title":"ETV6-SE/CDKN1B loss as a biomarker for BCL-2 dependency: venetoclax + dexamethasone in ETV6-rearranged ALL","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"CD19 re-engagement sequencing: T-cell engager AZD0486 after CAR-T failure, triggered by NGS-MRD/B-cell recovery","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L3","title":"T-ALL subtype-directed therapy: CAR-T for relapsed T-ALL/LBL and ABL1-fusion-directed TKI","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L4","title":"Low-confidence: exosomal MALAT1/METTL14 → HMGB1 axis as an NK-directed chemoresistance node","level":"LEAD","status":"NEW","confidence":0.2}],"unverifiedCitations":0,"openQuestions":["Does venetoclax + dexamethasone in ETV6-rearranged ALL produce more than additivity in vivo, and is CDKN1B/p27 level a better predictive biomarker than the rearrangement itself?","Is MCL1 upregulation the dominant escape from BCL-2 inhibition in ALL PDX, and does BH3 profiling prospectively identify BCL-XL-dominant cases that would justify navitoclax despite thrombocytopenia?","In post-CAR-T B-ALL relapse, what fraction retains surface CD19, and are there reported response data for CD19xCD3 engagers (AZD0486/surovatamig) in CAR-exposed patients?","For T-ALL, which subtype-defining lesions (NUP214::ABL1, TAL1/STIL, TLX1/TLX3) have published pharmacological dependencies rather than only expression correlations?","Can the MALAT1/METTL14/HMGB1 NK-suppression axis be replicated by an independent group using primary NK cells and patient blasts — or should the lead be retired?","Does glucocorticoid resistance in non-ETV6 ALL converge on the same NF-κB→BCL-2/BCL-XL node, which would widen the venetoclax hypothesis beyond one genotype?"],"nextQueries":["(\"acute lymphoblastic leukemia\" AND (venetoclax OR navitoclax OR \"BCL-2\" OR MCL1 OR \"BH3 profiling\") AND (dexamethasone OR glucocorticoid OR resistance)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"B-cell acute lymphoblastic leukemia\" AND (\"CD19\" OR \"CD22\") AND (\"bispecific\" OR \"T-cell engager\" OR blinatumomab OR \"antigen loss\") AND (\"after CAR\" OR relapse OR resistance)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"T-cell acute lymphoblastic leukemia\" AND (TAL1 OR TLX1 OR TLX3 OR \"NUP214-ABL1\" OR \"ABL1 fusion\" OR MYB) AND (inhibitor OR dependency OR \"synthetic lethal\" OR CRISPR)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42538321","doi":"10.1080/15592324.2026.2710523","year":2026,"isNew":true,"title":"Foliar serotonin and allantoin mitigate tellurium toxicity in Quinoa (&lt;i&gt;Chenopodium quinoa&lt;/i&gt; Willd.) through antioxidant activation and nutrient homeostasis to enhan"},{"pmid":"42473738","doi":"10.1080/21645515.2026.2690723","year":2026,"isNew":true,"title":"Research trends and hotspots of CAR-T cell therapy for acute lymphoblastic leukemia: A bibliometric analysis"},{"pmid":"42316771","doi":"10.1080/21645515.2026.2690841","year":2026,"isNew":true,"title":"Knowledge mapping and research trends of chimeric antigen receptor T-cell immunotherapy in breast cancer: A bibliometric and visual analytics study"},{"pmid":"42275298","doi":"10.1080/13510002.2026.2687238","year":2026,"isNew":true,"title":"Significance of GSH and H&lt;sub&gt;2&lt;/sub&gt;S regulation for cancer: an intricate interplay between diet, microbiota, metabolic reprogramming, and immune health"},{"pmid":"42240055","doi":"10.1080/15384047.2026.2683171","year":2026,"isNew":true,"title":"Leveraging the bacteria for enhanced cancer immunotherapy: from a perspective of synthetic biology"},{"pmid":"42223211","doi":"10.1080/21505594.2026.2679815","year":2026,"isNew":true,"title":"Do BKPyV genomic features underlie clinical divergence between kidney and hematopoietic transplant recipients?"},{"pmid":"42204757","doi":"10.1080/10717544.2026.2679844","year":2026,"isNew":true,"title":"Lysosome-directed targeted protein degradation technologies for overcoming cancer drug resistance: mechanisms, design principles, and therapeutic opportunities"},{"pmid":"42180176","doi":"10.1016/j.apjon.2026.100959","year":2026,"isNew":true,"title":"Best evidence summary of dietary management during chemotherapy in children with acute lymphoblastic leukemia"},{"pmid":"42525958","doi":"10.1158/0008-5472.can-25-3743","year":2026,"isNew":true,"title":"ETV6 Rearrangement Suppresses CDKN1B Transcription by Disrupting an Intragenic Super-Enhancer in Acute Lymphoblastic Leukemia"},{"pmid":"42390539","doi":"10.1007/s00262-026-04413-z","year":2026,"isNew":true,"title":"HMGB1 ubiquitination inhibition and extracellular secretion, mediated by m&lt;sup&gt;6&lt;/sup&gt;A modified-exosomal lncRNA MALAT1, creates a communication between NK92-MI cells a"}],"trialsShown":[{"nct":"NCT05480904","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Characterizing Sleep Among Long-term Survivors of Childhood Cancer"},{"nct":"NCT07070219","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study of CTD402 in T-ALL/LBL Patients"},{"nct":"NCT03876769","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06137118","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"AZD0486 as Monotherapy in B-cell Acute Lymphoblastic Leukaemia"},{"nct":"NCT06710418","phase":"NA","status":"RECRUITING","isNew":true,"title":"Evaluating the Effects of Hemoglobin Threshold-specific Packed Red Blood Cell Transfusions on Quality of Life and Functional Outcomes in Pat"},{"nct":"NCT03007147","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblasti"},{"nct":"NCT05621291","phase":"NA","status":"RECRUITING","isNew":true,"title":"A Multicenter Study to Evaluate Next-Generation Sequencing (NGS) Testing and Monitoring of B-Cell Recovery to Guide Management Following Chi"}],"usage":{"input":8933,"output":5711},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"acute lymphoblastic leukemia\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"acute lymphoblastic leukemia\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42538321","PMID:42473738","PMID:42316771","PMID:42275298","PMID:42240055","PMID:42223211","PMID:42204757","PMID:42180176","PMID:42525958","PMID:42390539","NCT05480904","NCT07070219","NCT03876769","NCT06904066","NCT06137118","NCT06710418","NCT03007147","NCT05621291"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787156153337","cycle":38,"visit":4,"ts":"2026-08-19T16:15:53.337Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Asciminib's frontline superiority now replicates in an independent ASC4FIRST subgroup and holds as salvage after ponatinib/T315I, but three visits have produced zero MR4.5/TFR or asciminib-failure mutation data, so dual-site occupancy stays a CANDIDATE hypothesis while a new sequential ATP-site-to-a","confidence":0.62,"notebook":"Fresh pack is review-heavy; only two items carry primary data, and both concern asciminib.\n\nThe ASC4FIRST East Asian subgroup (PMID:42339511) reproduces the pivotal result in an independent stratum: MMR 64.9%/77.0% at weeks 48/96 vs 45.3%/57.8% for investigator-selected TKI, and 67.9%/78.6% vs 30.8%/46.2% in the imatinib stratum. This is the third evidence-bearing visit for L1, but I am deliberately **not** promoting it to DOSSIER: every new datum still validates the myristoyl-pocket *backbone* as monotherapy, while the lead's actual hypothesis — simultaneous orthosteric + allosteric occupancy requiring compound mutations to escape — has generated no data across three visits. Open question 1 remains unanswered (no MR4.5, no TFR-attempt rates in any abstract) and question 2 entirely unanswered (no mutation spectrum at asciminib failure anywhere in the pack). NCT03906292 remains ACTIVE_NOT_RECRUITING with no readout.\n\nThe Turkish managed-access cohort (PMID:42090741, n=49, ≥2 prior TKI, median 4) adds a mechanistically interesting real-world signal: EMR at 3 months was *higher* in ponatinib-pretreated (94%) than ponatinib-naïve (72%) patients, and 71.4% of T315I patients maintained/improved response. [INFERRED] prior ATP-site saturation does not induce cross-resistance to allosteric autoinhibition, consistent with non-overlapping binding sites — this deserves its own lead (L8) separate from L1's frontline-combination logic. Caveat: the abstract reports cumulative DMR (37.2%) exceeding MMR (32.6%), internally inconsistent unless denominators differ; ambiguous as written, and asciminib dose (80 mg daily vs 200 mg BID for T315I) is not stated.\n\nAnswering my own question 3: the interferon window is not closed, but it is not immunological. Fi-LMC (PMID:42557142) positions peg-IFN-α as a TKI-free bridge during organogenesis/pregnancy, where TKIs are teratogenic — a pharmacological-necessity niche, not immune retrofitting. ENDURE's negative result stands for post-cessation use; do not re-propose it.\n\nL7 gains real pharmacology: the reduced-dose nilotinib tablet gives bioequivalent exposure without food effect (PMID:42584922), and frontline choice is now explicitly framed as individualised exposure/tolerability trade-off with ASXL1 as a disease-risk modifier (PMID:41376561). Both support an exposure-plateau argument rather than fixed licensed dosing.\n\nL2 weakens by silence: NCT02689440 has now passed a second visit with no LSC/BH3 readout, and the LSC-targeting field itself flags antigen overlap with normal progenitors and assay non-harmonisation as the binding constraints (PMID:41745087). L6's phenotype-first framing gains conceptual support (PMID:41213958) but the TRIM28/SETDB1 node itself remains uncorroborated in CML LSCs.","leadChanges":[{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.74},{"id":"L8","title":"Sequential ATP-site to allosteric switch: asciminib as non-cross-resistant salvage after ponatinib and in T315I disease","level":"LEAD","status":"NEW","confidence":0.48},{"id":"L2","title":"BCL2 co-dependence of the TKI-persistent CML clone: dasatinib + venetoclax","level":"LEAD","status":"WEAKENED","confidence":0.46},{"id":"L5","title":"Immune-readiness gating of TKI discontinuation: IL-6/MCP-1 cytokine signature plus innate-like CD8dim/NK effector clonality, with peg-IFN-alpha as expansion age","level":"LEAD","status":"WEAKENED","confidence":0.32},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"LEAD","status":"STRENGTHENED","confidence":0.44}],"unverifiedCitations":0,"openQuestions":["Do any ASC4FIRST publications or conference datasets report MR4.5 and subsequent TFR-attempt/TFR-success rates by prerandomisation stratum, or does the asciminib advantage remain confined to MMR and tolerability?","What is the kinase-domain mutation spectrum at asciminib failure (myristoyl-pocket A337V/P465S/F359 vs ATP-site T315I), and do any data - including NCT03906292 - show compound mutants under dual-site pressure?","In ponatinib-pretreated and T315I patients, is asciminib's apparent non-cross-resistance dose-dependent (80 mg QD vs 200 mg BID), and does it survive adjustment for intolerance- versus resistance-driven switching?","Is ASXL1 mutation an independent modifier of frontline TKI choice, DMR depth and TFR success, and should it exclude patients from dose de-escalation?","Has NCT02689440 reported CD34+CD38- clearance or BH3 profiling, and is there any other CML dataset implicating MCL1/BCL-xL switching in BH3-mimetic non-responders?","Is there any experimental evidence that TRIM28/SETDB1 regulons are enriched in TKI-persistent CML LSCs specifically, and does their disruption spare normal CD34+ HSPCs from the same donors?"],"nextQueries":["\"chronic myeloid leukemia\" AND asciminib AND (\"MR4.5\" OR \"treatment-free remission\" OR \"resistance mutation\" OR \"myristoyl\" OR A337V OR P465S) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","\"chronic myeloid leukemia\" AND (\"dose reduction\" OR \"de-escalation\" OR \"low-dose\") AND (dasatinib OR nilotinib OR imatinib) AND (\"molecular response\" OR pharmacokinetic) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic myeloid leukemia\" AND (\"leukemic stem cell\" OR \"CD34+CD38-\") AND (TRIM28 OR SETDB1 OR \"gene regulatory network\" OR venetoclax OR \"BH3 profiling\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41727472","doi":"10.3389/fimmu.2026.1743920","year":2026,"isNew":true,"title":"The tumor microenvironment in leukemia: molecular pathways of immune evasion"},{"pmid":"41745087","doi":"10.3390/diseases14020050","year":2026,"isNew":true,"title":"Decoding Leukemic Stem Cells in AML: From Identification to Targeted Eradication"},{"pmid":"42584922","doi":"10.1080/17474086.2026.2715450","year":2026,"isNew":true,"title":"Nilotinib in chronic myeloid leukemia: clinical value, real-world challenges, and the potential of nilotinib tablets to improve therapeutic outcomes"},{"pmid":"42557142","doi":"10.1016/j.bulcan.2026.04.002","year":2026,"isNew":true,"title":"[Sexual and reproductive life of men and women with chronic myeloid leukemia: Opinion and practical considerations of the Fi-LMC group]"},{"pmid":"42090741","doi":"10.1016/j.leukres.2026.108239","year":2026,"isNew":true,"title":"Real-world data on the use of asciminib in chronic-phase chronic myeloid leukemia after two or more prior tyrosine kinase inhibitors: Results of the Turkish managed access program "},{"pmid":"41376561","doi":"10.3324/haematol.2025.287813","year":2026,"isNew":true,"title":"Is there a best frontline therapy in chronic myeloid leukemia?"},{"pmid":"42352456","doi":"10.3390/cancers18121922","year":2026,"isNew":true,"title":"Four Decades of Molecular Innovation in Chronic Myeloid Leukemia: From Antisense Targeting to Treatment-Free Remission"},{"pmid":"42339511","doi":"10.1002/cam4.72019","year":2026,"isNew":true,"title":"Asciminib Provides Better Efficacy and Favorable Safety and Tolerability Against Investigator-Selected Tyrosine Kinase Inhibitors in East Asian Patients With Newly Diagnosed Chroni"},{"pmid":"42303626","doi":"10.1038/s41392-026-02729-x","year":2026,"isNew":true,"title":"Non-receptor tyrosine kinase signaling pathways and therapeutic implications"},{"pmid":"41213958","doi":"10.1038/s41419-025-08127-5","year":2025,"isNew":true,"title":"Genes-first and phenotypes-first paths to treatment resistance in hematological malignancies"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":13294,"output":8307},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic myeloid leukemia\" AND asciminib AND (\"MR4.5\" OR \"deep molecular response\" OR \"treatment-free remission\" OR \"kinase domain mutation\") AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","\"chronic myeloid leukemia\" AND (\"leukemic stem cell\" OR \"CD34+CD38-\") AND (venetoclax OR BCL2 OR \"BH3 profiling\" OR SETDB1 OR TRIM28) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41727472","PMID:41745087","PMID:42584922","PMID:42557142","PMID:42090741","PMID:41376561","PMID:42352456","PMID:42339511","PMID:42303626","PMID:41213958","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787155918884","cycle":37,"visit":1,"ts":"2026-08-19T16:11:58.884Z","cancer":{"key":"acute myeloid leukemia","name":"acute myeloid leukemia","mondo":{"id":"MONDO:0018874","name":"acute myeloid leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"Open AML programme with four ranked leads led by FLT3i+venetoclax/HMA triplets (NCT06317649) and XPO1+BCL2 co-inhibition (NCT06399640), plus a cystine/ferroptosis axis (OTUD5-SLC7A11) and a low-confidence raloxifene/ANP32B repurposing claim flagged for falsification.","confidence":0.46,"notebook":"Programme opens. The pack is low-yield: P4 (HOXA/bone), P5 (BKPyV), P6 (TFPI2), P7 (palmitoylation), P8 (UBE2C/pancreas) carry no AML-actionable content and are logged as non-informative so the desk does not re-query them. Nothing in the pack is a negative trial or a failed mechanism, so no retirements are warranted; the useful signal is three mechanism papers and two trial architectures.\n\nStrongest starting position is not a novel target but a combination logic already in phase 2. NCT06317649 tests gilteritinib with azacitidine/venetoclax in older/unfit FLT3-mutant AML. Mechanistically [KNOWN]: FLT3-ITD [SOMATIC, though FLT3 sits in the causal/germline-likely anchor set — the anchor conflates predisposing germline FLT3 with the somatic ITD/TKD lesions that maintain disease] signals through STAT5/PIM to sustain MCL1 and BCL-xL; FLT3 inhibition collapses that buffer and reroutes apoptotic dependence onto BCL2, the venetoclax target. Predicted resistance: on-target F691L gatekeeper, RAS/MAPK-pathway outgrowth, monocytic/AMLmono differentiation with MCL1 dependence, and CYP3A4-driven exposure loss. Window argument: FLT3 is required for normal HSPC and cDC development, so the toxicity is cytopenia/infection, not organ failure — tolerable but dose-limiting in triplets.\n\nSecond lead: XPO1 plus BCL2 (eltanexor + venetoclax, NCT06399640). [KNOWN] XPO1 blockade renuclearises p53, FOXO and IκB and lowers MCL1; [INFERRED] this is exactly the axis that mediates venetoclax escape, making the pair a rational resensitisation strategy in R/R AML and MDS. Expected resistance: TP53 loss, MCL1 amplification; window limited by ubiquitous XPO1 (anorexia, thrombocytopenia).\n\nThird, ferroptosis. P2 places OTUD5 as a deubiquitinase stabilising SLC7A11, with knockdown inducing labile iron/ROS and rescue by SLC7A11 or GSH — a clean epistatic chain in THP-1/HL-60 and xenograft. [INFERRED] the druggable node is cystine import, not the DUB. This is a lead precisely because venetoclax-refractory monocytic AML is GSH/GPX4-dependent [KNOWN, needs verification next visit].\n\nFourth, held at low confidence: raloxifene/ANP32B/MYC (P1). Virtual-screening origin, single-agent, no target-engagement or ANP32B-rescue experiment reported in the abstract; SERM pharmacology plausibly explains activity off-target. Its killing test is explicit below.\n\nFifth, exploratory: CD69 blockade remodelled the marrow niche and delayed leukemogenesis in Nras^G12D CMML (P3) — transformation prevention, not established AML.\n\nWatch item, not yet a lead: NCT07504458 (QTX-2101+ATRA vs IV ATO+ATRA in APL) — abstract does not disclose the agent's composition; check next visit.","leadChanges":[{"id":"L1","title":"FLT3 inhibition plus BCL2/HMA triplet in FLT3-mutant AML unfit for intensive therapy","level":"LEAD","status":"NEW","confidence":0.62},{"id":"L2","title":"XPO1 inhibition (eltanexor) to resensitise R/R AML/MDS to venetoclax","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"Cystine-import/ferroptosis vulnerability in AML via the OTUD5-SLC7A11 axis","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L4","title":"Raloxifene repurposing against the ANP32B-MYC super-enhancer axis in pediatric AML","level":"LEAD","status":"NEW","confidence":0.18},{"id":"L5","title":"CD69 blockade to remodel the marrow immune niche and delay RAS-mutant myeloid transformation to AML","level":"LEAD","status":"NEW","confidence":0.2}],"unverifiedCitations":0,"openQuestions":["Does gilteritinib + azacitidine + venetoclax show MCL1-dependent or RAS/MAPK-driven relapse in reported correlatives, and is the triplet tolerable enough to beat doublet FLT3i+HMA?","Is venetoclax-refractory monocytic AML genuinely GSH/GPX4/SLC7A11-dependent in primary samples, and does system xc- blockade spare normal HSPCs?","Has anyone shown cellular target engagement of raloxifene on ANP32B, or ANP32B-dependency epistasis, outside the originating group?","What is the composition and mechanism of QTX-2101 (NCT07504458) and does it displace IV arsenic trioxide in APL?","For TP53-mutant and CBF-AML subsets, which of venetoclax versus gemtuzumab ozogamicin adds benefit to 7+3 (NCT06917911), and does menin inhibition belong in this programme for KMT2A/NPM1 disease?"],"nextQueries":["(\"acute myeloid leukemia\") AND (venetoclax) AND (resistance OR \"MCL1\" OR monocytic) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"acute myeloid leukemia\") AND (ferroptosis OR SLC7A11 OR GPX4 OR cystine) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"acute myeloid leukemia\") AND (menin OR revumenib OR ziftomenib OR KMT2A OR NPM1) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"42372253","doi":"10.1080/16078454.2026.2691533","year":2026,"isNew":true,"title":"Raloxifene inhibits the proliferation of pediatric acute myeloid leukemia by targeting the ANP32B gene and regulating C-MYC expression"},{"pmid":"42333513","doi":"10.1080/15384101.2026.2687836","year":2026,"isNew":true,"title":"OTUD5 promotes AML progression by stabilizing SLC7A11 to suppress ferroptosis"},{"pmid":"42330053","doi":"10.1080/15384047.2026.2692184","year":2026,"isNew":true,"title":"CD69 blockade restores the bone marrow niche and delays leukemogenesis in a mouse model of &lt;i&gt;Nras&lt;/i&gt; &lt;sup&gt;G12D&lt;/sup&gt;-driven chronic myelomonocytic leukemi"},{"pmid":"42296055","doi":"10.1080/07853890.2026.2685993","year":2026,"isNew":true,"title":"The HOXA gene cluster: a critical regulator in bone-related disorders"},{"pmid":"42223211","doi":"10.1080/21505594.2026.2679815","year":2026,"isNew":true,"title":"Do BKPyV genomic features underlie clinical divergence between kidney and hematopoietic transplant recipients?"},{"pmid":"42216563","doi":"10.1080/15384047.2026.2678642","year":2026,"isNew":true,"title":"TFPI2 in tumor metastasis: a double-edged sword with clinical implications"},{"pmid":"42210736","doi":"10.1080/07853890.2026.2673182","year":2026,"isNew":true,"title":"The role of protein palmitoylation in disease pathogenesis and therapeutic innovation"},{"pmid":"42157383","doi":"10.1080/15384101.2026.2668450","year":2026,"isNew":true,"title":"UBE2C promotes pancreatic cancer progression through PI3K/Akt/mTOR signaling pathway"}],"trialsShown":[{"nct":"NCT07504458","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Pivotal Open-label Phase 3 Clinical Study of QTX-2101 in Adult Patients With Acute Promyelocytic Leukemia"},{"nct":"NCT06399640","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Eltanexor and Venetoclax in Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT05554393","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Comparing Cytarabine + Daunorubicin Therapy Versus Cytarabine + Daunorubicin + Venetoclax Versus Venetoclax + Azacitidine in Younger Patient"},{"nct":"NCT06710418","phase":"NA","status":"RECRUITING","isNew":true,"title":"Evaluating the Effects of Hemoglobin Threshold-specific Packed Red Blood Cell Transfusions on Quality of Life and Functional Outcomes in Pat"},{"nct":"NCT06317649","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Venetoclax and HMA Treatment of Older and Unfit Adults With FLT3 Mutated Acute Myeloid Leukemia (AML) (A MyeloMATCH Treatment Trial)"},{"nct":"NCT06917911","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Testing the Addition of Venetoclax or Gemtuzumab Ozogamicin (GO) to Usual Treatment Regimen (Cytarabine and Daunorubicin, \"7+3\") for Core Bi"},{"nct":"NCT02521493","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syn"}],"usage":{"input":7996,"output":5428},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"acute myeloid leukemia\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"acute myeloid leukemia\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42372253","PMID:42333513","PMID:42330053","PMID:42296055","PMID:42223211","PMID:42216563","PMID:42210736","PMID:42157383","NCT07504458","NCT06399640","NCT06904066","NCT05554393","NCT06710418","NCT06317649","NCT06917911","NCT02521493"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787155669743","cycle":36,"visit":3,"ts":"2026-08-19T16:07:49.743Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Asciminib is now the validated frontline ABL-directed backbone (ASC4FIRST week-96 MMR 74.1% vs 52.0%), while the phase 3 ENDURE trial shows ropeginterferon alfa-2b maintenance after TKI discontinuation does not improve molecular relapse-free survival (HR 1.02) — retire unselected post-cessation inte","confidence":0.62,"notebook":"This visit the pack does two decisive things: it validates the myristoyl-pocket arm and it kills my interferon intervention arm.\n\nASC4FIRST week-96 data (PMID:41397287) show asciminib beating investigator-selected TKIs (MMR 74.1% vs 52.0%) and imatinib (76.2% vs 47.1%) with better tolerability and fewer dose reductions; the systematic review (PMID:42458108, >500 patients, 8 studies) concurs. Mechanistically this is the cleanest available clinical proof that restoring ABL1 autoinhibition via the myristate pocket is at least as good as ATP-site occupancy, and better tolerated — consistent with fewer off-kinome liabilities [INFERRED]. Two caveats the abstracts make explicit: superiority over 2G TKIs was nominal only (Δ15.1%, not formally confirmed), and neither report gives MR4.5 depth per stratum, TFR eligibility, or the relapse mutation spectrum. NCT03906292 (asciminib + ATP-site TKI) still has no readout, so the specific dual-occupancy/compound-mutation hypothesis of L1 remains untested; what is now established is the backbone. L1 promoted to CANDIDATE on that basis, with the comparator raised — any combination must beat asciminib alone, not imatinib. Control-calibration note: the desk converges on BCR-ABL1 [SOMATIC] fusion → ABL-directed inhibition, with asciminib as the current best frontline instantiation (PMID:42174092).\n\nENDURE/CML-IX (PMID:41526617) is the high-value negative: 203 DMR patients randomised post-TKI-discontinuation to ropeg-IFN 100 µg q2w × 15 months vs observation, 25-month MRFS 56% vs 59%, HR 1.02, P=0.91. Interferon maintenance after stopping does not rescue TFR in unselected patients. Recorded so the desk never re-proposes it. L5 weakened to 0.35 and re-scoped: the intervention arm (IFN) is retired in the post-cessation, unselected setting; what survives is the *biomarker* hypothesis — that IL-6/MCP-1 (PMID:42121891) and CD56+CD57+CD8dim NK-like clonality (PMID:42377752) index host surveillance. ENDURE arguably tested the wrong timing (after LSC re-expansion has begun) and the wrong population (no immune-readiness gating), and IFN toxicity/efficacy limits are generic (PMID:41373826). Reassuringly, 95% of relapsers regained ≥MMR on restart (median 3 months), so cessation-strategy trials remain low-risk. Cessation-practice uncertainties are catalogued in PMID:41225725; pregnancy is a distinct forced-discontinuation model worth mining (PMID:40758938).\n\nNew lead L7 from PMID:41510882: low-dose dasatinib 50 mg in imatinib-resistant CML-CP gave MR4.5 in 41.5%; T315I, high ELTS and baseline BCR-ABL1 >100% independently predicted failure. Dose de-escalation as a window-widening strategy, explicitly excluding T315I/high-risk patients who need ponatinib or asciminib.","leadChanges":[{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.72},{"id":"L5","title":"Immune-readiness gating of TKI discontinuation: IL-6/MCP-1 cytokine signature plus innate-like CD8dim/NK effector clonality, with peg-IFN-alpha as expansion age","level":"LEAD","status":"WEAKENED","confidence":0.35},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["Does ASC4FIRST report MR4.5 and subsequent TFR-attempt rates by stratum, and does asciminib's MMR advantage convert into more DMR/TFR candidates or only better tolerability?","What is the kinase-domain mutation spectrum at asciminib failure (myristoyl-pocket variants A337V/P465S/F359 versus ATP-site T315I), and does NCT03906292 show compound mutants under dual-site pressure?","Given ENDURE's null result, is there any interferon window left — i.e. peg/ropeg-IFN added to TKI before cessation in biomarker-selected immune-unready patients — or should the desk abandon interferon in CML entirely?","Does the IL-6/MCP-1 decision tree of PMID:42121891 replicate in an independent DMR cohort after adjustment for TKI duration and prior IFN exposure, and can ENDURE's stored samples be used to test immune-readiness gating retrospectively?","Has NCT02689440 (dasatinib + venetoclax) reported CD34+CD38- LSC clearance, and does BH3 profiling implicate MCL1/BCL-xL switching in non-responders?","Are TRIM28/SETDB1 regulons experimentally enriched in TKI-persistent CML LSCs, and does their disruption spare normal CD34+ HSPCs?"],"nextQueries":["\"chronic myeloid leukemia\" AND asciminib AND (\"MR4.5\" OR \"deep molecular response\" OR \"treatment-free remission\" OR \"kinase domain mutation\") AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","\"chronic myeloid leukemia\" AND (\"leukemic stem cell\" OR \"CD34+CD38-\") AND (venetoclax OR BCL2 OR \"BH3 profiling\" OR SETDB1 OR TRIM28) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"chronic myeloid leukemia\" AND (\"dose reduction\" OR \"de-escalation\" OR \"low-dose\") AND (dasatinib OR imatinib OR nilotinib OR bosutinib) AND (\"molecular response\" OR relapse) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41397287","doi":"10.1182/blood.2025029210","year":2026,"isNew":true,"title":"Asciminib demonstrates superior efficacy and safety in newly diagnosed chronic myeloid leukemia in the ASC4FIRST trial"},{"pmid":"41526617","doi":"10.1038/s41375-025-02859-1","year":2026,"isNew":true,"title":"Randomized phase 3 trial of Ropeginterferon alfa-2b versus surveillance after tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia (ENDURE/CML-IX)"},{"pmid":"40758938","doi":"10.1182/blood.2024026513","year":2026,"isNew":true,"title":"How I manage chronic myeloid leukemia during pregnancy"},{"pmid":"41373826","doi":"10.3390/ijms262311679","year":2025,"isNew":true,"title":"Interferon-Based Therapeutics in Cancer Therapy: Past, Present, and Future"},{"pmid":"41225725","doi":"10.1002/hon.70155","year":2025,"isNew":true,"title":"Treatment Cessation in Chronic Myeloid Leukemia: Evidence and Uncertainties"},{"pmid":"42174092","doi":"10.1038/s41375-026-02984-5","year":2026,"isNew":true,"title":"From fatal disease to functional cure: 25 years of tyrosine kinase inhibition in chronic myeloid leukemia"},{"pmid":"41978829","doi":"10.1002/mco2.70729","year":2026,"isNew":true,"title":"Post-translational Modifications in Proteins: Prediction Methods, Biological Functions, and Diseases"},{"pmid":"41510882","doi":"10.1002/cnr2.70400","year":2026,"isNew":true,"title":"Real-World Outcomes With Low-Dose Dasatinib (50 mg) in Imatinib-Resistant Chronic Myeloid Leukemia in Chronic Phase: A Retrospective Analysis of Efficacy and Safety"},{"pmid":"41351789","doi":"10.1007/s12672-025-04223-2","year":2025,"isNew":true,"title":"Bibliometric analysis and recent trends on tyrosine kinase inhibitors in leukemia"},{"pmid":"42458108","doi":"10.1007/s44313-026-00153-2","year":2026,"isNew":true,"title":"Asciminib as first-line therapy in chronic myeloid leukemia: a systematic review"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":12496,"output":6190},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic myeloid leukemia\" AND (\"interferon alfa\" OR peginterferon) AND (\"treatment-free remission\" OR discontinuation OR \"deep molecular response\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"chronic myeloid leukemia\" AND (asciminib) AND (combination OR \"compound mutation\" OR MR4.5 OR resistance) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:41397287","PMID:41526617","PMID:40758938","PMID:41373826","PMID:41225725","PMID:42174092","PMID:41978829","PMID:41510882","PMID:41351789","PMID:42458108","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787155463671","cycle":35,"visit":1,"ts":"2026-08-19T16:04:23.671Z","cancer":{"key":"renal cell carcinoma","name":"renal cell carcinoma","mondo":{"id":"MONDO:0005086","name":"renal cell carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Test deferasirox as an ITPRIP/DANGER-NRF2-FTH1 axis inhibitor in VHL-null ccRCC, alone and combined with GPX4/system-xc⁻ blockade, as the pack's most actionable repurposing hypothesis.","confidence":0.42,"notebook":"Programme opens. Pack is thin on RCC-specific mechanism (four of ten papers are off-target: DKD lncRNA, CRC lidocaine, TFPI2 and GSH/H₂S reviews) but yields three usable hypotheses and one cautionary frame.\n\nStrongest new mechanism is P10 (PMID:42448062): VHL-null ccRCC lives in a high-labile-iron state yet resists ferroptosis via ITPRIP/DANGER → NRF2 nuclear translocation → FTH1-mediated iron sequestration, with concurrent ALOX5 upregulation creating a \"pre-conditioned\" high-threshold state. Two things make this a lead rather than a curiosity: the vulnerability is coupled to the defining somatic driver [SOMATIC] VHL loss, and the proposed agent is deferasirox, an approved chelator reported as a direct DANGER binder — repurposing-first. Counter-intuitively, chelation lowers labile iron, so the mechanism must be NRF2/FTH1 collapse and redistribution of iron into the peroxidation-competent pool rather than bulk iron reduction; the abstract does not resolve this and I cannot see the full text. P4 supplies the orthogonal arm: GSH overproduction is the second ferroptosis buffer, so deferasirox + system xc⁻/GPX4 pressure (or ALOX5-dependent lipid peroxidation as an execution node) is the combination to test. Normal-tissue window: FTH1/NRF2 are ubiquitous, but ITPRIP overexpression is claimed ccRCC-selective — that selectivity claim is the whole argument and needs orthogonal validation.\n\nP3 (PMID:42343214) changes not the agents but the schedule: in orthotopic RENCA, axitinib first opens an immune-permissive window (vascular normalisation, hypoxia relief, myeloid suppression lifted), and survivin long-peptide vaccine plus anti-PD-1 given after — not during — TKI produces frequent complete responses. This is mechanistically important because [KNOWN] the failed RCC vaccine programmes (IMA901 + sunitinib phase 3; TroVax/5T4 TRIST) dosed vaccine concurrently with TKI, i.e. in the schedule this paper says is inferior. Recorded so the desk never re-proposes concurrent TKI+vaccine as if untested. Same caution discounts P5's 5T4-conditional 4-1BB bispecific (CT26/MC38 only, no RCC data) — logged, not promoted to a lead.\n\nP2 (PMID:42366526) gives real-world cabozantinib+nivolumab activity across nccRCC (ORR 45%, responses in FH-deficient and TFE3-rearranged [SOMATIC fusion; TFE3 is a KG anchor]), consistent with MET/AXL/VEGFR2 dependence; NCT03866382 and NCT05361720 (OPTIC RCC) are the prospective/biomarker-selected reads. Lead is about subtype stratification, not a new drug.\n\nP9 (ZC3H13 m⁶A → sFRP-4 → Wnt/β-catenin in sunitinib resistance) is correlative single-group work; restoring a secreted antagonist is not druggable, so I frame it as a Wnt-pathway resistance hypothesis testable with porcupine/tankyrase inhibitors, low confidence. P1 histotripsy is a local ablation modality — no molecular hypothesis, no lead.","leadChanges":[{"id":"L1","title":"Deferasirox-mediated disruption of the ITPRIP(DANGER)/NRF2/FTH1 axis to force ferroptosis in VHL-null ccRCC","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"Sequence-defined axitinib priming → survivin peptide vaccine + PD-1 blockade (vaccine AFTER, not during, VEGFR TKI)","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L3","title":"Histology/genotype-stratified cabozantinib + nivolumab in non-clear-cell RCC, anchored on MET and TFE3-rearranged biology","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L4","title":"Wnt/β-catenin reactivation as a targetable node in sunitinib-resistant RCC (ZC3H13/m6A–sFRP-4 axis)","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Does genetic ITPRIP/DANGER knockdown phenocopy deferasirox in VHL-null ccRCC, and is the killing ferrostatin-rescuable (i.e. genuinely ferroptotic) rather than chelation-driven proliferative arrest?","Is ITPRIP overexpression ccRCC-selective at protein level versus normal proximal tubule, and does deferasirox reach tumour concentrations that inhibit it at approved doses?","What is the duration and cellular definition of the post-axitinib immune-permissive window, and does any human RCC dataset show the myeloid/hypoxia shift the RENCA model predicts?","Which nccRCC genotypes (MET-altered papillary vs FH-deficient vs TFE3-fusion partner) actually drive the 45% ORR with cabozantinib+nivolumab, and do OPTIC RCC / NCT03866382 report subtype-resolved responses?","Are ALOX5, GPX4/system xc⁻, or FSP1 the dominant escape node when the DANGER/NRF2/FTH1 axis is blocked?","Is there any RCC-specific evidence for 5T4/TPBG expression that would justify revisiting 5T4-conditional 4-1BB agonism after the TroVax failure?"],"nextQueries":["(\"renal cell carcinoma\" OR ccRCC) AND (ferroptosis OR GPX4 OR NRF2 OR FTH1 OR \"labile iron\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"renal cell carcinoma\") AND (deferasirox OR \"iron chelation\" OR ITPRIP OR ALOX5) AND SRC:MED","(\"non-clear cell renal cell carcinoma\" OR \"papillary renal\" OR \"FH-deficient\" OR \"TFE3\") AND (cabozantinib OR MET OR nivolumab) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"42495873","doi":"10.1080/02656736.2026.2685123","year":2026,"isNew":true,"title":"Histotripsy for renal cell carcinoma: from animal studies to clinical application"},{"pmid":"42366526","doi":"10.1080/2162402x.2026.2694175","year":2026,"isNew":true,"title":"Efficacy and safety of cabozantinib plus nivolumab in advanced non-clear cell renal cell carcinoma: a nationwide multicenter study"},{"pmid":"42343214","doi":"10.1080/2162402x.2026.2689769","year":2026,"isNew":true,"title":"Sequential axitinib and survivin vaccination unlock curative PD-1 immunotherapy in renal carcinoma"},{"pmid":"42275298","doi":"10.1080/13510002.2026.2687238","year":2026,"isNew":true,"title":"Significance of GSH and H&lt;sub&gt;2&lt;/sub&gt;S regulation for cancer: an intricate interplay between diet, microbiota, metabolic reprogramming, and immune health"},{"pmid":"42268792","doi":"10.1080/2162402x.2026.2684136","year":2026,"isNew":true,"title":"FTL008.16, a 5T4-Conditional 4-1BB bispecific antibody, potently enhances antitumor immunity via tumor-directed t-cell activation"},{"pmid":"42261203","doi":"10.1080/0886022x.2026.2680813","year":2026,"isNew":true,"title":"Overexpression of LINC00472 alleviates diabetic kidney disease progression via the miR-21-5p/STAT3 axis"},{"pmid":"42253188","doi":"10.1080/14756366.2026.2678755","year":2026,"isNew":true,"title":"Lidocaine enhances antitumor effects of sorafenib and GW5074 in colorectal cancer cells"},{"pmid":"42216563","doi":"10.1080/15384047.2026.2678642","year":2026,"isNew":true,"title":"TFPI2 in tumor metastasis: a double-edged sword with clinical implications"},{"pmid":"42374135","doi":"10.1038/s41598-026-58416-y","year":2026,"isNew":true,"title":"sFRP-4 regulated by n6‑methyladenosine writer ZC3H13 attenuates sunitinib resistance of renal cell carcinoma via inactivating Wnt/β-catenin pathway"},{"pmid":"42448062","doi":"10.1016/j.freeradbiomed.2026.07.022","year":2026,"isNew":true,"title":"DANGER/ITPRIP-mediated iron homeostasis mediates ferroptosis resistance and presents a potential therapeutic target in ccRCC"}],"trialsShown":[{"nct":"NCT03866382","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare G"},{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT05361720","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Genetic Testing to Select Therapy for the Treatment of Advanced or Metastatic Kidney Cancer, OPTIC RCC Study"},{"nct":"NCT05155033","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Phase II Trial of Combination Anti-PD-1 and Aldesleukin for Metastatic Melanoma and Renal Cell Carcinoma"},{"nct":"NCT04788095","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"App-Based Mindfulness Intervention for the Improvement of Quality of Life in Patients With Metastatic Renal Cell Cancer"},{"nct":"NCT06966024","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Study of DCC-2812 in Participants With Advanced Genitourinary Cancers"},{"nct":"NCT07160335","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Phase I Clinical Study to Evaluate the PK Profile, Efficacy, Safety and Immunogenicity of HLX17 vs. Keytruda® in Multiple Resected Solid T"}],"usage":{"input":9247,"output":5972},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"renal cell carcinoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"renal cell carcinoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42495873","PMID:42366526","PMID:42343214","PMID:42275298","PMID:42268792","PMID:42261203","PMID:42253188","PMID:42216563","PMID:42374135","PMID:42448062","NCT03866382","NCT07115043","NCT07636785","NCT05361720","NCT05155033","NCT04788095","NCT06966024","NCT07160335"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787155259885","cycle":34,"visit":1,"ts":"2026-08-19T16:00:59.885Z","cancer":{"key":"papillary renal cell carcinoma","name":"papillary renal cell carcinoma","mondo":{"id":"MONDO:0017884","name":"papillary renal cell carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"In papillary RCC, dual ICI (ipi/nivo) shows a modest unconfirmed OS signal in the centrally-reviewed SUNNIFORECAST subgroup while the strongest new mechanistic thread is proximal-tubule lineage targeting (KIM-1/HAVCR1 antigen, orellanine) layered onto the MET axis being tested in PAPMET2.","confidence":0.45,"notebook":"Visit 1 opens the programme with a pack that is clinically richer than it is mechanistically deep. Highest-value item is P7 (PMID:42235464): the pRCC subgroup of SUNNIFORECAST (n=127 after central review, 56/173 local pRCC diagnoses revised) shows ipilimumab/nivolumab 12-month OS 74.8% vs 63.4% SOC (p=0.085), mOS 24.9 vs 18.9 mo — a consistent but non-significant signal in the largest randomised pRCC dataset available. Two readings: dual ICI is a real but modest option, and pRCC histological assignment is unreliable without central pathology (32% revision rate), which contaminates every retrospective pRCC series including P3's PSM analysis. I record that as a methodological constraint on the desk, not a lead.\n\nMechanistically, the KG anchor MET [causal/GERMLINE, HPRC type 1; also [SOMATIC] gain/trisomy 7 in sporadic type 1 — [KNOWN]] remains the only validated driver axis, and the pack keeps it alive only indirectly: CALYPSO (savolitinib arm, NCT02819596, via PMID:41934036) and PAPMET2 (NCT05411081, cabozantinib ± atezolizumab). Cabozantinib's MET+VEGFR2+AXL polypharmacology is why it beats sunitinib here [INFERRED]; expected resistance = MET kinase-domain second-site mutation, HGF-independent bypass via EGFR/ERBB3, and NF2/Hippo-mediated escape [KNOWN/SPECULATIVE].\n\nNew and genuinely interesting: P5 shows circulating KIM-1 (HAVCR1) is higher in pRCC than ccRCC (7835 vs 5470 pg/ml) and falls with therapy; responders had lower baseline. KIM-1 is a proximal-tubule injury antigen, near-absent in healthy adult tissue — the lineage from which pRCC arises. That converges with orellanine (NCT05287945), a proximal-tubule-selective toxin now in phase 1/2 including pRCC. I am therefore opening a \"proximal-tubule lineage as therapeutic window\" lead spanning antigen-directed (ADC/CAR against KIM-1) and metabolic/tubule-toxin strategies; the central open risk is on-target AKI in the remaining nephron and whether KIM-1 is shed (soluble decoy) rather than membrane-retained.\n\nTwo computational leads enter at low confidence: P9's LOY paradox (Y-low pRCC = better survival, de-repressed immune milieu, WASF1/MTHFD2/CHMP1A signature — MTHFD2 is the only tractable node, mitochondrial one-carbon, minimal adult expression) and P10's SGO1/SGO2 overexpression with knockdown-confirmed proliferation/invasion loss, suggesting a cohesion-stress phenotype exploitable by MPS1/AURKB/PLK1 inhibition rather than by drugging shugoshins directly.\n\nNotebook negatives, so the desk never re-proposes them: limonene in ACHN (P6) is nonspecific ROS/NF-κB pharmacology at implausible exposures — not pursuable; CRP/albumin ratio (P1) is generic RCC prognostication, not pRCC-specific and not actionable; P2/P8 are surgical/diagnostic case reports with no therapeutic content. P4 (SMARCA4-deficient collision pRCC with durable IO response) is a single letter — parked, but flags an SMARCA4-loss/EZH2i synthetic-lethality question for a later visit.","leadChanges":[{"id":"L1","title":"MET-axis inhibition in type 1/MET-altered pRCC (cabozantinib backbone, savolitinib in MET-driven subset)","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"Ipilimumab/nivolumab as first-line systemic therapy in advanced pRCC","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L3","title":"Proximal-tubule lineage as the therapeutic window: KIM-1/HAVCR1-directed agents and tubule-selective toxins","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"MTHFD2 / one-carbon metabolism dependency in the LOY-associated pRCC transcriptional programme","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L5","title":"Cohesion/mitotic stress vulnerability in SGO1/SGO2-high pRCC","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":1,"openQuestions":["In the SUNNIFORECAST pRCC subgroup, do responders to ipi/nivo segregate by MET alteration status, type 1 vs type 2 morphology, or PD-L1 CPS — and is any biomarker-defined subset large enough to justify a confirmatory randomised trial?","Does PAPMET2 (NCT05411081) show that adding atezolizumab to cabozantinib improves PFS in pRCC, and does benefit track with MET alteration or with PD-L1/inflamed signatures?","Is KIM-1/HAVCR1 retained on the pRCC cell membrane at ADC/CAR-tractable density, or predominantly shed as ectodomain — and what is the on-target renal toxicity ceiling given proximal-tubule expression during injury?","Does loss of chromosome Y define an immunologically de-repressed pRCC subset that predicts checkpoint-inhibitor benefit, and is MTHFD2 protein actually overexpressed and essential in that subset?","What is the dominant acquired resistance mechanism to MET inhibition in pRCC in the clinic (second-site MET mutation vs EGFR/ERBB3 or NF2 bypass), and is it detectable in ctDNA?","How should the desk handle pRCC histology uncertainty (32% local-vs-central diagnostic revision in SUNNIFORECAST) when weighting any retrospective pRCC dataset, including SMARCA4-deficient or ESC-RCC outliers?"],"nextQueries":["(\"papillary renal cell carcinoma\" OR \"KIRP\") AND (MET AND (savolitinib OR cabozantinib OR crizotinib) AND resistance) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(HAVCR1 OR \"KIM-1\" OR \"kidney injury molecule\") AND (\"antibody-drug conjugate\" OR CAR-T OR immunoconjugate OR \"renal cell\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"papillary renal cell carcinoma\" OR \"non-clear cell renal cell carcinoma\") AND (\"immune checkpoint\" OR nivolumab OR ipilimumab) AND (biomarker OR \"PD-L1\" OR \"loss of Y\" OR SMARCA4) AND SRC:MED AND PUB_YEAR:[2024 TO 2026"],"papersShown":[{"pmid":"41566198","doi":"10.1080/07853890.2026.2618431","year":2026,"isNew":true,"title":"Elevated C-reactive protein to albumin ratio is a promising predictive biomarker for prognosis in patients with renal cell carcinoma"},{"pmid":"42518670","doi":"10.1016/j.eucr.2026.103537","year":2026,"isNew":true,"title":"&lt;i&gt;Ex vivo&lt;/i&gt; partial nephrectomy and renal autotransplantation for an ultra-long ureteral stricture with incidental papillary renal cell carcinoma: A 4-year follow-up"},{"pmid":"42545669","doi":"10.1007/s10147-026-03159-z","year":2026,"isNew":true,"title":"Propensity score-matched comparison of survival outcomes between clear cell and non-clear cell renal cell carcinoma in cT1N0M0 disease"},{"pmid":"42270544","doi":"10.1016/j.pathol.2026.03.010","year":2026,"isNew":true,"title":"SMARCA4-deficient collision papillary renal cell carcinoma and chromophobe renal cell carcinoma with long-term response to immunotherapy"},{"pmid":"41934036","doi":"10.1016/j.eururo.2026.03.005","year":2026,"isNew":true,"title":"KIM-1 in Advanced Papillary and Clear Cell Renal Cell Carcinoma"},{"pmid":"42388892","doi":"10.1016/j.cdnut.2026.109392","year":2026,"isNew":true,"title":"Potential Anticancer Effects of Limonene Associated with Reactive Oxygen Species Generation, Apoptosis Induction, and NF-κB Modulation in Papillary Renal Cell Carcinoma: A Prelimin"},{"pmid":"42235464","doi":"10.1016/j.ejca.2026.116816","year":2026,"isNew":true,"title":"Papillary renal cell carcinoma - exploratory results of the SUNNIFORECAST trial comparing Ipilimumab plus Nivolumab vs standard of care as first line therapy based on central patho"},{"pmid":"42232815","doi":"10.1016/j.eucr.2026.103482","year":2026,"isNew":true,"title":"Insights from a rare case of eosinophilic solid and cystic renal cell carcinoma: Diagnostic highlights and therapeutic directions"},{"pmid":"42259100","doi":"10.1016/j.compbiomed.2026.111803","year":2026,"isNew":true,"title":"Computational analysis of bulk and single-cell RNAseq identifies prognostic signature genes in papillary renal cell carcinoma with Y chromosome loss"},{"pmid":"42287003","doi":"10.1002/cam4.72034","year":2026,"isNew":true,"title":"SGO1 and SGO2 are Associated With Disease Progression and an Immunosuppressive Microenvironment in Papillary Renal Cell Carcinoma"}],"trialsShown":[{"nct":"NCT03866382","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare G"},{"nct":"NCT06792552","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"A Phase I Study of SIM0505 in Participants With Advanced Solid Tumors"},{"nct":"NCT05287945","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Study of Orellanine in Metastatic Clear-Cell or Papillary Renal Cell Carcinoma"},{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT05411081","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Testing Cabozantinib With or Without Atezolizumab in Patients With Advanced Papillary Kidney Cancer, PAPMET2 Trial"},{"nct":"NCT05433142","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Study of XmAb®819 in Subjects With Advanced Clear Cell Renal Cell Carcinoma"},{"nct":"NCT04981509","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Testing of Bevacizumab, Erlotinib, and Atezolizumab in Combination for Advanced-Stage Kidney Cancer"},{"nct":"NCT04071223","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer "}],"usage":{"input":8326,"output":6692},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"papillary renal cell carcinoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"papillary renal cell carcinoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41566198","PMID:42518670","PMID:42545669","PMID:42270544","PMID:41934036","PMID:42388892","PMID:42235464","PMID:42232815","PMID:42259100","PMID:42287003","NCT03866382","NCT06792552","NCT05287945","NCT00001238","NCT05411081","NCT05433142","NCT04981509","NCT04071223"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787155047833","cycle":33,"visit":1,"ts":"2026-08-19T15:57:27.833Z","cancer":{"key":"medullary thyroid carcinoma","name":"medullary thyroid carcinoma","mondo":{"id":"MONDO:0015277","name":"medullary thyroid gland carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise selpercatinib + trametinib in RET-inhibitor-refractory MTC, stratified by NF1 loss / MAPK reactivation versus on-target RET G810S, which instead directs patients to next-generation RET inhibitors.","confidence":0.55,"notebook":"Programme opens with a strong, mechanistically specific anchor. P9 (PMID:42258786) is the visit's highest-value item: in a vandetanib-derived resistant RET-mutant MTC model, resistance arose via RET copy-number gain plus the clinically observed solvent-front/gatekeeper-adjacent RET p.G810S, and — independently — whole-genome CRISPR knockout screening showed NF1 loss alone suffices to confer RET-inhibitor resistance through RAS/MAPK reactivation, with selpercatinib+trametinib active in vivo. That converts \"MAPK bypass\" from hand-waving into a testable, repurposing-ready combination (both agents approved) with a candidate patient-selection biomarker: NF1 [SOMATIC] loss or MAPK reactivation on progression biopsy/ctDNA. Reviews P8 (PMID:42525389) and P10 (PMID:42520863) independently frame the same two resistance classes (on-target gatekeeper/solvent-front mutations vs off-target MAPK bypass) and name next-generation RET agents (zeteletinib, SYHA1815, BOS172738, SY-5007) — so the desk should keep two distinct leads: on-target re-inhibition vs bypass-pathway combination, since they demand different resistance genotypes. P8 also records pralsetinib market withdrawal, narrowing the selective-RET field to selpercatinib (NCT04280081) and reinforcing the need for alternatives. [INFERRED] The therapeutic-window argument for RET+MEK is the weak point: RET is required for enteric neurogenesis and nephrogenesis in development, MEK inhibition adds rash/cardiomyopathy/ocular toxicity, and P4 (PMID:42606612) is a cautionary long-horizon signal — fatal hepatic failure at 27 months of selpercatinib where PK argued impaired clearance secondary to circulatory compromise rather than overexposure. Notebook: any RET+MEK trial needs cardiac and hepatic surveillance schedules, not just DLT windows.\n\nSecond axis: FAP. Two independent cases (PMID:41984869, PMID:41950235) show ⁶⁸Ga-FAPI PET/CT outperforming ⁶⁸Ga-DOTATATE/⁹⁹ᵐTc-octreotide in MTC, including SSTR-negative hepatic and skeletal disease and a low-secretory phenotype — i.e., MTC stroma is FAP-rich while SSTR2 expression is unreliable. But the same case reports ¹⁷⁷Lu-FAPI-2286 failing to produce biochemical response. Recorded as a negative: FAP is a staging/selection biomarker first; monotherapy FAP RLT should not be re-proposed without evidence of improved tumour residence time (FAPI-46/-2286 dimers, albumin binders) — enter as a low-confidence lead, not a candidate.\n\nNot pursued: GLP-1RA safety (PMID:42541759) is pharmacovigilance, not therapy, though GLP-1R expression on C cells raises a receptor-targeting question; NCT07713901 is a registry. T1/T2/T4/T8 are genitourinary and irrelevant. Tarlatamab in poorly differentiated NECs (NCT07016230) is only a speculative read-across pending DLL3/ASCL1 profiling in MTC. KG anchors ESR2 and NTRK1 received zero support this pack.","leadChanges":[{"id":"L1","title":"RET + MEK dual blockade for MAPK-bypass resistance in RET-mutant MTC","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"Next-generation RET inhibitors for on-target gatekeeper/solvent-front resistance","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"FAP as a selection/imaging biomarker in SSTR-poor MTC, with FAP radioligand therapy currently unsupported as monotherapy","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["What is the true prevalence of NF1 loss and other MAPK-bypass alterations in clinical RET-inhibitor-refractory MTC (paired pre/post biopsies or ctDNA), versus RET secondary mutations?","Is there any human dosing precedent for selective RET inhibitor + MEK inhibitor (any tumour type) that defines a tolerable schedule, and what were the cardiac/hepatic/ocular AEs?","Do MTC tumours express DLL3, SSTR2, CEACAM5 or GLP-1R at levels supporting T-cell engager or radioligand targeting, and are these anti-correlated with FAP positivity?","Does the fatal selpercatinib hepatotoxicity in PMID:42606612 reflect an emerging late-toxicity class signal, or an isolated circulatory-compromise event?","Do the KG anchors NTRK1 [SOMATIC] and ESR2 [SOMATIC] have any real role in RET-wildtype MTC, which accounts for a minority of tumours with no standard targeted option?"],"nextQueries":["(\"medullary thyroid\" AND (\"NF1\" OR \"MAPK reactivation\" OR \"RET G810\") AND resistance) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"medullary thyroid carcinoma\" AND (\"DLL3\" OR \"CEACAM5\" OR \"SSTR2\" OR \"GLP-1 receptor\" OR \"bispecific\" OR \"antibody-drug conjugate\")) AND SRC:MED","(\"RET wild-type\" OR \"RAS-mutant\") AND \"medullary thyroid\" AND (target OR therapy) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"papersShown":[{"pmid":"42596830","doi":"10.3892/ijo.2026.5927","year":2026,"isNew":true,"title":"Signaling pathways and targeted therapy in high‑risk refractory thyroid cancer: From bench to bedside (Review)"},{"pmid":"41984869","doi":"10.1097/rlu.0000000000006455","year":2026,"isNew":true,"title":"Superior Diagnostic Performance of ⁶⁸Ga-FAPI PET/CT Compared With ⁶⁸Ga-DOTATATE PET/CT in Medullary Thyroid Carcinoma"},{"pmid":"41950235","doi":"10.1097/rlu.0000000000006450","year":2026,"isNew":true,"title":"Widespread Skeletal Metastases in Medullary Thyroid Carcinoma: Diagnostic Superiority of 68 Ga-FAPI PET/CT Over Somatostatin Receptor-Targeted Imaging"},{"pmid":"42606612","doi":"10.1007/s00280-026-04942-5","year":2026,"isNew":true,"title":"Circulatory compromise as a potential mechanism of fatal hepatic failure during long-term selpercatinib therapy: pharmacokinetic and clinical insights."},{"pmid":"42583354","doi":"10.1097/ms9.0000000000005320","year":2026,"isNew":true,"title":"Collision tumor of medullary and papillary thyroid carcinoma with coexisting follicular adenoma: a unique triple pathology case report and review of literature"},{"pmid":"42569820","doi":"10.1002/wjs.70524","year":2026,"isNew":true,"title":"Predicting Structural Progression-Free Survival After Surgery for Medullary Thyroid Carcinoma"},{"pmid":"42541759","doi":"10.1093/ejendo/lvag135","year":2026,"isNew":true,"title":"Safety of glucagon-like peptide-1 receptor agonists in neuroendocrine neoplasms"},{"pmid":"42525389","doi":"10.1093/oncolo/oyag300","year":2026,"isNew":true,"title":"Targeted therapies in the management of advanced medullary thyroid cancer"},{"pmid":"42258786","doi":"10.1200/po-26-00091","year":2026,"isNew":true,"title":"Combination of Selpercatinib and Trametinib Overcomes Resistance to RET Inhibitors in RET-Mutant Medullary Thyroid Carcinoma"},{"pmid":"42520863","doi":"10.1016/j.critrevonc.2026.105506","year":2026,"isNew":true,"title":"RET alterations in thyroid cancer: Molecular mechanisms, targeted therapies, and emerging resistance"}],"trialsShown":[{"nct":"NCT03866382","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare G"},{"nct":"NCT06161532","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Sacituzumab Govitecan With or Without Atezolizumab Immunotherapy in Rare Genitourinary Tumors (SMART) Such as High Grade Neuroendocrine Carc"},{"nct":"NCT04280081","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study of Selpercatinib (LY3527723) in Participants With Advanced Solid Tumors Including RET Fusion-positive Solid Tumors, Medullary Thyroi"},{"nct":"NCT06444880","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Phase II Trial of Ubamatamab Alone or in Combination With Cemiplimab in MUC16-Expressing SMARCB1-Deficient Malignancies"},{"nct":"NCT07713901","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Database Linkage Study to Evaluate the Risk of Medullary Thyroid Carcinoma"},{"nct":"NCT07016230","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study Investigating Tarlatamab (AMG 757) in Patients With Metastatic/Locally Advanced Small-Cell Lung Cancer (SCLC) and Other Poorly Differe"},{"nct":"NCT07259304","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Social Health, Activity Behaviors, and Quality of Life Among Young Adult Cancer Survivors"},{"nct":"NCT04071223","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer "}],"usage":{"input":8457,"output":4625},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"medullary thyroid carcinoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"medullary thyroid carcinoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42596830","PMID:41984869","PMID:41950235","PMID:42606612","PMID:42583354","PMID:42569820","PMID:42541759","PMID:42525389","PMID:42258786","PMID:42520863","NCT03866382","NCT06161532","NCT04280081","NCT06444880","NCT07713901","NCT07016230","NCT07259304","NCT04071223"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787154862691","cycle":32,"visit":1,"ts":"2026-08-19T15:54:22.691Z","cancer":{"key":"paraganglioma","name":"paraganglioma","mondo":{"id":"MONDO:0000448","name":"paraganglioma"}},"control":false,"modelLabel":"SCIENCE","summary":"Anchor the paraganglioma programme on HIF2α antagonism (belzutifan) for the SDHx/VHL/EPAS1 pseudohypoxic cluster plus SSTR2 radioligand escalation from 177Lu to 212Pb alpha emitters, with DLK1 as the emerging surface target to validate next.","confidence":0.58,"notebook":"**Visit 1 — programme initiation, paraganglioma.**\n\nThe pack is mostly noise (P2, P3, P4, P5, P6, P7, P8 have no bearing on PGL biology; recorded here only so the desk does not re-query them). Four items are usable, and they cleanly partition the disease along the axis that matters: PGL splits into a pseudohypoxic/Krebs-cycle cluster (SDHA/B/C/D, SDHAF2, SLC25A11, DLST [GERMLINE]; VHL, EPAS1 [SOMATIC]) and a kinase-signalling cluster (RET [GERMLINE in MEN2 / SOMATIC], NF1, HRAS) — the anchor gene list is dominated by the former, so cluster-1-directed therapy is the programme's spine.\n\nLead 1 (strongest): HIF2α antagonism. Mechanism is mechanistically tight — SDHx loss causes succinate accumulation, competitive inhibition of α-ketoglutarate-dependent prolyl hydroxylases, and constitutive HIF2α stabilisation; EPAS1 gain-of-function mutations reach the same node directly [KNOWN]. P10 states belzutifan has shown efficacy in PPGL and treats HIF2α as clinically validated; T7 is the live registrational-intent phase 2 arm. This is the repurposing-first play. Normal-tissue window argument: HIF2α drives renal interstitial EPO and pulmonary hypoxic response, hence anaemia and hypoxia as on-target toxicity, both flagged in P10. Expected resistance: PAS-B pocket mutations abolishing drug binding, HIF1α-dominant rewiring, and MYC/mTOR-driven escape [SPECULATIVE for PGL specifically].\n\nLead 2: SSTR2 radioligand therapy, with the escalation step from β to α emitters. SDHB-mutant metastatic PGL is characteristically SSTR2-high on 68Ga-DOTATATE [KNOWN]; T3 tests 177Lu-DOTATATE, and T1/T2 test 212Pb-VMT-alpha-NET explicitly in patients who progressed on prior radioligand therapy — i.e. the field has already built the sequencing experiment. Resistance: SSTR2 downregulation, intra-lesional uptake heterogeneity, cumulative marrow/renal dose.\n\nLead 3 (new target, thin evidence): DLK1. P9 places PPGL among the highest-prevalence DLK1-re-expressing tumours, with adult expression restricted to endocrine stem/progenitor compartments — a genuine surface-target window — and lists afucosylated mAbs, ADCs and DC vaccines in development. This is review-level only; I have no PPGL-specific IHC prevalence, no SDHx-status correlation, no ADC preclinical data in PGL.\n\nLead 4 (speculative, cross-indication): MBTA intratumoral innate immunotherapy (mannan-BAM + resiquimod + poly(I:C) + LTA + anti-CD40). P1 reports 87.5% survival in Panc02, but in pancreatic/colon models, not PGL; the platform's PGL provenance is [KNOWN] to me and unsupported by this pack. Low confidence pending PGL-model data.\n\nNot proposed, deliberately: SDHx loss is tumour-suppressor loss and not directly druggable — next visit must test synthetic-lethality routes (PARP, PARP+temozolomide with MGMT methylation, NAD+/NAMPT, glutamine/reductive-carboxylation dependence) rather than reach for direct SDH restoration.","leadChanges":[{"id":"L1","title":"HIF2α antagonism in pseudohypoxic (cluster 1) paraganglioma","level":"LEAD","status":"NEW","confidence":0.68},{"id":"L2","title":"SSTR2-directed radioligand therapy with β→α emitter escalation in metastatic paraganglioma","level":"LEAD","status":"NEW","confidence":0.62},{"id":"L3","title":"DLK1 as a cell-surface target for ADC or antibody therapy in paraganglioma","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L4","title":"MBTA intratumoral innate-immune agonist cocktail for locally accessible or recurrent paraganglioma","level":"LEAD","status":"NEW","confidence":0.22}],"unverifiedCitations":0,"openQuestions":["What are the actual response rates, duration and genotype breakdown (SDHB vs SDHD vs EPAS1 vs VHL) for belzutifan in the PPGL cohort of NCT04924075, and are there published on-treatment biopsies showing HIF2α PAS-B mutation or HIF1α switchi","Is there any citable synthetic-lethality axis for SDHx loss — PARP inhibition, PARP+temozolomide with MGMT promoter methylation, NAMPT/NAD+ dependence, or glutamine/reductive carboxylation — with in vivo data in SDH-deficient models?","What is the quantitative prevalence and intensity of DLK1 protein in PPGL by genotype, and does ectodomain shedding compromise ADC targeting?","Do 177Lu-DOTATATE and 212Pb-VMT-alpha-NET produce durable responses in SDHB-mutant metastatic PGL, and is post-radioligand progression driven by SSTR2 loss or by uptake heterogeneity?","Does succinate-driven DNA/histone hypermethylation (TET/KDM inhibition) create an exploitable dependency — e.g. hypomethylating agents or EZH2/LSD1 inhibitors — and does it explain the immune-cold phenotype of SDHx tumours?","Is there any evidence for MBTA or other intratumoral innate agonists in paraganglioma or pheochromocytoma models specifically?"],"nextQueries":["(\"pheochromocytoma\" OR \"paraganglioma\") AND (\"succinate\" OR \"SDHB\") AND (\"synthetic lethality\" OR PARP OR temozolomide OR NAD OR glutamine) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","belzutifan AND (pheochromocytoma OR paraganglioma OR \"HIF2\" ) AND (resistance OR \"response rate\" OR biomarker) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\") AND (\"DOTATATE\" OR \"radioligand\" OR \"MIBG\" OR \"212Pb\" OR \"alpha emitter\") AND (outcome OR \"progression-free\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42318705","doi":"10.1080/15384047.2026.2683273","year":2026,"isNew":true,"title":"Opsonization and timing as key determinants of MBTA immunotherapy efficacy in pancreatic adenocarcinoma and recurrence treatment"},{"pmid":"42199818","doi":"10.1016/j.apjon.2026.100968","year":2026,"isNew":true,"title":"Effectiveness of a tele-nursing system for palliative cancer pain in patients with advanced cancer: A pilot randomized controlled trial"},{"pmid":"42048609","doi":"10.1080/15592294.2026.2660022","year":2026,"isNew":true,"title":"&lt;i&gt;NOS1&lt;/i&gt; hypermethylation may participate in the colorectal cancer development and be associated with its prognosis"},{"pmid":"41875257","doi":"10.1080/02813432.2026.2623877","year":2026,"isNew":true,"title":"Mild hyperventilation with preserved exercise capacity in patients with self-reported long-term dyspnea after COVID-19-a prospective cohort study in a primary healthcare setting"},{"pmid":"41866332","doi":"10.1080/01652176.2026.2648283","year":2026,"isNew":true,"title":"Propranolol enhances the oncolytic effect of newcastle disease virus on canine mammary tumor cell by modulating the IFN-I-mediated JAK-STAT signaling pathway"},{"pmid":"41688873","doi":"10.1080/13685538.2026.2627014","year":2026,"isNew":true,"title":"Is transurethral enucleation of the prostate combined with internal incision of peripheral zone abscesses a safe treatment for prostate multilocular abscesses?"},{"pmid":"41649882","doi":"10.1080/07853890.2026.2624240","year":2026,"isNew":true,"title":"Heterogeneity in the efficacy of bosentan for hypertensive nephropathy: a study on individualized benefit prediction models based on pathological subtyping and dynamic trajectories"},{"pmid":"41630799","doi":"10.1016/j.apjon.2025.100848","year":2026,"isNew":true,"title":"Latent profiles and influencing factors of sense of coherence in patients with advanced cancer: A cross-sectional study"},{"pmid":"42023826","doi":"10.1530/erc-25-0513","year":2026,"isNew":true,"title":"DLK1: a novel therapeutic target in cancer"},{"pmid":"42050152","doi":"10.1038/s41571-026-01145-y","year":2026,"isNew":true,"title":"The clinical landscape of HIF2α inhibitors in oncology"}],"trialsShown":[{"nct":"NCT06427798","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Somatostatin-Receptors (SSTR)-Agonist [212Pb]VMT-alpha-NET in Metastatic or Inoperable SSTR+ Gastrointestinal Neuroendocrine Tumor and Pheoc"},{"nct":"NCT06479811","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"[212Pb]VMT-Alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive Gastrointestinal Neuroendocrine Tumors, Pheochromocytoma/Par"},{"nct":"NCT03206060","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma"},{"nct":"NCT00004847","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Diagnosis of Pheochromocytoma"},{"nct":"NCT06377033","phase":"NA","status":"RECRUITING","isNew":true,"title":"Using the EHR to Advance Genomic Medicine Across a Diverse Health System"},{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT01660984","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Natural History Study of Children and Adults With Medullary Thyroid Cancer"}],"usage":{"input":8830,"output":5786},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"paraganglioma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"paraganglioma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42318705","PMID:42199818","PMID:42048609","PMID:41875257","PMID:41866332","PMID:41688873","PMID:41649882","PMID:41630799","PMID:42023826","PMID:42050152","NCT06427798","NCT06479811","NCT03206060","NCT00004847","NCT06377033","NCT00001238","NCT04924075","NCT01660984"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787154664739","cycle":31,"visit":1,"ts":"2026-08-19T15:51:04.739Z","cancer":{"key":"pheochromocytoma","name":"pheochromocytoma","mondo":{"id":"MONDO:0008233","name":"pheochromocytoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Found three actionable PPGL axes this visit — HIF-2α inhibition in VHL/pseudohypoxic (cluster-1) disease (NCT04924075), a β-to-α SSTR2 radioligand sequence (¹⁷⁷Lu-DOTATATE → [²¹²Pb]VMT-alpha-NET after RLT failure), and adrenergic/innate-immune adjuncts; next step is to determine whether post-¹⁷⁷Lu f","confidence":0.5,"notebook":"Visit 1 opens the programme. Signal density in this pack is low: P1 (BuChE/Alzheimer), P3 (canine Cushing ML), P5 (aldosterone-degrading gut microbe), P7 (bosentan nephropathy) and P8 (pan-cancer CHRNA7) are query-leakage artefacts with no bearing on PPGL therapeutics — logged so the desk never re-mines them. P10 is a diagnostic-mimicry case report (pheo as pseudo-ACS); it fixes clinical context only. Real content is in the trial set plus two mechanistically usable papers.\n\nThree programme axes are now founded. First, pseudohypoxia. The KG anchors VHL [GERMLINE, causal] and the cluster-1 biology it implies: VHL loss → constitutive HIF-2α → EPAS1 transcriptional programme. NCT04924075 puts belzutifan (HIF-2α inhibitor) into advanced PPGL/pNET/VHL tumours, i.e. the synthetic-lethal-by-pathway-addiction play for a tumour suppressor that is not itself druggable. Normal-tissue window: HIF-2α drives EPO and iron handling, so anaemia/hypoxia-mimicry toxicity is the expected dose-limiter [KNOWN]. Anticipated resistance: EPAS1 gatekeeper mutations, HIF-1α switching, MYC/mTOR bypass [INFERRED].\n\nSecond, SSTR2 radioligand therapy as a *sequence*, not a single agent. NCT03206060 tests β-emitting ¹⁷⁷Lu-DOTATATE; NCT06427798 and NCT06479811 explicitly enrol PPGL that has already failed systemic radioligand therapy and offer α-emitting [²¹²Pb]VMT-alpha-NET with a [²⁰³Pb] imaging surrogate. Mechanistically this is a shift from sparse β double-strand-break kinetics to dense α-particle, largely repair-independent killing — the interesting question is whether β-RLT failure is dosimetric (recoverable by α) or antigenic (SSTR2 loss, not recoverable). That is testable with paired ⁶⁸Ga/²⁰³Pb imaging.\n\nThird, adrenergic/innate-immune adjuncts. P9 establishes that catecholamine excess drives β-adrenoceptor-mediated bone resorption, low BMD and elevated CTX in PPGL, partly reversible after resection — arguing β-blockade in bone-metastatic PPGL may be skeletal-protective, not merely symptomatic; P6 independently shows propranolol suppresses IFN-I/JAK-STAT (in canine mammary/NDV, cross-species). P4 optimises intratumoral MBTA (resiquimod, poly(I:C), LTA, anti-CD40, mannan-BAM) with an opsonisation-dependent 5×2 schedule in Panc02/MC38; MBTA arose in PPGL models [KNOWN], so schedule/opsonisation rules are portable to injectable PPGL metastases — but this pack contains no PPGL efficacy data, so confidence stays low.\n\nNot yet a lead: RET [GERMLINE, causal] MEN2-associated pheo. The pack gives only NCT01660984 (MTC natural history) — no selpercatinib/pralsetinib PPGL evidence. Held as an open question. TMEM127/MAX [SOMATIC-likely] have no actionable content this visit.\n\nNext visit needs: SDHx/cluster-1 synthetic lethality (PARP, MGMT-low temozolomide), HIF-2α resistance genetics, and SSTR2 expression by molecular cluster.","leadChanges":[{"id":"L1","title":"HIF-2α inhibition (belzutifan) in cluster-1 pseudohypoxic PPGL","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"Sequenced SSTR2 radioligand therapy: β-emitter first, α-emitter [²¹²Pb]VMT-alpha-NET on failure","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L3","title":"Intratumoral innate-immune agonist cocktail (MBTA) for injectable PPGL metastases","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L4","title":"β-adrenoceptor blockade as skeletal-protective and immune-modulatory adjunct in metastatic PPGL","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["In prior-¹⁷⁷Lu-DOTATATE PPGL, is failure driven by SSTR2 antigen loss or insufficient absorbed dose — what do paired ⁶⁸Ga-DOTATATE / [²⁰³Pb]VMT-alpha-NET scans show?","Which molecular cluster (VHL, SDHx, EPAS1 vs RET/NF1/HRAS) predicts belzutifan response in PPGL, and what are the acquired-resistance genotypes?","Is there exploitable synthetic lethality in SDHx-deficient PPGL (PARP inhibition, MGMT-low temozolomide, 2-HG/TET-driven hypermethylation, glutamine or NAD dependency)?","Does RET-mutant (MEN2) pheochromocytoma respond to selective RET inhibitors (selpercatinib/pralsetinib), or is the evidence confined to medullary thyroid carcinoma?","Do TMEM127 and MAX lesions [SOMATIC-likely per anchor] converge on an mTORC1/MYC-MAX axis that is druggable (rapalogs, MYC-MAX dimerisation, aurora/CDK)?","Has MBTA or any intratumoral innate-agonist regimen been tested in a PPGL model, and can catecholamine-crisis risk be managed?"],"nextQueries":["(\"pheochromocytoma\" OR \"paraganglioma\") AND (SDHB OR SDHx) AND (\"synthetic lethality\" OR PARP OR temozolomide OR MGMT) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\") AND (belzutifan OR \"HIF-2\" OR EPAS1) AND (response OR resistance) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\") AND (SSTR2 OR DOTATATE OR \"radioligand\") AND (expression OR cluster OR dosimetry OR outcome) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"41645747","doi":"10.1080/14756366.2026.2623314","year":2026,"isNew":true,"title":"Thymol carbamates bearing cyclic amines as potent and selective BuChE inhibitors alleviate memory impairments for Alzheimer's disease therapy"},{"pmid":"41856545","doi":"10.1080/15476286.2026.2647903","year":2026,"isNew":true,"title":"Change of guards: ELAVL proteins switch miRNA export responsibility to regulate differentiation of PC12 cells"},{"pmid":"41431376","doi":"10.1080/01652176.2025.2604643","year":2026,"isNew":true,"title":"Machine learning-assisted screening for canine Cushing's syndrome"},{"pmid":"42318705","doi":"10.1080/15384047.2026.2683273","year":2026,"isNew":true,"title":"Opsonization and timing as key determinants of MBTA immunotherapy efficacy in pancreatic adenocarcinoma and recurrence treatment"},{"pmid":"41964107","doi":"10.1080/19490976.2026.2657047","year":2026,"isNew":true,"title":"Gut microbiota signatures in primary aldosteronism and functional identification of an aldosterone-degrading gut bacterium"},{"pmid":"41866332","doi":"10.1080/01652176.2026.2648283","year":2026,"isNew":true,"title":"Propranolol enhances the oncolytic effect of newcastle disease virus on canine mammary tumor cell by modulating the IFN-I-mediated JAK-STAT signaling pathway"},{"pmid":"41649882","doi":"10.1080/07853890.2026.2624240","year":2026,"isNew":true,"title":"Heterogeneity in the efficacy of bosentan for hypertensive nephropathy: a study on individualized benefit prediction models based on pathological subtyping and dynamic trajectories"},{"pmid":"42292701","doi":"10.1016/j.bbrep.2026.102649","year":2026,"isNew":true,"title":"Pan-cancer expression, methylation, and prognostic significance of α7 nicotinic acetylcholine receptor in tumor immunology"},{"pmid":"41715942","doi":"10.1210/clinem/dgag069","year":2026,"isNew":true,"title":"Effects of catecholamines on bone and mineral metabolism in patients with pheochromocytoma and paraganglioma"},{"pmid":"42569281","doi":"10.1093/ehjcr/ytag544","year":2026,"isNew":true,"title":"When chest pain and troponin elevation aren't acute coronary syndrome: a cardiovascular case report of atypical pheochromocytoma"}],"trialsShown":[{"nct":"NCT06427798","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Somatostatin-Receptors (SSTR)-Agonist [212Pb]VMT-alpha-NET in Metastatic or Inoperable SSTR+ Gastrointestinal Neuroendocrine Tumor and Pheoc"},{"nct":"NCT06479811","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"[212Pb]VMT-Alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive Gastrointestinal Neuroendocrine Tumors, Pheochromocytoma/Par"},{"nct":"NCT03206060","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma"},{"nct":"NCT00004847","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Diagnosis of Pheochromocytoma"},{"nct":"NCT06377033","phase":"NA","status":"RECRUITING","isNew":true,"title":"Using the EHR to Advance Genomic Medicine Across a Diverse Health System"},{"nct":"NCT00001238","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant "},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT01660984","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Natural History Study of Children and Adults With Medullary Thyroid Cancer"}],"usage":{"input":8543,"output":6203},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"pheochromocytoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"pheochromocytoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41645747","PMID:41856545","PMID:41431376","PMID:42318705","PMID:41964107","PMID:41866332","PMID:41649882","PMID:42292701","PMID:41715942","PMID:42569281","NCT06427798","NCT06479811","NCT03206060","NCT00004847","NCT06377033","NCT00001238","NCT04924075","NCT01660984"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787154460970","cycle":30,"visit":1,"ts":"2026-08-19T15:47:40.970Z","cancer":{"key":"gastrointestinal stromal tumor","name":"gastrointestinal stromal tumor","mondo":{"id":"MONDO:0011719","name":"gastrointestinal stromal tumor"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise the SDH-deficient pseudohypoxia axis (belzutifan/rogaratinib/olverembatinib) and independently verify whether the HRD signature of the newly defined G4 metabolic GIST subtype reflects genuine biallelic HR-gene loss before backing PARP inhibitors.","confidence":0.53,"notebook":"Programme opens with an unusually rich pack: five orthogonal therapeutic axes, all citable, none previously logged.\n\nMost novel is P9 (PMID:42384257). Whole-exome + RNA on 106 primary GISTs yields four transcriptional subtypes; the metabolic G4 subtype (non-gastric predominance, poor neoadjuvant imatinib response, synchronous metastasis) carries HRD mutational signatures with measured loss of homologous recombination activity and compensatory NHEJ upregulation, and olaparib suppressed growth in subtype-matched cell lines/xenografts. [KNOWN] GIST is canonically genomically quiet and BRCA-mutant GIST is vanishingly rare, so signature-level HRD without demonstrated biallelic BRCA1/2/PALB2/RAD51C loss is a soft biomarker; the abstract does not state the genetic lesion generating the signature, so [INFERRED] the dependency may be transcriptional (e.g. HR-gene downregulation) rather than mutational, which historically predicts PARPi response less reliably. Logged as LEAD, not higher. Resistance routes to pre-name: HR restoration, ABCB1 efflux, 53BP1/Shieldin loss. Window: PARPi toxicity is haematologic, and G4's aerobic-metabolism phenotype invites a second hit (OXPHOS/IACS-type agents) [SPECULATIVE].\n\nSecond axis: SDH-deficient GIST, matching three of five KG anchors (SDHA/SDHB/SDHC; SDHB/SDHC [GERMLINE], SDHA typically germline with somatic second hit — the pack's \"correlated\" label understates this). Three trials now converge on the pseudohypoxia consequence rather than the undruggable TCA-cycle loss: olverembatinib phase 3 (NCT06640361), belzutifan (NCT04924075) targeting HIF-2α directly, rogaratinib (NCT04595747) targeting the FGF/FGFR output. This is textbook synthetic-lethality-by-downstream-node reasoning for a tumour-suppressor loss and is the strongest structural lead of the visit.\n\nThird: TKI-persister biology. P3 (PMID:42440135) shows radiographic response plateaus at 4–6 months while pathology-integrated response keeps improving to 10–12 months in KIT exon 11 disease — imatinib leaves viable tumour for many months. Deciphera's inlexisertib (ULK1/2) + ripretinib (NCT05957367) attacks exactly that autophagy-dependent residual pool. Fourth: velzatinib vs imatinib frontline (NCT07585266) tests whether upfront broad exon 13/14/17/18 coverage prevents the polyclonal secondary resistance P4 (PMID:42584765) frames as the central unsolved problem. Fifth, weakest: KQB198 (HPK1) + imatinib frontline (NCT07406633) against the immune-cold sarcoma baseline of P1.\n\nNotebook negatives/non-leads: P5's late-onset-hypertension-as-PFS-biomarker signal is RCC-driven (GIST 11.3%) — do not re-propose as GIST biomarker. P2 (FAERS) is a tolerability ceiling for any doublet, not a hypothesis. P6, P7, P10 are non-therapeutic. P8 records NF1-associated GIST [GERMLINE] as an unaddressed KIT/PDGFRA-wild-type niche.","leadChanges":[{"id":"L1","title":"PARP inhibition in the HRD-signature G4 (metabolic) GIST subtype","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L2","title":"Pseudohypoxia-axis blockade in SDH-deficient (KIT/PDGFRA wild-type) GIST","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L3","title":"Autophagy-dependent TKI-persister eradication (ULK1/2 + KIT inhibition)","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L4","title":"Frontline broad-spectrum KIT coverage to pre-empt polyclonal secondary resistance","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L5","title":"Immune-adjuvant KIT inhibition: HPK1 blockade plus imatinib in first-line GIST","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does the G4/HRD GIST subtype carry demonstrable biallelic loss or mutation of BRCA1/2, PALB2, RAD51C/D, or is the HRD signature purely transcriptional - and has any second cohort reproduced olaparib sensitivity in GIST?","In SDH-deficient GIST, is HIF-2alpha inhibition (belzutifan) or FGFR inhibition (rogaratinib) the dominant dependency, and are there data on combining them or on olverembatinib's actual mechanism of benefit in SDHx-null disease?","Which resistance mechanisms have been documented after ripretinib/avapritinib failure - KIT-independent bypass (FGFR, AXL, MAPK, cell-cycle) versus new KIT mutations - and do any support autophagy or MAPK-directed combinations?","Is velzatinib (IDRX-42) supported by published phase 1/2 response and ctDNA clonal-suppression data, or is NCT07585266 running ahead of the biology?","What is the current evidence-based option set for the KIT/PDGFRA wild-type, SDH-proficient niches - NF1-associated [GERMLINE], BRAF V600E, NTRK/FGFR-fusion GIST (plixorafenib NCT05503797)?","Does PDGFRA D842V-mutant GIST show avapritinib resistance mechanisms distinct from KIT-mutant disease that would justify a separate lead?"],"nextQueries":["(\"gastrointestinal stromal tumor\" OR GIST) AND (\"homologous recombination\" OR \"HRD\" OR PARP OR olaparib) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"SDH-deficient\" OR SDHA OR SDHB OR succinate) AND (GIST OR \"gastrointestinal stromal\") AND (HIF2 OR belzutifan OR FGFR OR pseudohypoxia OR methylation) AND SRC:MED","(GIST OR \"gastrointestinal stromal tumor\") AND (ripretinib OR avapritinib OR \"IDRX-42\" OR velzatinib OR \"KIT-independent\" OR \"bypass resistance\" OR autophagy OR ULK1) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42172443","doi":"10.1080/21645515.2026.2674185","year":2026,"isNew":true,"title":"The promise of immunotherapy in the treatment of sarcoma: A state-of-the-art review of practice changing research and future directions"},{"pmid":"42136545","doi":"10.1080/20565623.2026.2672016","year":2026,"isNew":true,"title":"A comprehensive analysis of the adverse drug events of metastatic and unresectable gastrointestinal stromal tumor treatment options: avapritinib, imatinib, regorafenib, ripretinib,"},{"pmid":"42440135","doi":"10.1097/sla.0000000000007141","year":2026,"isNew":true,"title":"Radiographic Versus Pathology-Integrated Response for Assessing Optimal Surgical Timing After Neoadjuvant Imatinib in Patients With Locally Advanced KIT Exon 11-Mutant GIST"},{"pmid":"42584765","doi":"10.1007/s11523-026-01249-6","year":2026,"isNew":true,"title":"Rare Molecular Variants of Gastrointestinal Stromal Tumors (GISTs): Clinical Implications and Overview of Current Evidence"},{"pmid":"42577631","doi":"10.1253/circrep.cr-26-0054","year":2026,"isNew":true,"title":"Late-Onset Hypertension Is Associated With Improved Clinical Outcomes in Cancer Patients Treated With Sunitinib"},{"pmid":"42576077","doi":"10.1007/s00464-026-13261-y","year":2026,"isNew":true,"title":"Clinical utility of single-balloon enteroscopy for malignant small bowel tumors"},{"pmid":"42547856","doi":"10.1186/s12885-026-16537-7","year":2026,"isNew":true,"title":"Precision oncology meets Generative AI: assessing large language models in multidisciplinary GIST tumor boards"},{"pmid":"42453302","doi":"10.1210/jcemcr/luag187","year":2026,"isNew":true,"title":"A case of neurofibromatosis type 1 with malignant peripheral nerve sheath tumor and metastatic pheochromocytoma"},{"pmid":"42384257","doi":"10.1007/s13402-026-01247-w","year":2026,"isNew":true,"title":"Molecular classification identifies aggressive gastrointestinal stromal tumor subtype targetable by PARP inhibitors"},{"pmid":"42536685","doi":"10.1371/journal.pone.0353357","year":2026,"isNew":true,"title":"Real-world regorafenib use among patients with advanced gastrointestinal stromal tumor in the United States"}],"trialsShown":[{"nct":"NCT07585266","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Study to Investigate Velzatinib Compared With Imatinib in Adult Participants With Previously Untreated Metastatic and/or Unresectable Gast"},{"nct":"NCT04557969","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Surgery in Gastrointestinal Stromal Tumors (GISTs) for Treatment, Tumor Modeling, and Genomic Analysis"},{"nct":"NCT07406633","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"KQB198 in Combination With Imatinib in Participants With Advanced/Metastatic GIST in 1st Line Setting (SynerGIST-1st Line)"},{"nct":"NCT04924075","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-L"},{"nct":"NCT04595747","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Testing the Anti-cancer Drug, Rogaratinib (BAY 1163877), for Treatment of Advanced Sarcoma With Alteration in Fibroblast Growth Factor Recep"},{"nct":"NCT05503797","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations"},{"nct":"NCT06640361","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"A Study of Olverembatinib in SDH-deficient GIST."},{"nct":"NCT05957367","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study of Inlexisertib (DCC-3116) in Combination With Anticancer Therapies in Participants With Advanced Malignancies"}],"usage":{"input":8863,"output":6761},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"gastrointestinal stromal tumor\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"gastrointestinal stromal tumor\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42172443","PMID:42136545","PMID:42440135","PMID:42584765","PMID:42577631","PMID:42576077","PMID:42547856","PMID:42453302","PMID:42384257","PMID:42536685","NCT07585266","NCT04557969","NCT07406633","NCT04924075","NCT04595747","NCT05503797","NCT06640361","NCT05957367"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787154245952","cycle":29,"visit":1,"ts":"2026-08-19T15:44:05.952Z","cancer":{"key":"synovial sarcoma","name":"synovial sarcoma","mondo":{"id":"MONDO:0010434","name":"synovial sarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise cancer-testis-antigen TCR-T (MAGE-A4/NY-ESO-1) as the lead axis in synovial sarcoma and test SPP1/OPN blockade as the rational combination to relieve PD-L1-mediated CD8 exhaustion; TRK inhibition is retired for SS18-rearranged tumours even when an NTRK fusion is present.","confidence":0.55,"notebook":"Programme initialised. The pack is thin on SS-specific mechanism but rich on clinical-stage immunotherapy, so the desk starts with one strong translational axis and three speculative ones.\n\nImmunotherapy is the only axis with clinical-stage assets. Four trials converge on cancer-testis antigen (CTA)-directed cell therapy: afami-cel (MAGE-A4 TCR, NCT05642455, now extending into paediatrics), lete-cel (NY-ESO-1/LAGE-1a TCR, NCT03967223), NY-ESO-1 TCR-transduced IL-15-armoured NK cells (NCT06083883), and NY-ESO-1 TIL engineered with a dominant-negative TGF-βRII ± decitabine (NCT02650986). Mechanistically this is downstream of the fusion: [KNOWN] SS18::SSX-driven BAF/PRC2 rewiring produces near-uniform, homogeneous CTAG1B/MAGE-A4 derepression, which is why an immune-\"cold\" histology (P1, PMID:42172443) is nonetheless the flagship TCR-T indication. The decitabine arm and the TGF-β-decoy design are the two most informative resistance experiments in the pack — antigen downregulation and TGF-β/exclusionary stroma are the named escape routes; HLA-A*02 restriction plus HLA-LOH is the third. Normal-tissue window: MAGE-A4/NY-ESO-1 are testis-restricted, hence tolerable off-tumour risk apart from on-target skin/marrow toxicity from cross-reactive TCRs [KNOWN].\n\nNew mechanistic lead: OPN/SPP1 knockdown in SS lines reduces proliferation/invasion and lowers PD-L1 with reversal of CD8 exhaustion, with OPN–PD-L1 co-immunoprecipitation and IHC correlation in sarcoma tissue (PMID:42399829). [INFERRED] This nominates secreted SPP1 (or its CD44/integrin receptors) as a combinable target to convert SS from checkpoint-refractory to checkpoint-sensitive, and as a possible adjunct to TCR-T. Abstract only; no in vivo blockade shown — hypothesis, not corroboration.\n\nNegative results recorded so the desk never re-proposes them: larotrectinib in an SS with a concurrent PDE3A-NTRK2 fusion produced explosive progression (PMID:42376758) — tissue-agnostic TRK targeting is retired for SS18-rearranged tumours; the fusion is a passenger under an epigenetically dominant driver. Also logged: in PDX, ecubectedin and PM54 shrank CIC-rearranged sarcoma but only stabilised the synovial model (PMID:42600063) — next-generation ecteinascidins are not an SS-preferential strategy.\n\nWeak clinical signal: AI ± anlotinib in lung-metastatic SS, mPFS 8.1 vs 6.2 mo, mOS 14.8 vs 6.8 mo (PMID:41983866). The control OS is implausibly short for first-line SS [INFERRED: era/selection confounding across 2007–2024], so this is registered at low confidence pending prospective data.\n\nCarried as a paper hypothesis only: degrader-based attack on the fusion's chromatin dependencies (BRD9, PRC2), supported here only by a general PROTAC review (PMID:41885448) plus the \"master epigenetic driver\" framing (PMID:42376758). Next visit must find SS-specific BRD9-degrader data or this lead dies.","leadChanges":[{"id":"L1","title":"Cancer-testis antigen TCR-T (MAGE-A4, NY-ESO-1/LAGE-1a) as the backbone therapy in SS18::SSX-driven synovial sarcoma","level":"LEAD","status":"NEW","confidence":0.7},{"id":"L2","title":"SPP1/OPN-PD-L1 axis as a combinable immune-evasion target in synovial sarcoma","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L3","title":"Degrader-based attack on SS18::SSX chromatin dependencies (BRD9, PRC2)","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L4","title":"Anlotinib added to anthracycline/ifosfamide in lung-metastatic synovial sarcoma","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["What are the published resistance mechanisms in afami-cel/lete-cel-treated synovial sarcoma - antigen downregulation, HLA-A*02 LOH, TCR-T exhaustion, or stromal exclusion - and which is dominant?","What fraction of SS tumours co-express MAGE-A4 and NY-ESO-1 at TCR-T-qualifying intensity, and can hypomethylating agents or EZH2 inhibition raise antigen density in antigen-low tumours?","Is there any SS-specific preclinical or clinical data for BRD9 degraders or other ncBAF/PRC2-directed agents, and does it show fusion-selective dependency?","Can SPP1/OPN blockade (or CD44/integrin receptor blockade) be shown in vivo to restore CD8 function in SS, and does it synergise with PD-1 blockade or TCR-T?","Are there prospective randomised data for antiangiogenic TKIs (anlotinib, pazopanib) specifically in SS with lung metastases, and how does the retrospective OS gain hold up?","Beyond NTRK, which other 'actionable' co-mutations have failed in SS18::SSX tumours, so the desk can generalise the driver-versus-passenger rule?"],"nextQueries":["\"synovial sarcoma\" AND (\"MAGE-A4\" OR \"NY-ESO-1\" OR afamitresgene OR letetresgene) AND (resistance OR relapse OR \"antigen loss\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"SS18-SSX\" OR \"SS18::SSX\") AND (BRD9 OR ncBAF OR PRC2 OR EZH2 OR degrader OR PROTAC) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(SPP1 OR osteopontin) AND (sarcoma OR \"synovial sarcoma\") AND (\"PD-L1\" OR CD44 OR \"immune evasion\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42172443","doi":"10.1080/21645515.2026.2674185","year":2026,"isNew":true,"title":"The promise of immunotherapy in the treatment of sarcoma: A state-of-the-art review of practice changing research and future directions"},{"pmid":"41885448","doi":"10.1080/14756366.2026.2636394","year":2026,"isNew":true,"title":"PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators"},{"pmid":"42569522","doi":"10.1016/j.eucr.2026.103562","year":2026,"isNew":true,"title":"Bilateral corpus cavernosum thrombosis revealing penile synovial sarcoma"},{"pmid":"42564586","doi":"10.1016/j.jot.2026.101184","year":2026,"isNew":true,"title":"Intra-articular delivery of VEGF targeting miR-126-3p and miR-140-5p ameliorates synovitis and pain in a rat model of post-traumatic knee osteoarthritis"},{"pmid":"42024101","doi":"10.1177/10668969261437722","year":2026,"isNew":true,"title":"A Primary Dedifferentiated Melanoma, Masquerading as a Soft Tissue Sarcoma, Displaying &lt;i&gt;BRAF p.V600E, CDKN2A, TP53&lt;/i&gt;, and &lt;i&gt;TERT&lt;/i&gt; Promoter Mutations"},{"pmid":"41983866","doi":"10.1002/ijc.70501","year":2026,"isNew":true,"title":"The Efficacy and Safety of AI With Anlotinib Versus AI for Treating Synovial Sarcoma Patients With Lung Metastasis: A Retrospective Cohort Study"},{"pmid":"42600063","doi":"10.1158/2767-9764.crc-26-0377","year":2026,"isNew":true,"title":"Antitumor activity of novel transcriptional inhibitors ecubectedin and PM54 in soft tissue sarcoma patient-derived xenografts"},{"pmid":"42562371","doi":"10.5435/jaaosglobal-d-25-00237","year":2026,"isNew":true,"title":"Diagnosis and Management of Soft-Tissue Sarcomas: Current Insights"},{"pmid":"42376758","doi":"10.1177/03008916261458950","year":2026,"isNew":true,"title":"Driver vs. passenger: Primary resistance to larotrectinib in synovial sarcoma harboring concurrent SS18 rearrangement and PDE3A-NTRK2 fusion"},{"pmid":"42399829","doi":"10.1186/s12885-026-16363-x","year":2026,"isNew":true,"title":"Preliminary study on the mechanism of OPN up-regulating PD-L1 to induce CD8 + T cell exhaustion in synovial sarcoma"}],"trialsShown":[{"nct":"NCT05642455","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"SPEARHEAD-3 Pediatric Study"},{"nct":"NCT03967223","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Master Protocol to Assess the Safety and Antitumor Activity of Genetically Engineered T Cells in NY-ESO-1 and/or LAGE-1a Positive Solid Tumo"},{"nct":"NCT06239272","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhab"},{"nct":"NCT05711615","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Testing Low-Dose Common Chemotherapy (Liposomal Doxorubicin) in Combination With an Anti-Cancer Drug, Peposertib, in Advanced Sarcoma"},{"nct":"NCT06083883","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Phase I/Ib Study of NK Expressing an Affinity-enhanced T-cell Receptor (TCR) Against the NY-ESO-1"},{"nct":"NCT05227326","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"AOH1996 for the Treatment of Refractory Solid Tumors"},{"nct":"NCT02650986","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Gene-Modified T Cells With or Without Decitabine in Treating Patients With Advanced Malignancies Expressing NY-ESO-1"},{"nct":"NCT06625190","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors"}],"usage":{"input":8651,"output":5550},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"synovial sarcoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"synovial sarcoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42172443","PMID:41885448","PMID:42569522","PMID:42564586","PMID:42024101","PMID:41983866","PMID:42600063","PMID:42562371","PMID:42376758","PMID:42399829","NCT05642455","NCT03967223","NCT06239272","NCT05711615","NCT06083883","NCT05227326","NCT02650986","NCT06625190"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787154051843","cycle":28,"visit":1,"ts":"2026-08-19T15:40:51.843Z","cancer":{"key":"chondrosarcoma","name":"chondrosarcoma","mondo":{"id":"MONDO:0008977","name":"chondrosarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise genotype-directed mutant-IDH1/2 inhibition (LY3410738) with an epigenetic partner in conventional chondrosarcoma, and pursue two independent cisplatin-resensitisation axes — REGγ/WDR6/STK11-AMPK ferroptosis release and circHMGB2-IGF2BP1-Grb10-AKT — as the desk's opening programme.","confidence":0.55,"notebook":"Programme opens with four leads; the pack is thin on chondrosarcoma-specific biology but two mechanistic papers and three trial arms are directly usable. Everything else (P3 ethnobotany, P4 canine liposarcoma, P6 GCTB case, P7 OA/SW1353 as an inflammation reporter, P8 fibulectomy series) is not decision-relevant for target selection; note that P7 and P5 use SW1353 as a chondrocyte surrogate rather than as a tumour model, so their readouts do not support anti-tumour claims. P5's vitamin D result is explicitly weak in chondrosarcoma (10% viability loss in SW-1353 vs 23% in MG-63, no proliferation-arrest signal reported) — logged as a dead end, do not re-propose 1,25D3 monotherapy.\n\nThe strongest new mechanism is chemoresistance biology. P9 (PMID:42360152) places REGγ (PSME3) as a ubiquitin-independent proteasome activator that degrades WDR6, releasing STK11/AMPK-dependent ferroptosis suppression; the REGγ–20S inhibitor RLY01 suppressed growth and sensitised to cisplatin. This is a genuine synthetic-lethal-flavoured handle on a tumour where cytotoxics fail. [INFERRED] It predicts combinability with GPX4/SLC7A11 axis agents (sulfasalazine, imidazole ketone erastin) and a biomarker (REGγ-high, WDR6-low). Normal-tissue caveat: REGγ is broadly expressed and modulates proteostasis in immune and neural tissue, so window is unproven — need on-target toxicity data. P10 (PMID:42561431) gives an orthogonal, druggable-today route: circHMGB2 decoys IGF2BP1 off Grb10 mRNA, Grb10 loss de-represses PI3K/AKT, and silencing circHMGB2 restores cisplatin sensitivity in vivo. [INFERRED] Grb10-low/pAKT-high tumours should be testable with approved AKT/PI3K inhibitors plus platinum rather than with RNA therapeutics.\n\nTrials reframe the genotype-directed arm. NCT04521686 (LY3410738, covalent mutant IDH1/IDH2) is the cleanest route for the ~50% of conventional central chondrosarcomas carrying IDH1 R132/IDH2 R172 [KNOWN, SOMATIC]; NCT04340843 (belinostat + guadecitabine or ASTX727) attacks the same tumours through the hypermethylator phenotype 2-HG creates [INFERRED], making an IDHi + HMA sequence the obvious rational combination. NCT04040205 (abemaciclib) matches the recurrent CDKN2A/B deletion and CDK4 amplification in dedifferentiated/high-grade disease [KNOWN].\n\nTwo things I will not chase without new data: Hedgehog blockade (NCT01267955 vismodegib has sat active-not-recruiting for years with no positive readout in the pack, and EXT1 [GERMLINE] heparan-sulfate loss in secondary peripheral disease is predisposition, not necessarily maintenance), and single-agent checkpoint inhibition — P2 characterises sarcoma as predominantly immune-cold, which constrains NCT04458922 (atezolizumab) to a biomarker-driven or combination question. P1 contributes no chondrosarcoma-relevant antibody.\n\nNext visit: IDH-mutant dependency and resistance, ferroptosis pharmacology in cartilage tumours, and whether Grb10/AKT status stratifies platinum response.","leadChanges":[{"id":"L1","title":"Mutant IDH1/IDH2 inhibition plus hypomethylating/HDAC therapy in conventional central chondrosarcoma","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"REGγ (PSME3) inhibition to release WDR6/STK11-AMPK-dependent ferroptosis and resensitise chondrosarcoma to cisplatin","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"PI3K/AKT blockade to reverse Grb10-loss-driven platinum resistance (circHMGB2-IGF2BP1 axis)","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"CDK4/6 inhibition in CDKN2A/B-deleted or CDK4-amplified high-grade and dedifferentiated chondrosarcoma","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["Has any clinical readout been published for mutant-IDH inhibition (LY3410738, ivosidenib) in chondrosarcoma, and what is the 2-HG-independent resistance spectrum?","Is the REGγ-WDR6-STK11/AMPK ferroptosis axis reproduced by any independent group, and does RLY01 (or genetic REGγ loss) have a tolerable normal-tissue profile?","Do IDH1/2-mutant chondrosarcomas show a distinct ferroptosis or GPX4/SLC7A11 dependency that could be co-targeted with mutant-IDHi?","Does Grb10/pAKT status stratify platinum response in primary chondrosarcoma tissue, or is the circHMGB2 axis a cell-line artefact?","What is the actual efficacy record of Hedgehog inhibition (NCT01267955 vismodegib) in chondrosarcoma, and is EXT1/heparan-sulfate loss a maintenance dependency in secondary peripheral disease or purely germline predisposition?","Which immune-editing strategy (combination checkpoint, adoptive cell therapy, radiation priming) has any chondrosarcoma-specific signal given the immune-cold phenotype?"],"nextQueries":["(\"chondrosarcoma\" AND (IDH1 OR IDH2 OR \"2-hydroxyglutarate\" OR ivosidenib OR vorasidenib) AND SRC:MED AND PUB_YEAR:[2022 TO 2026])","(\"chondrosarcoma\" AND (ferroptosis OR GPX4 OR SLC7A11 OR \"lipid peroxidation\" OR PSME3 OR \"REG gamma\") AND SRC:MED)","(\"chondrosarcoma\" AND (CDKN2A OR CDK4 OR \"hedgehog\" OR EXT1 OR \"heparan sulfate\" OR \"immune checkpoint\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026])"],"papersShown":[{"pmid":"41560619","doi":"10.1080/19420862.2026.2614669","year":2026,"isNew":true,"title":"Antibodies to watch in 2026"},{"pmid":"42172443","doi":"10.1080/21645515.2026.2674185","year":2026,"isNew":true,"title":"The promise of immunotherapy in the treatment of sarcoma: A state-of-the-art review of practice changing research and future directions"},{"pmid":"42095890","doi":"10.1080/13880209.2026.2663269","year":2026,"isNew":true,"title":"Medicinal food plants of Sabah (Eastern Malaysia): a source of potential natural products and nutraceuticals for the fight against cancer"},{"pmid":"41518587","doi":"10.1080/01652176.2026.2614697","year":2026,"isNew":true,"title":"CMLPS-N1: a novel preclinical cell line model for canine mammary tumor and its application in therapeutic screening"},{"pmid":"42598195","doi":"10.1016/j.jbo.2026.100792","year":2026,"isNew":true,"title":"Vitamin D decreases tumor cell growth and invasiveness in primary malignant bone tumors in vitro"},{"pmid":"42305371","doi":"10.1016/j.radcr.2026.05.016","year":2026,"isNew":true,"title":"Optimal management of giant cell tumor in the tibial plateau: A case report on curettage and cement reinforcement"},{"pmid":"42582610","doi":"10.4162/nrp.2026.20.4.571","year":2026,"isNew":true,"title":"Oyster hydrolysate attenuates osteoarthritis progression by modulating inflammatory signaling and extracellular matrix homeostasis"},{"pmid":"42561435","doi":"10.52628/92.2.15601","year":2026,"isNew":true,"title":"Fibulectomy for primary fibular tumors A Decade of experience at the National Cancer Institute, Egypt"},{"pmid":"42360152","doi":"10.1002/advs.76293","year":2026,"isNew":true,"title":"REGγ Suppresses Ferroptosis and Induces Drug Resistance by Degrading WDR6 in Chondrosarcoma"},{"pmid":"42561431","doi":"10.52628/92.2.14037","year":2026,"isNew":true,"title":"CircHMGB2 Acts as a Molecular Decoy for IGF2BP1 to Promote Cisplatin Resistance via Grb10/Akt Signaling in Chondrosarcoma"}],"trialsShown":[{"nct":"NCT01267955","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Vismodegib in Treating Patients With Advanced Chondrosarcomas"},{"nct":"NCT06239272","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhab"},{"nct":"NCT04340843","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Testing the Combination of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional C"},{"nct":"NCT01659203","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Proton or Photon RT for Retroperitoneal Sarcomas"},{"nct":"NCT04458922","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Testing Atezolizumab in People 2-17 Years Old With Clear Cell Sarcoma or Advanced Chondrosarcoma"},{"nct":"NCT07734805","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Radiological Diagnosis of Pediatric Neck Swellings"},{"nct":"NCT04040205","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Abemaciclib for Bone and Soft Tissue Sarcoma With Cyclin-Dependent Kinase (CDK) Pathway Alteration"},{"nct":"NCT04521686","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations"}],"usage":{"input":8699,"output":5595},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chondrosarcoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chondrosarcoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41560619","PMID:42172443","PMID:42095890","PMID:41518587","PMID:42598195","PMID:42305371","PMID:42582610","PMID:42561435","PMID:42360152","PMID:42561431","NCT01267955","NCT06239272","NCT04340843","NCT01659203","NCT04458922","NCT07734805","NCT04040205","NCT04521686"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787153856314","cycle":27,"visit":1,"ts":"2026-08-19T15:37:36.314Z","cancer":{"key":"chordoma","name":"chordoma","mondo":{"id":"MONDO:0008978","name":"chordoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Stratify chordoma therapeutics by the newly validated four copy-number clusters — CDKN2A/chr9-loss (C9) tumours to CDK4/6 inhibition, chr2+7-gain (C2) tumours to GLI/SHH-axis blockade — while TBXT degradation/peptide-CAR-T remains the lineage-addiction backbone.","confidence":0.46,"notebook":"Programme opens from zero; the pack is review- and radiotherapy-heavy, so I build few leads and grade them all LEAD (single evidence-bearing visit, no promotions possible).\n\nHighest-value new datum is P4 (PMID:42284679): two independent skull-base cohorts (n=32 methylation, n=71 WGS) resolve into four copy-number clusters — C1 CN-stable, C9 chromosomal loss incl. chr9/CDKN2A, C7 chr7 gain, C2 chr2+chr7 gain — validated by FISH at 84–89% concordance, explaining 31–33% of transcriptional variance, with SHH up-regulation in C2 and cell-cycle enrichment in C2/C9. This converts \"chordoma is CN-driven\" into an actionable stratification hypothesis: C9 (CDKN2A deletion) is the palbociclib/abemaciclib arm [INFERRED, KNOWN that CDKN2A loss de-represses CDK4/6-cyclin D]; C2 is the only rational GLI/SMO arm. Caveat from abstract only: SHH signature is transcriptional, not proven ligand- or SMO-dependent, so SMO inhibitors may be the wrong node versus GLI/BET.\n\nTBXT (brachyury) remains the axis-defining target and is the sole KG anchor with a mechanistic story in the pack: P8 (PMID:42571860) and P10 (PMID:42448412) describe covalent small-molecule binders, targeted degradation, and peptide-centric CAR-T against the intracellular oncoprotein. TBXT is a lineage-survival transcription factor [SOMATIC-acting, though the tandem-duplication susceptibility allele is [GERMLINE]] — normal-tissue expression in adults is minimal, which is the whole therapeutic window argument. Degrader/CAR-T resistance routes to name in advance: TBXT-low mesenchymal escape, HLA class I loss for peptide-centric TCR-mimic CAR, and paralogue substitution (TBX2/4).\n\nImmunotherapy: no chordoma-specific efficacy data in the pack. The only concrete clinical handles are baskets accruing SMARCB1/INI1-deficient tumours (NCT05286801 tiragolumab+atezolizumab; NCT04416568 nivo+ipi) and NCT02834013 rare tumours — relevant to poorly differentiated/INI1-negative chordoma [KNOWN]. Kept as a low-confidence lead pending arm-level readouts.\n\nBRCA2/PALB2 correlation in the anchor is unresolved germline-vs-somatic; NCT01200680 is precisely the susceptibility-gene ascertainment protocol, so I treat HR involvement as hypothesis-grade and pair it with the particle-therapy physics papers (P1 PMID:42499293, P6 PMID:42595265): LETd escalation inside GTV is now clinically deliverable (10 sacral patients, 73.6→67.2 Gy(RBE) MKM with LETd-min cost term), which makes a DDR-inhibitor + high-LET radiosensitisation hypothesis testable — while P1 quantifies the temporal-lobe-necrosis ceiling that any dose/LET escalation must respect.\n\nRecorded as non-leads so the desk does not re-propose them: DHX8 inhibitors (P7) have no chordoma link whatsoever; the circRNA/immuno-metabolic review (P2) is mechanistically diffuse; P3, P5, P9 are non-therapeutic (P9 does fix the denominator: 6,260 US cases, incidence rising 1.47%/yr, cranial 38.7%).","leadChanges":[{"id":"L1","title":"TBXT (brachyury) lineage addiction: degraders, covalent binders, peptide-centric CAR-T","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L2","title":"Copy-number cluster-directed therapy: CDK4/6 inhibition in chr9/CDKN2A-loss (C9), GLI/SHH blockade in chr2+chr7-gain (C2)","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L3","title":"SMARCB1/INI1-deficient (poorly differentiated) chordoma as a checkpoint-blockade subset","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L4","title":"DDR/HR inhibition as radiosensitiser under LETd-optimised particle therapy","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Do the C1/C2/C7/C9 copy-number clusters predict drug sensitivity in cluster-annotated chordoma lines/PDX, specifically CDK4/6i in C9 and GLI/BET inhibition in C2?","Is the C2 SHH signature ligand/SMO-dependent or driven by non-canonical GLI activation, which would make SMO inhibitors futile?","Are BRCA2/PALB2 alterations in chordoma germline predisposition, somatic, or artefacts of small-cohort correlation — and is there any functional HR deficiency (RAD51 foci, HRDetect) in chordoma tumours?","What chordoma-specific response rates emerge from the INI1/SMARCB1-deficient checkpoint baskets (NCT05286801, NCT04416568, NCT02834013), and does poorly differentiated chordoma differ from conventional?","Which TBXT-targeting modality has actual in vivo tumour regression data — degrader, covalent binder, or peptide-centric CAR-T — and what is the first documented resistance mechanism?","Do the CN clusters differ between skull-base and sacral/mobile-spine chordoma, given the near-equal site distribution in US incidence data?"],"nextQueries":["\"chordoma\" AND (brachyury OR TBXT) AND (degrader OR PROTAC OR \"CAR-T\" OR covalent) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"chordoma\" AND (CDKN2A OR \"CDK4/6\" OR palbociclib OR hedgehog OR GLI OR SMARCB1 OR EZH2) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"chordoma\" AND (\"patient-derived xenograft\" OR organoid OR \"drug screen\") AND (sensitivity OR resistance) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42499293","doi":"10.1002/mp.70562","year":2026,"isNew":true,"title":"Modelling dose and dose-averaged linear energy transfer to predict high-grade temporal lobe necrosis following skull-base proton therapy"},{"pmid":"41596634","doi":"10.3390/ijms27020990","year":2026,"isNew":true,"title":"CircRNAs in Immuno-Metabolic Reprogramming of Chordoma Cancer: Molecular Crosstalk and Therapeutic Potential"},{"pmid":"42598210","doi":"10.1016/j.radcr.2026.07.016","year":2026,"isNew":true,"title":"Cervical spine chordoma: Imaging features and diagnostic challenges of a rare C6 localization"},{"pmid":"42284679","doi":"10.1016/j.neo.2026.101325","year":2026,"isNew":true,"title":"The copy-number events in skull base chordoma stratify tumours into four biologically coherent groups"},{"pmid":"42595674","doi":"10.1016/j.eimce.2026.503242","year":2026,"isNew":true,"title":"Rhino-orbital-cerebral mycoses (Mucormycosis and Phaeohyphomycosis): A case series"},{"pmid":"42595265","doi":"10.1016/j.ijrobp.2026.07.062","year":2026,"isNew":true,"title":"Multi-model RBE and dose-averaged LET optimized carbon ion radiotherapy for sacral chordoma: results of the first year of clinical application"},{"pmid":"42593941","doi":"10.1021/acs.jmedchem.6c00732","year":2026,"isNew":true,"title":"Fragment-Based Discovery of Potent RNA-Competitive Inhibitors of the DEAH-Box RNA Helicase DHX8"},{"pmid":"42571860","doi":"10.1016/j.bbcan.2026.189678","year":2026,"isNew":true,"title":"The molecular landscape of chordoma: Current frontiers from multi-omics to artificial intelligence"},{"pmid":"42317481","doi":"10.1016/j.jbo.2026.100774","year":2026,"isNew":true,"title":"Incidence patterns and trends of chordoma in the United States: a population-based analysis of over 6,000 cases"},{"pmid":"42448412","doi":"10.1016/bs.apcsb.2026.04.003","year":2026,"isNew":true,"title":"Molecular characterization and experimental models of chordoma: Foundations for rational therapy development"}],"trialsShown":[{"nct":"NCT03910465","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Children and Adults With Chordoma"},{"nct":"NCT01200680","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Genetic Clues to Chordoma Etiology: A Protocol to Identify Sporadic Chordoma Patients for Studies of Cancer-Susceptibility Genes"},{"nct":"NCT05286801","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors"},{"nct":"NCT04416568","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study of Nivolumab and Ipilimumab in Children and Young Adults With INI1-Negative Cancers"},{"nct":"NCT06625190","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors"},{"nct":"NCT01346124","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"High Dose Intensity Modulated Proton Radiation Treatment +/- Surgical Resection of Sarcomas of the Spine, Sacrum and Base of Skull"},{"nct":"NCT02834013","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Nivolumab and Ipilimumab in Treating Patients With Rare Tumors"},{"nct":"NCT00496119","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Proton Beam Therapy for Chordoma Patients"}],"usage":{"input":8374,"output":5414},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chordoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chordoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42499293","PMID:41596634","PMID:42598210","PMID:42284679","PMID:42595674","PMID:42595265","PMID:42593941","PMID:42571860","PMID:42317481","PMID:42448412","NCT03910465","NCT01200680","NCT05286801","NCT04416568","NCT06625190","NCT01346124","NCT02834013","NCT00496119"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787153658836","cycle":26,"visit":1,"ts":"2026-08-19T15:34:18.836Z","cancer":{"key":"uveal melanoma","name":"uveal melanoma","mondo":{"id":"MONDO:0006486","name":"uveal melanoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Anchor the UM programme on darovasertib (PKC) as the Gq-pathway backbone and on next-generation ImmTAC/T-cell engagers for HLA-A*02:01-negative or post-tebentafusp disease, and require patient-derived organoid confirmation for any preclinical claim after PMID:42108204 showed commercial cell lines fa","confidence":0.55,"notebook":"Programme opens with a KG anchor that is mechanistically coherent: GNAQ/GNA11/CYSLTR2 all converge on Gq→PLCβ→PKC→MAPK [SOMATIC, KNOWN], with BAP1 [SOMATIC in tumour, though also a germline predisposition allele — keep the distinction] and SF3B1 [SOMATIC] as prognostic/epigenetic-splicing modifiers.\n\nThe single most useful item in the pack is P3 (PMID:42108204), a translational fidelity study: commercial UM cell lines reproduced the historical \"promising\" data for selumetinib, selumetinib+MK-2206, sotrastaurin+alpelisib and trametinib (pooled viability 32.5%), whereas patient-derived lines (52.8%) and organoids (80.4%) were resistant — matching the clinical failures of exactly those regimens. Darovasertib, the only agent with real neoadjuvant clinical signal, behaved as a positive control. Two consequences for this desk: (i) MEK-centric and MEK+AKT/PI3K combinations are recorded as dead and will not be re-proposed (concordant with T6, trametinib ± uprosertib, active-not-recruiting, no results in pack); (ii) any future preclinical claim must be organoid-anchored, ideally BAP1-genotyped, since P3 reports greater resistance in BAP1-loss context under some conditions.\n\nLead 1 is therefore PKC (darovasertib) as the obligatory Gq-pathway backbone, with combination partners chosen against the resistance routes I expect [INFERRED]: MAPK/ERK rebound, YAP/TAZ-mediated Gq-independent output, and non-genetic phenotype switching — the latter now given a framework by P4 (MITF plasticity, integrin–YAP/TAZ mechanotransduction, glycolysis/OXPHOS switching), which is cutaneous-weighted but hypothesis-generating for UM.\n\nLead 2 is the ImmTAC axis. P6 confirms tebentafusp's OS benefit is restricted to HLA-A*02:01 and gp100 presentation, and flags brenetefusp (PRAME-directed) plus the wider engager field (P1, P9 — 501 multispecifics, 112 formats, solid-tumour activity still the bottleneck). The unmet population is HLA-A*02:01-negative and post-tebentafusp progression; the mechanistic gap is the immunologically cold liver metastasis. T5 (MBS8, TLR7 agonist ± pembrolizumab) is the kind of innate-priming partner worth pairing with an engager.\n\nLead 3: bel-sar (AU-011), an HSPG-targeted virus-like drug conjugate photoactivated in the eye, now in randomised phase 3 (T7) with long-term follow-up (T1) — a primary-tumour eradication strategy whose interesting question is whether immunogenic cell death alters micrometastatic seeding, not just local control.\n\nLead 4 (weak, exploratory): MIAT/miR-4306/CXCR4 (P10) as an oxidative-stress survival axis, giving a repurposing handle (CXCR4 antagonists) — cell-line and bioinformatic only, no in vivo.\n\nNext visit: darovasertib combination data, SF3B1-mutant synthetic lethality, and post-tebentafusp resistance mechanisms.","leadChanges":[{"id":"L1","title":"PKC inhibition (darovasertib) as the obligate backbone in GNAQ/GNA11/CYSLTR2-mutant uveal melanoma, with rational partners against MAPK rebound and YAP/TAZ outp","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"Next-generation ImmTAC/T-cell engagers plus innate priming for HLA-A*02:01-negative and post-tebentafusp metastatic UM","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L3","title":"Bel-sar (AU-011) virus-like drug conjugate for primary small choroidal melanoma — local control plus possible immunogenic-death effect on micrometastasis","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L4","title":"MIAT/miR-4306/CXCR4 oxidative-stress survival axis as a repurposing handle (CXCR4 antagonism plus ROS induction)","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Do darovasertib combinations (with MET/ALK, MEK, or TEAD/YAP inhibitors) retain activity in patient-derived organoids, and does BAP1 status stratify that response?","What are the mechanisms of acquired resistance after tebentafusp (HLA class I/B2M loss, gp100 downregulation, T-cell exhaustion), and is PRAME-directed brenetefusp active in that setting?","Is there a validated synthetic-lethal vulnerability for SF3B1-mutant UM (splicing modulators, PARP/ATR, neoantigen load from mis-splicing) and for BAP1-null UM beyond HDAC inhibition?","Did NCT01587352 (vorinostat) and NCT01979523 (trametinib +/- uprosertib) report results, and do they close out the epigenetic-differentiation and MEK/AKT branches definitively?","Does immunogenic ablation of the primary tumour (bel-sar) alter metastasis-free survival, and is there any measurable systemic immune priming?","Which liver-metastasis-specific microenvironmental features (macrophage/CAF, ECM stiffness, YAP/TAZ mechanotransduction) explain UM's resistance to checkpoint blockade, and are any pharmacologically addressable?"],"nextQueries":["\"uveal melanoma\" AND (darovasertib OR IDE196 OR \"protein kinase C inhibitor\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"uveal melanoma\" AND (tebentafusp OR ImmTAC OR PRAME OR brenetefusp) AND (resistance OR \"HLA loss\" OR biomarker) AND SRC:MED","\"uveal melanoma\" AND (SF3B1 OR BAP1) AND (\"synthetic lethal\" OR splicing OR PARP OR HDAC) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"41542910","doi":"10.1080/19420862.2026.2613548","year":2026,"isNew":true,"title":"The making of multispecific immunoglobulins - a clinical perspective"},{"pmid":"41781347","doi":"10.1080/21645515.2026.2628424","year":2026,"isNew":true,"title":"mRNA vaccines and therapeutics beyond COVID-19: A review of the global clinical development landscape, low- and middle-income countries involvement and relevance to their contexts"},{"pmid":"42108204","doi":"10.1097/cmr.0000000000001103","year":2026,"isNew":true,"title":"Novel uveal melanoma patient-derived cell line and organoid models show increased treatment resistance compared with commercially available cell lines"},{"pmid":"42290218","doi":"10.1080/15384101.2026.2684937","year":2026,"isNew":true,"title":"MITF-Driven melanoma plasticity as a core mechanism of therapy resistance: integrating microenvironmental signaling, mechanotransduction, and metabolic reprogramming"},{"pmid":"42216563","doi":"10.1080/15384047.2026.2678642","year":2026,"isNew":true,"title":"TFPI2 in tumor metastasis: a double-edged sword with clinical implications"},{"pmid":"42163062","doi":"10.1080/21645515.2026.2675068","year":2026,"isNew":true,"title":"Tebentafusp (IMCgp100), a first in class immune-mobilizing monoclonal T-cell receptors against cancer (ImmTAC) for HLA-A*02:01 positive uveal melanoma: Product review"},{"pmid":"41775345","doi":"10.1080/15476286.2026.2640489","year":2026,"isNew":true,"title":"LINC00852 inhibits colorectal cancer progression by regulating cell apoptosis, epithelial‒mesenchymal transition, invasion, and cuproptosis through miR-1276/LACTB"},{"pmid":"41732954","doi":"10.1080/2162402x.2026.2631244","year":2026,"isNew":true,"title":"A mixed inflammatory peripheral signature defines clinical outcomes in a phase II trial combining pembrolizumab with paclitaxel and carboplatin in melanoma"},{"pmid":"41700001","doi":"10.1080/2162402x.2026.2632421","year":2026,"isNew":true,"title":"Trial Watch - bispecific T cell engagers and higher-order multispecific immunotherapeutics"},{"pmid":"42067178","doi":"10.1016/j.exer.2026.111043","year":2026,"isNew":true,"title":"Long non-coding RNA MIAT functions as a ceRNA to protect uveal melanoma from oxidative stress by sponging miR-4306 and upregulating CXCR4"}],"trialsShown":[{"nct":"NCT07338968","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"A Long-Term Follow-Up Study of Subjects Completing the AU-011-301(CoMpass) for Early Choroidal Melanoma"},{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT03025256","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Intravenous and Intrathecal Nivolumab in Treating Patients With Leptomeningeal Disease"},{"nct":"NCT04588662","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Prospective Natural History Study in Uveal Melanoma"},{"nct":"NCT04855435","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Safety and Preliminary Efficacy of MBS8(1V270) in Cancer Patients With Advanced Solid Tumours"},{"nct":"NCT01979523","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Trametinib With or Without GSK2141795 in Treating Patients With Metastatic Uveal Melanoma"},{"nct":"NCT06007690","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Phase 3 Randomized, Masked, Controlled Trial to Evaluate Efficacy and Safety of Belzupacap Sarotalocan (AU-011) Treatment Compared to Sham"},{"nct":"NCT01587352","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Vorinostat in Treating Patients With Metastatic Melanoma of the Eye"}],"usage":{"input":8449,"output":5408},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"uveal melanoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"uveal melanoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41542910","PMID:41781347","PMID:42108204","PMID:42290218","PMID:42216563","PMID:42163062","PMID:41775345","PMID:41732954","PMID:41700001","PMID:42067178","NCT07338968","NCT07636785","NCT03025256","NCT04588662","NCT04855435","NCT01979523","NCT06007690","NCT01587352"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787153463944","cycle":25,"visit":1,"ts":"2026-08-19T15:31:03.944Z","cancer":{"key":"juvenile myelomonocytic leukemia","name":"juvenile myelomonocytic leukemia","mondo":{"id":"MONDO:0011908","name":"juvenile myelomonocytic leukemia"}},"control":false,"modelLabel":"SCIENCE","summary":"In PTPN11-mutant JMML, test the repurposable triplet IL-17A neutralisation + PTGS2 inhibition (celecoxib) + NLRP3 inhibition layered on MEK blockade, using primary patient samples and Shp2E76K/+ and humanized NF1-LOF models as the read-outs.","confidence":0.55,"notebook":"Programme opens with one genuinely new mechanistic axis, one pharmacology/biomarker question, and two enabling-model results; most of the pack is off-target noise (P1 ASO review, P5 autophagy review, P8 MDS NGS review, P9 PTLD, T5–T8 transplant/AML platform trials) and is logged as such so it is not re-mined.\n\nThe highest-value item is P6 (PMID:42233403): in Shp2^E76K/+ JMML mice, mutant macrophages upregulate IL-17A, driving NLRP3 inflammasome assembly, caspase-1 cleavage, IL-1β maturation and PTGS2 induction, with Treg expansion and CD8 exhaustion. Therapeutically, IL-17A neutralisation plus dual NLRP3/PTGS2 blockade reversed myeloproliferation and extended survival, and — critically for translation — dual NLRP3/PTGS2 inhibition *plus MEK blockade* reduced leukemic progenitor output ex vivo in primary patient samples. This converts the long-standing \"JMML is an inflammatory disease\" observation into a repurposable triplet: secukinumab/ixekizumab (or downstream anakinra/canakinumab), celecoxib, and trametinib [KNOWN for the individual agents' approvals]. Window argument: IL-17A blockade's normal-tissue role is mucosal antifungal defence (candidiasis risk); PTGS2 inhibition costs GI/renal prostaglandins; NLRP3 is innate sensing — all tolerated chronically in autoimmune indications, whereas MEK inhibition is the toxicity ceiling (rash, ocular, cardiac). Expected escape: MAPK reactivation via CRAF/PI3K, IL-1β-independent NF-κB inflammation, and Treg-driven immune suppression persisting after cytokine blockade. [SOMATIC] PTPN11 for somatic JMML; note PTPN11 is also the [GERMLINE] Noonan/NS-MPD allele — the axis may differ between them, an open question.\n\nP10 supplies a second, independent mechanistic thread: RAS-mutant LSCs arise in GMPs, drive monocytic differentiation and venetoclax resistance through MCL-1/BCL2L1 rewiring. Since JMML is definitionally RAS-pathway-driven and monocytic, naked BCL2 inhibition should be predicted to fail; the testable lead is MEK (or SHP2) inhibitor + MCL-1/BCL-xL-directed priming. T3 (venetoclax+ASTX727 in CMML) is the adult read-out to watch, not evidence for JMML.\n\nP4 makes hypomethylating-agent choice a real question: pooled pre-HSCT data (87 patients, 36 JMML) show CR strongly associated with decitabine in MDS; the JMML-specific split is not resolvable from the abstract. Azacitidine is the labelled JMML bridge [KNOWN], so a DAC-vs-AZA distinction, if real and methylation-subtype-linked, is immediately actionable.\n\nP2 and P7 are enabling: a humanized NF1^LOF cord-blood HSPC/NSG-SGM3 model with GM-CSF hypersensitivity and 32-day lethality, and CRISPR evidence that Nf1 loss confers clonal dominance across serial transplant. NF1 loss is undruggable directly; these give the platform for vertical MEK+PI3K/mTOR or synthetic-lethal screening.\n\nP3 (anti-CD69 in Nras^G12D CMML) is cross-species, cross-disease and stays a low-confidence lead only because it converges on the same Treg/marrow-niche immunology as P6.","leadChanges":[{"id":"L1","title":"IL-17A/NLRP3/PTGS2 inflammatory axis blockade combined with MEK inhibition in PTPN11-mutant JMML","level":"LEAD","status":"NEW","confidence":0.62},{"id":"L2","title":"Monocytic/RAS-driven BCL2-family rewiring predicts venetoclax failure in JMML; MCL-1/BCL-xL-directed priming plus MAPK blockade","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L3","title":"Hypomethylating agent selection (decitabine vs azacitidine) as a modifiable pre-HSCT variable in JMML","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"Humanized NF1-LOF HSPC model enables synthetic-lethal screening for the undruggable 20% of JMML","level":"LEAD","status":"NEW","confidence":0.38},{"id":"L5","title":"CD69 blockade to reverse Treg-dominated marrow niche in RAS-mutant myelomonocytic leukemia","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Does the IL-17A/NLRP3/PTGS2 axis operate in non-PTPN11 JMML genotypes (NRAS/KRAS/NF1/CBL), and does it differ between somatic PTPN11 JMML and germline Noonan-associated myeloproliferative disease?","Which single agent in the P6 triplet is dispensable — is IL-1beta blockade (anakinra/canakinumab) sufficient downstream of NLRP3, allowing an all-approved combination with trametinib?","In the pooled pre-HSCT HMA data, what are the JMML-only CR and post-HSCT survival rates for decitabine vs azacitidine, and do they track with JMML methylation class?","Is venetoclax resistance in JMML actually MCL-1/BCL2L1-driven, and does MEK or SHP2 pre-treatment re-prime BCL2 dependence in primary samples?","What dependencies emerge from synthetic-lethal screens in the humanized NF1-LOF HSPC model, and does vertical MEK+PI3K blockade extend survival there?","Do JMML clinical trials of MEK inhibitors (trametinib) report inflammatory-cytokine pharmacodynamics that could serve as the biomarker for the triplet?"],"nextQueries":["(\"juvenile myelomonocytic leukemia\" OR \"Noonan syndrome\" ) AND (trametinib OR \"MEK inhibitor\" OR SHP2 OR \"SHP099\" OR \"RMC-4630\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"juvenile myelomonocytic leukemia\" AND (methylation OR \"hypomethylating\" OR azacitidine OR decitabine OR relapse) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]","(\"juvenile myelomonocytic leukemia\" OR \"chronic myelomonocytic leukemia\") AND (venetoclax OR MCL1 OR \"BH3 profiling\" OR NLRP3 OR \"IL-1beta\" OR \"IL-17\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42239496","doi":"10.1016/j.omtn.2026.102953","year":2026,"isNew":true,"title":"Expanding the toolbox: Emerging antisense oligonucleotide mechanisms for modulating gene expression"},{"pmid":"41201956","doi":"10.1182/bloodadvances.2024015191","year":2026,"isNew":true,"title":"Novel humanized loss-of-function NF1 mouse model of juvenile myelomonocytic leukemia"},{"pmid":"42330053","doi":"10.1080/15384047.2026.2692184","year":2026,"isNew":true,"title":"CD69 blockade restores the bone marrow niche and delays leukemogenesis in a mouse model of &lt;i&gt;Nras&lt;/i&gt; &lt;sup&gt;G12D&lt;/sup&gt;-driven chronic myelomonocytic leukemi"},{"pmid":"42393761","doi":"10.1186/s13148-026-02191-0","year":2026,"isNew":true,"title":"Azacitidine and decitabine show distinct response patterns in pediatric Myelodysplastic Syndromes and Juvenile Myelomonocytic Leukemia before HSCT: a systematic review and quantita"},{"pmid":"42236674","doi":"10.1038/s41392-026-02688-3","year":2026,"isNew":true,"title":"Transcriptional and epigenetic regulation of autophagy: mechanisms, disease relevance and therapeutic opportunities"},{"pmid":"42233403","doi":"10.1182/blood.2025032588","year":2026,"isNew":true,"title":"Therapeutic Targeting of IL-17A-Driven PTGS2/NLRP3 Inflammasome Activation in Juvenile Myelomonocytic Leukemia"},{"pmid":"42220553","doi":"10.1097/bs9.0000000000000294","year":2026,"isNew":true,"title":"Sequential in vivo CRISPR screens identify the clonal dominance of &lt;i&gt;Nf1&lt;/i&gt; loss in long-term hematopoiesis"},{"pmid":"41821552","doi":"10.1097/bs9.0000000000000281","year":2026,"isNew":true,"title":"Application of next-generation sequencing in the treatment of myelodysplastic syndrome: from mechanisms to clinical practice"},{"pmid":"41778738","doi":"10.4274/tjh.galenos.2026.55376","year":2026,"isNew":true,"title":"Frequency, Characteristics, Management, and Outcomes of Posttransplant Lymphoproliferative Disorder After Allogeneic Hematopoietic Stem Cell Transplantation in Children: A Multicen"},{"pmid":"42087923","doi":"10.1016/j.lrr.2026.100589","year":2026,"isNew":true,"title":"The role of RAS mutations in leukemia progression, differentiation, and drug resistance"}],"trialsShown":[{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"},{"nct":"NCT07302776","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"TACrolimus Targeted Immunosuppression Cessation in ALlogeneic HCT"},{"nct":"NCT07143669","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Screening Study for KIT D816V Mutated Mast Cell Disease in Select Populations"},{"nct":"NCT04708054","phase":"phase 2/phase 3","status":"RECRUITING","isNew":true,"title":"Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS"}],"usage":{"input":8950,"output":5896},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"juvenile myelomonocytic leukemia\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"juvenile myelomonocytic leukemia\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42239496","PMID:41201956","PMID:42330053","PMID:42393761","PMID:42236674","PMID:42233403","PMID:42220553","PMID:41821552","PMID:41778738","PMID:42087923","NCT06904066","NCT06566742","NCT05600894","NCT07033598","NCT06001385","NCT07302776","NCT07143669","NCT04708054"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787153265350","cycle":24,"visit":2,"ts":"2026-08-19T15:27:45.350Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"Immune-reconstitution quality, not therapy duration, is the emerging determinant of CML treatment-free remission: build and test an immune-readiness gate (plasma IL-6/MCP-1 plus innate-like CD56+CD57+CD8dim/NK effector clonality) for discontinuation, with pegylated interferon-alpha as the approved a","confidence":0.6,"notebook":"Nothing in this pack touches the solved core: BCR-ABL1 [SOMATIC] fusion → ATP-site inhibition remains the axis, and L1 (asciminib + ATP-site TKI, NCT03906292) is unchanged because no trial readout appeared. The pack's centre of gravity is instead the two things TKIs do not do: erase the LSC and reconstitute immunity.\n\nThe strongest new signal is immunological. PMID:42121891 shows in a real-world discontinuation cohort that Sokal fails while total TKI duration, DMR depth, and — novel — plasma IL-6 and MCP-1 predict molecular relapse-free survival, with *lower* IL-6/MCP-1 marking higher relapse risk. That directionality is the opposite of what an LSC-niche argument predicts ([KNOWN] IL-6 supports CML LSC and skews myeloid output in murine models), so the desk records a negative-by-inference: naive anti-IL-6 (tocilizumab) peri-discontinuation should not be proposed; low IL-6/MCP-1 more plausibly reads out a hypofunctional immune compartment [INFERRED]. PMID:42377752 converges from a single patient: TFR >7 years after only 9 months of dasatinib and 128 days of DMR, with a persistent clonal CD56+CD57+CD8dim NK-like T-cell population — quality of innate-like effector reconstitution outranking therapy duration. PMID:41972591 gestures the same way (NK GRN signatures separating early relapse from late/durable remission) but n=6 with an AI pipeline as the actual subject; treat as hypothesis-generating only. Together these open new lead L5: an immune-readiness composite (IL-6/MCP-1 + innate-like CD8dim/NK effector clonality) to gate discontinuation, with pegylated interferon-α as the approved repurposing agent to expand those effectors pre-cessation.\n\nSecond, PMID:41952641 reframes persistence as GRN-defined LSC *states* rather than mutation-driven clonal selection, and PMID:41601208 names a candidate state-enforcing node: TIF1β/TRIM28 with SETDB1-dependent and -independent modes sustaining stemness while repressing differentiation programmes. New lead L6 (low confidence): SETDB1/TRIM28 disruption as kinase-independent LSC state collapse, with the testable bonus that ERV derepression could supply viral mimicry and interferon signalling — mechanistically continuous with L5. Normal-tissue caveat: TRIM28/SETDB1 are required for HSC maintenance and imprint/ERV silencing; window is the whole argument and is currently unproven.\n\nL3 (USP28–IFITM3) is weakened: a second visit with no independent replication in the pack. L2, L4 stand unmoved. P5 (BMI1 SNPs [GERMLINE], inconclusive), P3 (BMAT), P6 (galectins), P7 (menin, AML-only), P9 (lineage) generate no CML-specific lead this visit; menin in myeloid blast crisis is parked as a question, not a lead.","leadChanges":[{"id":"L5","title":"Immune-readiness gating of TKI discontinuation: IL-6/MCP-1 cytokine signature plus innate-like CD8dim/NK effector clonality, with peg-IFN-alpha as expansion age","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L6","title":"TIF1beta/TRIM28-SETDB1 chromatin node as a BCR-ABL1-kinase-independent LSC-state dependency","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L3","title":"USP28–BCR-ABL–IFITM3 axis as a BCR-ABL-kinase-independent resistance node permitting lower-dose ponatinib","level":"LEAD","status":"WEAKENED","confidence":0.2}],"unverifiedCitations":0,"openQuestions":["Does the IL-6/MCP-1 decision tree of PMID:42121891 validate in an independent DMR cohort, and does the counterintuitive low-cytokine/high-relapse direction survive adjustment for treatment duration and prior interferon exposure?","Is the CD56+CD57+CD8dim NK-like effector clone of PMID:42377752 detectable at population scale in durable-TFR versus relapsing patients, and does peg-IFN-alpha or a TKI switch (dasatinib-driven large granular lymphocytosis) induce it?","Do results exist yet from NCT03906292 (frontline asciminib + ATP-site TKI) on MR4.5 depth, TFR eligibility and the compound-mutation spectrum at relapse?","Has NCT02689440 (dasatinib + venetoclax) reported CD34+CD38- LSC clearance, and does BH3 profiling implicate MCL1/BCL-xL switching in non-responders?","Are TRIM28/SETDB1 regulons experimentally enriched in TKI-persistent CML LSCs, and does their disruption spare normal CD34+ HSPCs?","In myeloid blast crisis, do RUNX1 [SOMATIC] and HOX/MEIS-driven transcriptional states create a menin-inhibitor-sensitive subset analogous to KMT2A-r/NPM1-mutant AML?"],"nextQueries":["\"chronic myeloid leukemia\" AND (\"interferon alfa\" OR peginterferon) AND (\"treatment-free remission\" OR discontinuation OR \"deep molecular response\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"chronic myeloid leukemia\" AND (asciminib) AND (combination OR \"compound mutation\" OR MR4.5 OR resistance) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"blast crisis\" OR \"blast phase\") AND \"chronic myeloid leukemia\" AND (RUNX1 OR menin OR KMT2A OR venetoclax) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41601208","doi":"10.1111/cas.70334","year":2026,"isNew":true,"title":"Roles of TIF1β in Leukemic Stem Cell Through SETDB1-Dependent and Independent Mechanisms"},{"pmid":"41972591","doi":"10.3390/biology15070588","year":2026,"isNew":true,"title":"An AI-Enabled Single-Cell Transcriptomic Analysis Pipeline for Gene Signature Discovery in Natural Killer Cells Linked to Remission Outcomes in Chronic Myeloid Leukemia"},{"pmid":"42312095","doi":"10.1016/j.coemr.2026.100615","year":2026,"isNew":true,"title":"Remodeling the marrow fat niche: BMAT in cancer bone metastases and hematological malignancies"},{"pmid":"41952641","doi":"10.3324/haematol.2025.287767","year":2026,"isNew":true,"title":"Understanding drug resistance in chronic myeloid leukemia through the lens of leukemic stem cell states: insights from single-cell analyses"},{"pmid":"42327472","doi":"10.1002/hsr2.72579","year":2026,"isNew":true,"title":"Genetic Variants of BMI1 (rs1042059 and rs11591377) and Their Potential Role in Leukemia Susceptibility: A Narrative Review"},{"pmid":"42248861","doi":"10.1038/s41392-026-02768-4","year":2026,"isNew":true,"title":"Glycobiology-driven therapeutic targeting of glycan-binding proteins: mechanisms, diseases, and clinical translation"},{"pmid":"42278415","doi":"10.3390/ijms27114886","year":2026,"isNew":true,"title":"Menin Inhibition in Acute Myeloid Leukemia: Rewiring Leukemic Transcriptional Networks"},{"pmid":"42121891","doi":"10.3390/cells15090791","year":2026,"isNew":true,"title":"Identification of Predictive Biomarkers Based on Cytokine Profiles for Molecular Relapse After Treatment-Free Remission in Chronic Myeloid Leukemia Patients"},{"pmid":"41483983","doi":"10.1016/j.trecan.2025.12.004","year":2026,"isNew":true,"title":"Exploiting tumor lineage features for precision cancer therapy"},{"pmid":"42377752","doi":"10.1007/s12185-026-04241-y","year":2026,"isNew":true,"title":"Long-term treatment-free remission in CML after early dasatinib discontinuation due to interstitial pneumonitis"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":10435,"output":5608},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic myeloid leukemia\" AND (\"leukemic stem cell\" OR \"leukaemic stem cell\") AND (persistence OR quiescence OR eradication) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"chronic myeloid leukemia\" AND (\"treatment-free remission\" OR discontinuation) AND (NK OR immune OR predictor) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41601208","PMID:41972591","PMID:42312095","PMID:41952641","PMID:42327472","PMID:42248861","PMID:42278415","PMID:42121891","PMID:41483983","PMID:42377752","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787153068085","cycle":23,"visit":1,"ts":"2026-08-19T15:24:28.085Z","cancer":{"key":"atypical teratoid rhabdoid tumor","name":"atypical teratoid rhabdoid tumor","mondo":{"id":"MONDO:0020560","name":"atypical teratoid rhabdoid tumor"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise CoREST (LSD1/HDAC1-2) inhibition with corin as the lead mechanism-matched agent in SMARCB1-deleted ATRT, tested against the 49% 4-year EFS ACNS0333 benchmark, with intraventricular B7-H3 CAR T as the parallel immunotherapeutic axis.","confidence":0.42,"notebook":"Visit 1 establishes the programme from zero. The KG anchor is uninformative for druggability: SMARCB1 and SMARCA4 are both [SOMATIC] biallelic-loss tumour suppressors here (and [GERMLINE] in rhabdoid tumour predisposition syndromes 1/2 [KNOWN]) — nothing to inhibit directly, so every lead must be synthetic-lethal, epigenetic-rebalancing, or immunological.\n\nBenchmark first: the multi-institutional ACNS0333-style cohort gives 4-year EFS 49%/OS 53%, with only 63% completing therapy and post-induction complete response as the key prognostic variable (PMID:42453193). That is the bar any new regimen must clear, and it is set in infants (median 18 months). The companion cardiotoxicity cohort shows progressive systolic decline after craniospinal irradiation at modest mean cardiac dose (PMID:42296837) — an argument for radiation-sparing or radiation-deferring strategies rather than further intensification. P1, P3, P8, P9 are diagnostic/PK/imaging and carry no therapeutic hypothesis; I log them as non-actionable so they are not re-mined. P4 deserves a caution: it infers \"22q instability\" driving AT/RT from a 22q13.32–13.33 terminal deletion, but SMARCB1 sits at 22q11.23 [KNOWN], so the deletion does not encompass the locus — the mechanistic claim in that abstract is unsupported and I will not build a lead on it.\n\nStrongest new biology: corin, a bifunctional LSD1/HDAC1-2 CoREST inhibitor, suppressed growth across all three epigenetic subgroups, induced apoptosis plus neuronal differentiation with increased chromatin accessibility at synaptic/differentiation genes, and RCOR2 knockdown phenocopied and desensitised — clean on-target evidence, with orthotopic survival benefit (PMID:42479134). This is the mechanistic complement of SMARCB1 loss: SWI/SNF cannot oppose CoREST repression, so pharmacologic CoREST inhibition restores enhancer access. Lead 1.\n\nImmunotherapy is the second axis. BrainChild-03 Arm B delivered repeated intracerebroventricular B7-H3 CAR T cells with no DLTs and an MTD regimen of 10×10⁷ cells/dose, including five ATRT patients (PMID:42503899, NCT04185038) — feasibility established; the abstract is truncated so ATRT-specific response is unknown to me. Separately, a dedicated phase 2 of ONO-4538 (nivolumab) in rhabdoid tumour (NCT06622941) is a testable checkpoint hypothesis despite expected low TMB. Polyamine depletion (DFMO + the transport inhibitor AMXT 1501, NCT06465199) is a plausible ATRT-MYC-directed repurposing lead given ODC1 as a canonical MYC target [KNOWN], but ATRT-specific preclinical support is absent from this pack.\n\nNext visit I need: corin/LSD1 CNS pharmacokinetics and combination partners (EZH2, Aurora A per PMID:41289204), ATRT-subgroup immune microenvironment data, and any ATRT-specific polyamine or B7-H3 expression evidence.","leadChanges":[{"id":"L1","title":"CoREST complex inhibition (corin; bifunctional LSD1/HDAC1-2) to restore differentiation programmes in SMARCB1-deficient ATRT","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L2","title":"Repeated intracerebroventricular B7-H3 CAR T cells for recurrent/refractory ATRT","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"PD-1 blockade (ONO-4538/nivolumab) in SMARCB1-deficient rhabdoid tumour","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L4","title":"Polyamine depletion (DFMO + AMXT 1501) targeting the MYC-driven ATRT subgroup","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":1,"openQuestions":["Does corin (or another LSD1/HDAC1-2 bifunctional agent) achieve pharmacologically active CNS exposure, and what is its neurodevelopmental toxicity profile in infant models — the actual gating question for translation?","Which combination partner most potentiates CoREST inhibition in ATRT: EZH2 (tazemetostat), Aurora A (alisertib), retinoids, or radiation dose-sparing?","What is quantitative B7-H3 surface density across ATRT-MYC/SHH/TYR, and did the 5 ATRT patients in BrainChild-03 Arm B show any objective response or CSF CAR persistence?","Is there any ATRT-specific evidence that SMARCB1 loss derepresses interferon/ERV programmes and thereby rationalises checkpoint blockade, or is NCT06622941 empirical?","Can any regimen plausibly beat 4-year EFS 49% while omitting or deferring craniospinal irradiation, given documented late systolic dysfunction after CSI?","Are differentiation-inducing epigenetic agents synergistic with CAR T by raising target antigen density in ATRT?"],"nextQueries":["(\"rhabdoid tumor\" OR \"atypical teratoid\") AND (LSD1 OR KDM1A OR CoREST OR RCOR2 OR HDAC1) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"atypical teratoid rhabdoid\" OR \"rhabdoid tumor\") AND (B7-H3 OR CD276 OR \"CAR T\" OR PD-L1 OR \"immune microenvironment\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","SMARCB1 AND (\"synthetic lethal\" OR EZH2 OR \"Aurora A\" OR CDK4 OR \"MYC\" OR polyamine) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42594025","doi":"10.1148/rg.250201","year":2026,"isNew":true,"title":"Imaging Evaluation of Pediatric Supratentorial Tumors: Pearls and Pitfalls"},{"pmid":"42453193","doi":"10.1093/nop/npag014","year":2026,"isNew":true,"title":"A multi-institutional report of children with atypical teratoid rhabdoid tumor treated with intensive multimodal therapy"},{"pmid":"41869689","doi":"10.1177/10668969261422682","year":2026,"isNew":true,"title":"A Rare Thoracolumbar Spinal Atypical Teratoid/Rhabdoid Tumor in a 7-Year-Old Child: Diagnostic Challenges and Therapeutic Considerations"},{"pmid":"42598376","doi":"10.1159/000553440","year":2026,"isNew":true,"title":"Beyond the Spectrum: A Case Report of Phelan-McDermid Syndrome and the Atypical Teratoid/Rhabdoid Tumor Co-Occurrence"},{"pmid":"42503899","doi":"10.1093/neuonc/noag171","year":2026,"isNew":true,"title":"Intracerebroventricular B7-H3-targeting CAR T cells for non-pontine DMG and recurrent/refractory pediatric CNS tumors: a phase 1 trial"},{"pmid":"42479134","doi":"10.1093/neuonc/noag160","year":2026,"isNew":true,"title":"The CoREST complex inhibitor, corin, decreases tumor growth, increases cellular differentiation and extends lifespan in ATRT xenograft models"},{"pmid":"42296837","doi":"10.1016/j.jacadv.2026.102886","year":2026,"isNew":true,"title":"Longitudinal Assessment of Cardiac Function After Craniospinal Irradiation in Pediatric Central Nervous System Tumor Survivors"},{"pmid":"42053946","doi":"10.1007/s13318-026-01000-6","year":2026,"isNew":true,"title":"Population Pharmacokinetics of Melphalan in Pediatric Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation with Various Conditioning Regimens"},{"pmid":"42196881","doi":"10.3390/diagnostics16101515","year":2026,"isNew":true,"title":"Clinicopathological Characterization of Pediatric Atypical Teratoid/Rhabdoid Tumors and an HE-IHC Dual-Path Deep Learning Model for Auxiliary Diagnosis"},{"pmid":"41289204","doi":"10.1021/acs.molpharmaceut.5c00953","year":2026,"isNew":true,"title":"From Traditional Therapies to Nanomedicine: A Thorough Examination of Atypical Teratoid Rhabdoid Tumor Treatment Methods"}],"trialsShown":[{"nct":"NCT06465199","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Eflornithine (DFMO) and AMXT 1501 for Neuroblastoma, CNS Tumors, and Sarcomas"},{"nct":"NCT03959800","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Molecular Basis of Pediatric Liver Cancer"},{"nct":"NCT04715191","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors"},{"nct":"NCT03793166","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, T"},{"nct":"NCT06622941","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Study to ONO-4538 in Patients With Rhabdoid Tumor"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT04099797","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"C7R-GD2.CAR T Cells for Patients With GD2-expressing Brain Tumors (GAIL-B)"},{"nct":"NCT03911388","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"HSV G207 in Children With Recurrent or Refractory Cerebellar Brain Tumors"}],"usage":{"input":8790,"output":5759},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"atypical teratoid rhabdoid tumor\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"atypical teratoid rhabdoid tumor\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42594025","PMID:42453193","PMID:41869689","PMID:42598376","PMID:42503899","PMID:42479134","PMID:42296837","PMID:42053946","PMID:42196881","PMID:41289204","NCT06465199","NCT03959800","NCT04715191","NCT03793166","NCT06622941","NCT04320888","NCT04099797","NCT03911388"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787152869646","cycle":22,"visit":1,"ts":"2026-08-19T15:21:09.646Z","cancer":{"key":"rhabdomyosarcoma","name":"rhabdomyosarcoma","mondo":{"id":"MONDO:0005212","name":"rhabdomyosarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise CD28-costimulated L1CAM-CAR T cells for fusion-positive rhabdomyosarcoma, tested head-to-head against B7-H3 CAR and combined with TGF-beta-dominant-negative or IL-15/IL-21 armouring, while validating whether PAX3-FOXO1 drives L1CAM surface density.","confidence":0.46,"notebook":"Visit 1 opens the programme. Signal-to-noise in this pack is poor: P3 (anorectal malformation repair), P6 (cervical teratoma), P9 (prostate CRISPR/RNA) are off-target; P7 uses RD cells only as an EV71 host cell line and says nothing about RMS biology — logged as noise so the desk does not re-mine it. P4/P5 are generic immunotherapy reviews, useful only as background rationale.\n\nWhat actually moves the programme is cell therapy. P8 is the first concrete new dataset: L1CAM is expressed variably but with tissue-restricted specificity across RMS lines, PDXs and healthy tissue, more prominently in fusion-positive RMS, and CAR architecture — not scFv — determines potency, with a CD28-based L1CAM.III construct outperforming the clinically tested 4-1BB CE7 configuration and retaining partial activity at low antigen density, benchmarked head-to-head against B7-H3 CAR (PMID:42336095). That converts \"antigen density\" from a complaint into an engineerable variable. The enrichment in fusion-positive disease is mechanistically attractive because PAX3-FOXO1/PAX7-FOXO1 [SOMATIC, fusion] is a transcriptional master regulator of a neural/adhesion programme; L1CAM as a direct or indirect fusion-driven surface gene is [SPECULATIVE] and must be tested by fusion knockdown. Normal-tissue window: L1CAM is expressed in CNS neurons, adrenal medulla and renal tubule [KNOWN] — CE7-based CARs have prior clinical exposure in neuroblastoma [KNOWN], so the argument is precedent plus restricted RMS-relevant expression, not absence of expression.\n\nSecond, the platform layer. RMS sits inside an immune-cold sarcoma landscape where checkpoint blockade alone is inert (PMID:42172443), and the field-level review names antigen heterogeneity, immunosuppressive TME and manufacturing as the recurring failure modes with clinical activity so far limited (PMID:41709231). Two recruiting phase 1 trials supply the two obvious countermeasures: dominant-negative TGFβRII-armoured T cells co-administered with B7-H3 CAR T (NCT07172958) and IL-15/IL-21-armoured GPC3 CAR T in paediatric solid tumours (NCT04715191). I therefore open a distinct armouring/multitargeting lead rather than burying it inside L1CAM.\n\nThird, a repurposing lead with real caveats: osimertinib is reported to block MYLK4-mediated CDKAL1 phosphorylation, suppressing stemness and chemoresistance in RMS (PMID:41565624). This is a Letter, abstract-level only, no potency or PK data visible, and MYLK4 is a cardiac/skeletal-muscle-enriched kinase [KNOWN] — the window argument is unresolved. Kept at low confidence pending CRISPR MYLK4 dependency and phospho-site rescue.\n\nNot yet leads: SSTR2 radioligand therapy (NCT06441331) needs an RMS SSTR2 expression prior; disulfiram/Cu (NCT05210374) and methionine restriction (NCT07628634) are histology-agnostic; RET alterations in RMS are vanishingly rare (NCT04320888). Temsirolimus in intermediate-risk RMS (NCT02567435) is active-not-recruiting — its readout is a priority to capture next visit, positive or negative.","leadChanges":[{"id":"L1","title":"CD28-costimulated L1CAM-CAR T cells for moderate-/low-antigen-density, fusion-positive RMS","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"Armoured / multi-antigen CAR platform to break the immune-cold, TGF-beta-suppressed RMS microenvironment","level":"LEAD","status":"NEW","confidence":0.38},{"id":"L3","title":"Osimertinib repurposing against a MYLK4-CDKAL1 stemness/chemoresistance axis in RMS","level":"LEAD","status":"NEW","confidence":0.22}],"unverifiedCitations":0,"openQuestions":["Is L1CAM surface expression transcriptionally driven by PAX3/PAX7-FOXO1, and what molecules-per-cell threshold does the CD28-based L1CAM.III CAR require for lysis?","Does L1CAM-CAR add anything over B7-H3-CAR in matched fusion-negative RMS PDX, or is its value confined to fusion-positive disease?","What did the phase 3 temsirolimus-plus-chemotherapy arm in intermediate-risk RMS (NCT02567435) show — if negative, record mTOR-plus-VAC/VI as retired ground?","Do RMS tumours express SSTR2 at densities that would justify Lu-177 edotreotide radioligand therapy (NCT06441331), and is there any RMS IHC/expression dataset to support it?","Is MYLK4 a genuine genetic dependency in RMS lines, and does osimertinib achieve MYLK4 inhibition at clinically attainable free concentrations without cardiomyocyte toxicity?","Which armouring modality (dnTGFBRII vs IL-15/IL-21) is limiting in RMS specifically, and can they be combined on one CAR without unacceptable cytokine toxicity in a paediatric population?"],"nextQueries":["\"rhabdomyosarcoma\" AND (\"PAX3-FOXO1\" OR \"PAX7-FOXO1\") AND (\"surface\" OR \"immunotherapy target\" OR \"transcriptional target\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"rhabdomyosarcoma\" AND (\"L1CAM\" OR \"B7-H3\" OR \"CD276\" OR \"FGFR4\" OR \"somatostatin receptor\" OR SSTR2) AND SRC:MED","(\"rhabdomyosarcoma\" OR \"soft tissue sarcoma\") AND (temsirolimus OR mTOR OR \"maintenance therapy\") AND (\"randomized\" OR \"phase 3\" OR \"survival\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41565624","doi":"10.1038/s41392-025-02548-6","year":2026,"isNew":true,"title":"Osimertinib inhibits the MYLK4-mediated phosphorylation of CDKAL1 to suppress stemness and chemoresistance in rhabdomyosarcoma"},{"pmid":"42172443","doi":"10.1080/21645515.2026.2674185","year":2026,"isNew":true,"title":"The promise of immunotherapy in the treatment of sarcoma: A state-of-the-art review of practice changing research and future directions"},{"pmid":"42112665","doi":"10.1080/08941939.2026.2666959","year":2026,"isNew":true,"title":"Vascular and Wound-Healing Implications of Single-Stage Versus Multistage Repair of Anorectal Malformations: A Systematic Review and Meta-Analysis"},{"pmid":"42088834","doi":"10.1016/j.synbio.2026.04.012","year":2026,"isNew":true,"title":"Remodeling memory T cells with chemotherapy and immune checkpoint inhibitors as host pre-conditioning to empower in vivo CAR-T therapy"},{"pmid":"41491954","doi":"10.1080/2162402x.2025.2608436","year":2026,"isNew":true,"title":"Unlocking the therapeutic potential of immuno-radiotherapy: insights from preclinical and clinical research"},{"pmid":"42541120","doi":"10.1016/j.radcr.2026.06.112","year":2026,"isNew":true,"title":"Neonatal cervical teratoma with critical airway compression: A case report"},{"pmid":"42385639","doi":"10.1016/j.intimp.2026.117099","year":2026,"isNew":true,"title":"METTL3 promotes miR-146a maturation to suppress type I interferon responses in enterovirus 71 infection"},{"pmid":"42336095","doi":"10.1016/j.canlet.2026.218691","year":2026,"isNew":true,"title":"Optimized L1CAM-CAR T cells enhance activity against moderate-antigen-density rhabdomyosarcoma models"},{"pmid":"42253611","doi":"10.1016/j.ncrna.2026.05.001","year":2026,"isNew":true,"title":"CRISPR decodes the RNA regulatory network in prostate cancer: A review from mechanisms to precision therapeutics"},{"pmid":"41709231","doi":"10.1186/s12967-026-07773-3","year":2026,"isNew":true,"title":"CAR-T cell immunotherapy in rhabdomyosarcoma"}],"trialsShown":[{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"},{"nct":"NCT05210374","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Disulfiram With Copper Gluconate and Liposomal Doxorubicin in Treatment-Refractory Sarcomas"},{"nct":"NCT04715191","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors"},{"nct":"NCT06441331","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Phase I Trial to Determine the Dose and Evaluate the PK and Safety of Lutetium Lu 177 Edotreotide Therapy in Pediatric Participants With SST"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT06239272","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhab"},{"nct":"NCT02567435","phase":"phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma"},{"nct":"NCT07628634","phase":"EARLY_phase 1","status":"RECRUITING","isNew":true,"title":"Feasibility Study on the Effect of a Methionine-Reduced Diet on Serum Levels in Pts w/ Solid Tumors"}],"usage":{"input":8068,"output":5088},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"rhabdomyosarcoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"rhabdomyosarcoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41565624","PMID:42172443","PMID:42112665","PMID:42088834","PMID:41491954","PMID:42541120","PMID:42385639","PMID:42336095","PMID:42253611","PMID:41709231","NCT07172958","NCT05210374","NCT04715191","NCT06441331","NCT04320888","NCT06239272","NCT02567435","NCT07628634"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787152680402","cycle":21,"visit":1,"ts":"2026-08-19T15:18:00.402Z","cancer":{"key":"ewing sarcoma","name":"Ewing sarcoma","mondo":{"id":"MONDO:0012817","name":"Ewing sarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise ATR inhibition as an oncogene-induced synthetic lethality in EWSR1::FLI1 Ewing sarcoma (fusion recruitment to DSBs suppresses ATM, making ATR a collateral dependency), and retire single-agent PARP inhibition, which fails clinically and is further blunted by high autophagy.","confidence":0.55,"notebook":"Programme opens with one mechanistically strong anchor and three tractable clinical leads.\n\nP2 (PMID:41811428) is the visit's most valuable item: EWSR1::FLI1 [SOMATIC fusion] is recruited to DNA double-strand breaks and, in doing so, blunts ATM activation and downstream signalling, leaving ATR as a collateral dependency validated in PDX models of multiple FET-rearranged cancers. This reframes Ewing sarcoma's long-noted DNA-repair fragility as an oncogene-induced, ATM-hypomorphic state rather than a generic replication-stress phenotype — i.e. a BRCA/PARP-style synthetic lethality with the fusion itself as the \"lesion.\" It also predicts the mechanism is fusion-dose dependent and shared across EWSR1/FUS/TAF15 fusion sarcomas and leukaemias, giving a basket design [INFERRED]. Normal-tissue window: ATR is essential in proliferating tissue, so marrow and gut toxicity define the ceiling [KNOWN]; expected resistance = restored ATM signalling, CHK1/WEE1-independent checkpoint bypass, SLFN11 loss, fusion downregulation to a mesenchymal/low-EWSR1::FLI1 state [SPECULATIVE].\n\nP10 (PMID:42215796) is the counterweight and is recorded as a permanent negative: olaparib monotherapy failed clinically in Ewing sarcoma despite preclinical activity, and in WE-68/SK-ES-1 the high-autophagy subpopulation is significantly less killed by olaparib/veliparib. The desk should not re-propose single-agent PARPi. The abstract is ambiguous — PARPi induced autophagy and death \"in parallel,\" so whether autophagy is causal-protective or a co-marker is unresolved (no ATG5/7 knockout or lysosomal-inhibitor arm reported). The salvageable hypothesis is PARPi plus autophagy blockade, and it must be tested against the ATR axis, not instead of it.\n\nImmunotherapy (P3) confirms the structural problem: low TMB, few surface antigens, immunosuppressive TME. T2 (NCT07172958) attacks both arms at once — B7-H3 CAR T co-infused with dTβRII-armoured antigen-specific T cells — which is the first lead here where the resistance mechanism (TGF-β-mediated suppression) is engineered against a priori.\n\nT3 (NCT06465199) is worth a lead because ODC1 is a direct EWSR1::FLI1 transcriptional target [KNOWN]; DFMO plus the polyamine-transport inhibitor AMXT 1501 closes the canonical uptake escape route.\n\nFiled as context, not leads: cabozantinib in relapsed Ewing (NCT02243605) remains an active phase 2 with real but modest single-agent activity [KNOWN]; COG NCT06820957 defines the frontline metastatic backbone any new agent must beat; P7/P8 support ADC/SUV as response biomarkers for early-phase readouts; P4 (FLI1 in DLBCL), P5, P6, P9 are off-target for therapeutics. T5 (RET) and T6 (methionine diet) are not ES-specific and are parked.","leadChanges":[{"id":"L1","title":"ATR inhibition as synthetic lethality against fusion-induced ATM hypofunction in FET-rearranged sarcoma","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"PARP inhibitor monotherapy is dead in Ewing sarcoma; only autophagy-blockade combinations are worth revisiting","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L3","title":"B7-H3 CAR T cells armoured against TGF-beta signalling for relapsed/refractory Ewing sarcoma","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"Polyamine depletion (DFMO + polyamine transport inhibition) exploiting EWSR1::FLI1-driven ODC1","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["Which ATR inhibitor trials currently enrol EWSR1/FUS/TAF15-fusion sarcomas, and are any ES-specific response or pATM/pCHK1 pharmacodynamic data published?","Is ATM hypofunction in ES quantitative and fusion-dose dependent, and does it predict ATR-inhibitor sensitivity better than SLFN11 or STAG2 status?","Does genetic (ATG5/ATG7) rather than pharmacologic autophagy ablation restore PARPi killing in ES, and does the same autophagy axis blunt ATR inhibitors?","What is B7-H3 antigen density and heterogeneity across ES primaries versus metastases, and has any ES patient responded to a B7-H3 CAR construct?","Is there ES-specific evidence that DFMO/AMXT 1501 depletes tumour polyamines and suppresses the EWSR1::FLI1 transcriptional programme in vivo?","Can DWI-ADC and FDG-SUV (PMID:42208702, PMID:42314618) serve as early pharmacodynamic response endpoints for DDR-directed agents in phase 1/2 ES cohorts?"],"nextQueries":["\"Ewing sarcoma\" AND (\"ATR inhibitor\" OR elimusertib OR ceralasertib OR camonsertib OR berzosertib) AND SRC:MED","(\"Ewing sarcoma\" OR \"FET fusion\") AND (SLFN11 OR STAG2 OR \"replication stress\" OR \"ATM\") AND PUB_YEAR:[2023 TO 2026]","(\"Ewing sarcoma\" OR sarcoma) AND (\"B7-H3\" OR CD276) AND (\"CAR T\" OR \"chimeric antigen receptor\") AND SRC:MED"],"papersShown":[{"pmid":"41560619","doi":"10.1080/19420862.2026.2614669","year":2026,"isNew":true,"title":"Antibodies to watch in 2026"},{"pmid":"41811428","doi":"10.1158/0008-5472.can-25-2166","year":2026,"isNew":true,"title":"FET Fusion Oncoproteins Disrupt Physiologic DNA Repair and Create a Targetable Opportunity for ATR Inhibitor Therapy"},{"pmid":"42366590","doi":"10.1080/21645515.2026.2690876","year":2026,"isNew":true,"title":"Immunotherapy in pediatric bone sarcomas: Current progress and future directions"},{"pmid":"42247321","doi":"10.1080/15384047.2026.2684140","year":2026,"isNew":true,"title":"Neoplastic CD3⁺ B cells remodel the DLBCL tumor microenvironment via single-cell and spatial transcriptomics"},{"pmid":"42564846","doi":"10.3892/ol.2026.15779","year":2026,"isNew":true,"title":"Evaluation of limb function after treatment with chemotherapy and carbon ion radiotherapy for Ewing sarcoma of the scapula: A report of three cases"},{"pmid":"42403662","doi":"10.1016/j.radcr.2026.05.069","year":2026,"isNew":true,"title":"Primary Ewing sarcoma of the pancreas: A rare extraosseous presentation"},{"pmid":"42314618","doi":"10.1016/j.ejrad.2026.113024","year":2026,"isNew":true,"title":"Evaluation of standardized uptake value (SUV) and apparent diffusion coefficient (ADC) as prognostic imaging parameters for primary Ewing sarcoma in hybrid 18F-FDG-PET/MRI"},{"pmid":"42208702","doi":"10.1016/j.mri.2026.110706","year":2026,"isNew":true,"title":"Role of diffusion-weighted MRI in assessing Ewing sarcoma treatment response: Findings from a COG phase III trial"},{"pmid":"42535165","doi":"10.1055/s-0046-1817017","year":2026,"isNew":true,"title":"An Incidental EWSR1-Rearranged Sarcoma of the Orbit with Primitive Neuroectodermal Morphology and Myogenic Differentiation: A Case Report and Diagnostic Challenge\""},{"pmid":"42215796","doi":"10.1007/s00280-026-04907-8","year":2026,"isNew":true,"title":"Autophagy impairs the sensitivity of Ewing sarcoma cells to PARP inhibitors"}],"trialsShown":[{"nct":"NCT02243605","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Cabozantinib S-malate in Treating Patients With Relapsed Osteosarcoma or Ewing Sarcoma"},{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"},{"nct":"NCT06465199","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Eflornithine (DFMO) and AMXT 1501 for Neuroblastoma, CNS Tumors, and Sarcomas"},{"nct":"NCT05210374","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Disulfiram With Copper Gluconate and Liposomal Doxorubicin in Treatment-Refractory Sarcomas"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT07628634","phase":"EARLY_phase 1","status":"RECRUITING","isNew":true,"title":"Feasibility Study on the Effect of a Methionine-Reduced Diet on Serum Levels in Pts w/ Solid Tumors"},{"nct":"NCT04337177","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With Temozolomide for Treatment of Recurrent Pediatric Solid Tumors"},{"nct":"NCT06820957","phase":"phase 2/phase 3","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Testing a New Combination of Anti-cancer Drugs in Patients Newly Diagnosed With Ewing Sarcoma Who Have Cancer That Has Spread to Other Parts"}],"usage":{"input":8796,"output":5177},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Ewing sarcoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Ewing sarcoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41560619","PMID:41811428","PMID:42366590","PMID:42247321","PMID:42564846","PMID:42403662","PMID:42314618","PMID:42208702","PMID:42535165","PMID:42215796","NCT02243605","NCT07172958","NCT06465199","NCT05210374","NCT04320888","NCT07628634","NCT04337177","NCT06820957"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787152481720","cycle":20,"visit":1,"ts":"2026-08-19T15:14:41.720Z","cancer":{"key":"osteosarcoma","name":"osteosarcoma","mondo":{"id":"MONDO:0009807","name":"osteosarcoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise KIF18A inhibition (AM-1882-class) as a ploidy/CIN-selective synthetic lethality in TP53/RB1-null osteosarcoma, and pair B7-H3 immunoPET with B7-H3-directed cell therapy as an antigen-stratified immunotherapy programme.","confidence":0.52,"notebook":"Programme opens. The pack's single strongest mechanistic item is KIF18A. AM-1882 and KIF18A knockout kill a whole-genome-doubled SJSA1 derivative but spare the near-diploid parent, act through spindle-assembly-checkpoint activation (SAC loss rescues growth), and suppress U2OS/MG63 xenografts without the toxicity seen with cytotoxics (PMID:42328720). This is a genotype-agnostic synthetic lethality that matches osteosarcoma's defining biology — TP53 [SOMATIC] and RB1 [GERMLINE/SOMATIC] loss driving whole-genome doubling and chromothripsis [KNOWN] — i.e. a way to exploit undruggable suppressor loss rather than restore it. KIF18A is dispensable in normal diploid tissue (Kif18a-null mice viable, phenotype largely limited to male germ cells) [KNOWN], so the window argument is real. Expected resistance: SAC attenuation (MAD1/MAD2/BUB1B loss), reversion toward near-diploidy, MDR efflux. Priority experiment: correlate response with ploidy/CIN score across a PDX panel rather than cell-line passage number.\n\nImmunotherapy: the pediatric bone sarcoma review frames the barrier as immunosuppressive TME, low TMB, scarce surface antigens (PMID:42366590). Two pack items answer that concretely. B7-H3/CD276 is now getting a companion imaging tool — 68Ga-B7-H3 nanobody immunoPET in osteosarcoma (NCT07774533) — which is the missing selection assay for B7-H3 CAR-T/ADC/radioligand approaches; antigen-density-stratified enrolment is the testable hypothesis. Separately, membrane-anchored tumour-targeted IL-12 T cells/TILs (NCT05621668, NCT06474676) attack cold-TME biology by localising IL-12 and avoiding the systemic toxicity that killed unmodified IL-12 [KNOWN]; readouts to watch are intratumoural IFN-γ, myeloid repolarisation, and whether responses track baseline T-cell infiltrate.\n\nUSP7 in sarcoma is a plausible non-oncogene dependency (PMID:42556483), but the review is substrate-agnostic; the classical USP7→MDM2→p53 axis is largely irrelevant in TP53-null osteosarcoma [INFERRED], so the lead lives or dies on p53-independent substrates. Kept at low confidence pending primary data.\n\nRecorded but not promoted: FZD1/TCF7L1 Wnt-driven stemness with homoharringtonine (PMID:42472087) — attractive because omacetaxine is approved [KNOWN], but efficacy is entangled with a bespoke nanoplatform; CACNA1E/METTL3-m6A/WNT7B-Ca²⁺ chemoresistance (PMID:42327581) as a repurposing sketch [SPECULATIVE]; the NIR-II PDT scaffold (PMID:42494752) is local-control engineering, no systemic hypothesis; HOXA (PMID:42296055), shikonin/DLBCL (PMID:42295078), GSH/H₂S (PMID:42275298) are not osteosarcoma-actionable this visit. The TNBC macrophage CCL3/CCL4/CXCL2/IL-1β→lung-colonisation circuit blocked by maraviroc/navarixin/anakinra (PMID:42319344) is disease-mismatched but maps onto osteosarcoma's obligate lung tropism — an explicit cross-tumour question, not a lead. Antiangiogenic backbone trials (NCT02243605, NCT03900793) remain context for future combination arms.","leadChanges":[{"id":"L1","title":"KIF18A inhibition as CIN/whole-genome-doubling-selective synthetic lethality in osteosarcoma","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"B7-H3 (CD276) antigen-density-stratified targeting with companion immunoPET selection","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"Locally delivered IL-12 via membrane-anchored tumour-targeted T/TIL cells against the immunosuppressive osteosarcoma TME","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"USP7 as a p53-independent non-oncogene dependency in osteosarcoma","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L5","title":"FZD1/TCF7L1 Wnt-dependent osteosarcoma cancer stem cells and homoharringtonine repurposing","level":"LEAD","status":"NEW","confidence":0.28}],"unverifiedCitations":0,"openQuestions":["Does KIF18A-inhibitor sensitivity in osteosarcoma track quantitatively with WGD/CIN burden and SAC gene integrity across PDX panels, rather than with a single isogenic pair?","What are the p53-independent USP7 substrates in TP53-null osteosarcoma, and is any selective USP7 inhibitor active in that context?","Does 68Ga-B7-H3 immunoPET uptake correlate with tissue antigen density and predict response to B7-H3-directed cell therapy or ADC in bone sarcoma?","Is the macrophage CCL3/CCL4/CXCL2/IL-1beta to lung-colonisation circuit (shown in TNBC, PMID:42319344) operative in osteosarcoma pulmonary metastasis, making maraviroc/navarixin/anakinra repurposing testable?","Is METTL3-m6A stabilisation of CACNA1E and WNT7B/Ca2+ signalling a genuine, targetable chemoresistance node in osteosarcoma, and can calcium-channel or METTL3 inhibitors reverse doxorubicin/cisplatin resistance?","What is the mature efficacy signal for antiangiogenic backbones in relapsed osteosarcoma (cabozantinib, NCT02243605; losartan+sunitinib, NCT03900793) and are they suitable partners for immune or mitotic-targeted agents?"],"nextQueries":["\"osteosarcoma\" AND (KIF18A OR \"whole genome doubling\" OR \"chromosomal instability\" OR \"spindle assembly checkpoint\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"osteosarcoma\" OR \"bone sarcoma\") AND (\"B7-H3\" OR CD276 OR \"CAR T\" OR \"antibody-drug conjugate\" OR IL12) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"osteosarcoma\" AND (USP7 OR deubiquitinase OR \"lung metastasis\" AND macrophage) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42494752","doi":"10.1016/j.bioactmat.2026.07.026","year":2026,"isNew":true,"title":"NIR-II-activated supramolecular LDH nanoarchitecture integrated with 3D-printed bioactive glass for hypoxia-resistant photodynamic osteosarcoma therapy and bone regeneration"},{"pmid":"42472087","doi":"10.1016/j.bioactmat.2026.07.009","year":2026,"isNew":true,"title":"Single-cell and longitudinal transcriptomics-guided engineering of FZD1-targeting precision nanotherapy against osteosarcoma cancer stem cells"},{"pmid":"42366590","doi":"10.1080/21645515.2026.2690876","year":2026,"isNew":true,"title":"Immunotherapy in pediatric bone sarcomas: Current progress and future directions"},{"pmid":"42328720","doi":"10.1080/15384047.2026.2689181","year":2026,"isNew":true,"title":"KIF18A inhibitor prevents chromosomally unstable osteosarcoma growth by activating spindle assembly checkpoint"},{"pmid":"42319344","doi":"10.1080/2162402x.2026.2687381","year":2026,"isNew":true,"title":"Tumor-educated macrophages promote cytokine-driven lung colonization in triple-negative breast cancer"},{"pmid":"42296055","doi":"10.1080/07853890.2026.2685993","year":2026,"isNew":true,"title":"The HOXA gene cluster: a critical regulator in bone-related disorders"},{"pmid":"42295078","doi":"10.1080/14756366.2026.2674446","year":2026,"isNew":true,"title":"Shikonin suppresses diffuse large B-cell lymphoma progression by inducing ferritinophagy and ferroptosis &lt;i&gt;via&lt;/i&gt; lncRNA ADPGK-AS1 downregulation"},{"pmid":"42275298","doi":"10.1080/13510002.2026.2687238","year":2026,"isNew":true,"title":"Significance of GSH and H&lt;sub&gt;2&lt;/sub&gt;S regulation for cancer: an intricate interplay between diet, microbiota, metabolic reprogramming, and immune health"},{"pmid":"42556483","doi":"10.1016/j.bcp.2026.118319","year":2026,"isNew":true,"title":"Targeting USP7 in sarcomas: opportunities and challenges"},{"pmid":"42327581","doi":"10.7150/jca.133409","year":2026,"isNew":true,"title":"The Emerging Role of CACNA1E in Cancer: Molecular Mechanisms and Therapeutic Implications"}],"trialsShown":[{"nct":"NCT06859801","phase":"n/a","status":"RECRUITING","isNew":true,"title":"A Multi-Center Observational Trial of Symptomatic, High-Risk Bone Metastases Treated With Percutaneous Ablation and Palliative Radiation The"},{"nct":"NCT07774533","phase":"EARLY_phase 1","status":"RECRUITING","isNew":true,"title":"68Ga-B7-H3 Nanobody ImmunoPET in Osteosarcoma"},{"nct":"NCT06474676","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"T Cell Membrane-Anchored Tumor-Targeted IL12 -Modified TIL Cell Therapy (attIL12-TIL) for Advanced/Metastatic Soft Tissue and Bone Sarcoma P"},{"nct":"NCT06737172","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Functional and Structural Outcomes Following Childhood Bone or Soft Tissue Sarcomas of the Lower Extremity"},{"nct":"NCT06743958","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Prehabilitation in Childhood Soft Tissue or Bone Sarcomas"},{"nct":"NCT02243605","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Cabozantinib S-malate in Treating Patients With Relapsed Osteosarcoma or Ewing Sarcoma"},{"nct":"NCT05621668","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A First-In-Human Phase 1 Trial of T-Cell Membrane-Anchored Tumor Targeted Il12 (Attil12)- T-Cell Therapy in Subjects With Advanced/Metastati"},{"nct":"NCT03900793","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Losartan + Sunitinib in Treatment of Osteosarcoma"}],"usage":{"input":8443,"output":6067},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"osteosarcoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"osteosarcoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42494752","PMID:42472087","PMID:42366590","PMID:42328720","PMID:42319344","PMID:42296055","PMID:42295078","PMID:42275298","PMID:42556483","PMID:42327581","NCT06859801","NCT07774533","NCT06474676","NCT06737172","NCT06743958","NCT02243605","NCT05621668","NCT03900793"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787152282950","cycle":19,"visit":1,"ts":"2026-08-19T15:11:22.950Z","cancer":{"key":"wilms tumor","name":"Wilms tumor","mondo":{"id":"MONDO:0006058","name":"Wilms tumor"}},"control":false,"modelLabel":"SCIENCE","summary":"Wilms tumor's near-term actionable axis is surface-antigen cell therapy (GPC3 CAR-T per NCT04715191; B7-H3 CAR-T with TGF-beta dominant-negative per NCT07172958) plus an ATRA + hypomethylating differentiation combination biomarker-selected by CRABP2 localisation and RARB methylation.","confidence":0.44,"notebook":"Visit 1 opens the programme against a pack that is mostly off-target: folliculogenesis (PMID:41928388), diabetic podocyte lipotoxicity (PMID:42135621, PMID:41845912), MTDH in head/neck (PMID:42294496), pseudorabies m6A/WTAP (PMID:42398312 — \"Wilms tumor-associated protein\", a name collision, not disease-relevant), an endometrial case report (PMID:42077092) and a Jordanian RCC series (PMID:41403303). These are logged as noise so the desk does not revisit them. Four items carry signal, and the trial registry carries more than the literature.\n\nSurface-antigen immunotherapy is the strongest entry point. GPC3 sits in the KG as causal/[GERMLINE] (loss-of-function → Simpson-Golabi-Behmel with Wilms predisposition [KNOWN]), yet the druggable fact is somatic onco-fetal re-expression of the protein; NCT04715191 puts IL-15/IL-21-armored GPC3 CAR-T into pediatric solid tumours, and the window argument is that GPC3 is essentially silent in postnatal normal tissue [KNOWN]. NCT07172958 (SABRE) pairs B7-H3 CAR-T with TGF-β-insensitive (dTβRII) antigen-specific T cells in relapsed/refractory embryonal tumours — mechanistically attractive because blastemal WT is TGF-β-rich [INFERRED]; expected escape routes are antigen-low B7-H3 subclones and CAR-T exhaustion. NCT04616560 tests trastuzumab deruxtecan explicitly in recurrent WT — I will track its HER2-IHC/ISH inclusion data next visit rather than open a lead on a trial listing alone.\n\nWT1-directed TCR-T (NCT07645469, HLA-A*02:01, FH-WT1-E50, in MRD+ AML) is the obvious repurposing temptation and I flag it with a hard window caveat: WT1 [GERMLINE causal, but wild-type/overexpressed somatically in most WT] is expressed in podocytes, mesothelium and visceral adipose stem cells, where it gates PRDM16/UCP1 via UBC9 (PMID:42125880) — on-target renal and adipose toxicity is the predicted dose-limiter, so this stays low-confidence.\n\nPMID:42492627 gives a mechanistic switch worth testing: ATRA differentiates WT cells, but cytoplasmic CRABP2 retention and RARB promoter methylation keep blastema undifferentiated. That predicts ATRA + hypomethylating agent (azacitidine/decitabine), with nuclear-CRABP2 and RARB methylation as the enrichment biomarker — a repurposing combination of two approved drugs. PMID:42327581 reports CACNA1E amplification/overexpression correlating with relapse in favourable-histology WT; as a review-level claim this is thin, and Cav2.3 pharmacology is non-selective, so it enters as a biomarker lead only.\n\nNotable absence: nothing in this pack addresses TRIM28, DIS3L2, CTR9, REST or H19/IGF2 LOI biology, and no PARP/BRCA2 synthetic-lethality data for WT. Those are next visit's targets.","leadChanges":[{"id":"L1","title":"IL-15/IL-21-armored GPC3 CAR-T against onco-fetal GPC3 in Wilms tumor","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"B7-H3 CAR-T combined with TGF-beta-insensitive (dTbetaRII) antigen-specific T cells for relapsed embryonal WT","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"ATRA plus hypomethylating agent to force differentiation through the CRABP2/RARB switch in blastemal WT","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L4","title":"WT1-directed TCR-T repurposing — window-limited, held at low confidence","level":"LEAD","status":"NEW","confidence":0.22},{"id":"L5","title":"CACNA1E amplification as a relapse-risk biomarker in favourable-histology WT","level":"LEAD","status":"NEW","confidence":0.2}],"unverifiedCitations":0,"openQuestions":["What are the HER2 expression criteria and any reported WT responses in NCT04616560 (trastuzumab deruxtecan), and is HER2 genuinely expressed in WT epithelial components?","What is GPC3 and B7-H3 protein prevalence across WT histologic subtypes (blastemal vs epithelial vs stromal, anaplastic vs favourable) in primary human series?","Is there any preclinical or clinical evidence that TRIM28-mutant or DIS3L2/CTR9-mutant WT has a distinct exploitable dependency, and are these germline or somatic in the reported cases?","Does germline BRCA2 in WT predisposition translate into any somatic HR deficiency (PARP-inhibitor rationale) or is it purely a predisposition signal?","What primary data (not review-level) support ATRA-induced differentiation in WT models, and has ATRA plus a DNMT inhibitor ever been tested in WT?","What are the current dominant relapse mechanisms after standard COG/SIOP chemotherapy in high-risk WT, and which are drug-addressable?"],"nextQueries":["\"Wilms tumor\" AND (GPC3 OR \"glypican-3\" OR B7-H3 OR CD276 OR \"CAR T\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","\"Wilms tumor\" AND (TRIM28 OR DIS3L2 OR CTR9 OR \"IGF2\" OR \"loss of imprinting\") AND (dependency OR vulnerability OR inhibitor) AND SRC:MED","\"Wilms tumor\" AND (relapse OR refractory OR \"anaplastic\") AND (\"patient-derived xenograft\" OR organoid OR \"drug screen\") AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"papersShown":[{"pmid":"41928388","doi":"10.1080/19396368.2026.2631558","year":2026,"isNew":true,"title":"Molecular mechanisms of folliculogenesis and oogenesis"},{"pmid":"42294496","doi":"10.1016/j.jdsr.2026.05.003","year":2026,"isNew":true,"title":"Metadherin: A pivotal oncogene and therapeutic target in head and neck cancer - a systematic review"},{"pmid":"42135621","doi":"10.1080/0886022x.2026.2670806","year":2026,"isNew":true,"title":"Targeting LRH-1 alleviates diabetes-induced lipotoxicity in podocytes: role of PLIN5-mediated lipid droplet turnover"},{"pmid":"42125880","doi":"10.1080/21623945.2026.2658408","year":2026,"isNew":true,"title":"Wt1 facilitates visceral beige fat formation to combat abdominal obesity"},{"pmid":"42077092","doi":"10.1080/21645515.2026.2664297","year":2026,"isNew":true,"title":"Anlotinib plus envafolimab as neoadjuvant therapy in a patient with chemotherapy-refractory advanced endometrial cancer: A case report"},{"pmid":"41845912","doi":"10.1080/0886022x.2026.2640720","year":2026,"isNew":true,"title":"Exosomes in diabetic kidney disease: pathogenesis, biomarker discovery, and emerging therapeutics-a comprehensive systematic review"},{"pmid":"41403303","doi":"10.1080/20565623.2025.2601636","year":2026,"isNew":true,"title":"Clinicohistopathological characteristics of renal cell carcinoma in Jordan"},{"pmid":"42398312","doi":"10.1016/j.micres.2026.128611","year":2026,"isNew":true,"title":"Pseudorabies virus hijacks JNK to reprogram m&lt;sup&gt;6&lt;/sup&gt;A machinery for sustaining replication"},{"pmid":"42327581","doi":"10.7150/jca.133409","year":2026,"isNew":true,"title":"The Emerging Role of CACNA1E in Cancer: Molecular Mechanisms and Therapeutic Implications"},{"pmid":"42492627","doi":"10.1016/j.bbcan.2026.189667","year":2026,"isNew":true,"title":"The dual role of retinoic acid signaling in clear cell renal cell carcinoma and wilms tumor: A tale of two entities"}],"trialsShown":[{"nct":"NCT07645469","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"FH-WT1-E50 TCR T Cells With Azacitidine for the Treatment of Minimal Residual Disease Positive Acute Myeloid Leukemia"},{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"},{"nct":"NCT04616560","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Trastuzumab Deruxtecan (DS-8201a) for the Treatment of Recurrent or Refractory Osteosarcoma, Wilms Tumor, and Desmoplastic Small Round Cell "},{"nct":"NCT04715191","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT03155620","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin L"},{"nct":"NCT02867592","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumor"},{"nct":"NCT04284774","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Trea"}],"usage":{"input":9147,"output":5646},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"Wilms tumor\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"Wilms tumor\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41928388","PMID:42294496","PMID:42135621","PMID:42125880","PMID:42077092","PMID:41845912","PMID:41403303","PMID:42398312","PMID:42327581","PMID:42492627","NCT07645469","NCT07172958","NCT04616560","NCT04715191","NCT04320888","NCT03155620","NCT02867592","NCT04284774"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787152071214","cycle":18,"visit":1,"ts":"2026-08-19T15:07:51.214Z","cancer":{"key":"retinoblastoma","name":"retinoblastoma","mondo":{"id":"MONDO:0008380","name":"retinoblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise transcriptional-CDK (CDK7) inhibition as an RB1-loss-selective vulnerability in retinoblastoma — piggybacking on the RB1-negative-selected REC-617 trial — while testing GPC2 surface expression in retinoblastoma primaries/metastases to support the already-open GPC2 CAR-T arm.","confidence":0.42,"notebook":"Visit 1 opens the programme. The pack is mostly noise for this indication — HPV vaccine work (P2, P3), prostate lncRNA (P4), TG2/innate immunity (P5), parental distress (P6), polyphenols and Aβ lncRNAs (P7, P9), AML CAR-T (P8) carry no retinoblastoma content and are logged as non-citable-for-RB background. Four items are usable: P1, P10, T1, T3/T4.\n\nMechanistic frame. Retinoblastoma is biallelic RB1 inactivation (germline first hit in heritable disease, somatic second hit; sporadic unilateral = two somatic hits) with consequent RB–E2F checkpoint collapse, plus a minority MYCN-amplified/RB1-proficient subtype (P1, P10). Both lesions converge on E2F/MYC transcriptional addiction [INFERRED]. That makes transcriptional CDKs, not cell-cycle CDK4/6, the mechanistically coherent target class: [KNOWN] RB1 loss is a canonical resistance mechanism to palbociclib/abemaciclib, so P1's report that CRISPR organoids \"validated CDK4/6 inhibitors\" is internally suspect and I treat it as unresolved rather than supporting — abemaciclib in CDK-pathway-altered sarcoma (T4) is not a transferable precedent and should not be re-proposed for RB1-null RB without an explanation of retained cyclin D dependence. Conversely T3 is a clinical experiment built exactly on the opposite premise: REC-617, a selective CDK7 inhibitor, enrolling RB1-negative leiomyosarcoma. That is the first cross-indication clinical test of RB1-loss-selective transcriptional-CDK vulnerability and becomes my anchor lead (LEAD-1). Expected resistance: ABCB1/ABCG2 efflux (relevant for intravitreal dosing), CDK12/13 or CDK9 compensation, cyclin-C/CDK8 rewiring [SPECULATIVE].\n\nLEAD-2 is GPC2 CAR T (T1), which explicitly enrols metastatic retinoblastoma alongside neuroblastoma. GPC2 is a MYCN-transactivated surface glycoprotein with restricted postnatal normal expression [KNOWN]; the window argument is developmental-CNS-restricted expression versus an ocular/metastatic tumour. Key uncertainties: GPC2 surface density in RB primaries versus neuroblastoma, T-cell trafficking into vitreous/subretinal sanctuaries, antigen-low escape.\n\nLEAD-3 (low confidence) from P10: PTM-enzyme pharmacology — ubiquitin-ligase/deubiquitinase and SUMO circuits around the RB–E2F axis, with targeted degraders, plus proposed PTM–immunotherapy combinations. Review-level only; I have no primary data and will not raise it without a named enzyme and a genetic dependency.\n\nLEAD-4 (low confidence): sunitinib, an approved multi-RTK inhibitor reportedly active in CRISPR retinal organoid RB models (P1). Repurposing-first appeal, but abstract-level, no dose/target attribution, and systemic sunitinib in infants is a real toxicity question.\n\nInfrastructure note: patient-derived/CRISPR retinal organoids with cone-precursor origin (P1) are the screening substrate I should demand for any lead here; T2/T8/T7 are specimen and standard-of-care contexts (vincristine/topotecan/carboplatin backbone) against which combinations must be framed.","leadChanges":[{"id":"L1","title":"CDK7 / transcriptional-CDK inhibition as synthetic lethality with RB1 loss and MYCN amplification in retinoblastoma","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L2","title":"GPC2-directed CAR T cells for metastatic/extraocular retinoblastoma","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"PTM-enzyme pharmacology (ubiquitin/SUMO/acetylation circuits) around the RB-E2F axis, with immunotherapy combination","level":"LEAD","status":"NEW","confidence":0.2},{"id":"L4","title":"Sunitinib repurposing (multi-RTK inhibition) validated in CRISPR retinal organoid retinoblastoma models","level":"LEAD","status":"NEW","confidence":0.18}],"unverifiedCitations":0,"openQuestions":["Do RB1-null retinoblastoma models show genuine selective sensitivity to CDK7 (vs CDK9/CDK12) inhibition, and are there primary data from RB1-negative tumours in NCT07633756 or preclinical RB1-loss panels?","Is the P1 claim that CDK4/6 inhibitors were 'validated' in CRISPR retinoblastoma organoids reconcilable with RB1 loss causing CDK4/6i resistance — were those organoids RB1-proficient/MYCN-amplified?","What is GPC2 surface expression frequency and density in retinoblastoma primaries, vitreous seeds and metastatic deposits, and does it track with MYCN amplification?","What is the immune landscape of retinoblastoma (MHC-I level, T-cell infiltration, ocular immune privilege) that would gate any CAR-T or checkpoint-combination strategy?","Which specific PTM enzyme (E3 ligase, DUB, SUMO E1/E2) is a validated genetic dependency in RB1-null retinoblastoma rather than a review-level suggestion?","Which agents achieve tumoricidal intravitreal/intra-arterial exposure in retinoblastoma, and can transcriptional-CDK inhibitors be delivered locally to widen the window?"],"nextQueries":["(\"retinoblastoma\" OR \"RB1-deficient\" OR \"RB1 loss\") AND (\"CDK7\" OR \"CDK9\" OR \"CDK12\" OR \"transcriptional addiction\" OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"retinoblastoma\" AND (\"GPC2\" OR \"glypican-2\" OR \"CAR T\" OR \"immune microenvironment\" OR \"HLA class I\") AND SRC:MED AND PUB_YEAR:[2021 TO 2026]","\"retinoblastoma\" AND (\"MYCN amplification\" AND \"RB1 wild-type\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"papersShown":[{"pmid":"41782059","doi":"10.1186/s13287-026-04951-4","year":2026,"isNew":true,"title":"Retinoblastoma: unveiling molecular pathogenesis and pioneering organoid-driven therapeutic innovations"},{"pmid":"41571571","doi":"10.1080/21645515.2025.2610899","year":2026,"isNew":true,"title":"Toward next-generation therapeutic HPV vaccines: A review on expanding the antigen repertoire and an integrated bioinformatics selection framework"},{"pmid":"42301768","doi":"10.1080/21645515.2026.2686510","year":2026,"isNew":true,"title":"Preventive and therapeutic efficacy of mRNA/LNP vaccines encoding HPV16 E6 and E7 in an early-intervention HPV tumor mouse models"},{"pmid":"42187002","doi":"10.1080/15384047.2026.2678636","year":2026,"isNew":true,"title":"Diagnostic and prognostic value of lncSPATA8-AS1 in prostate cancer and its regulatory effect on tumor progression"},{"pmid":"42053427","doi":"10.1080/2162402x.2026.2665505","year":2026,"isNew":true,"title":"Transglutaminase 2 regulates innate immunity: mechanisms and therapeutic implications"},{"pmid":"41953235","doi":"10.1016/j.apjon.2026.100926","year":2026,"isNew":true,"title":"Fear of progression profiles in parents of children with cancer and their impact on psychological distress: The mediating role of sense of coherence"},{"pmid":"41918250","doi":"10.1080/07853890.2026.2634566","year":2026,"isNew":true,"title":"Epigenetic regulators polyphenols in neurodegenerative diseases: a promising intervention strategy"},{"pmid":"41800605","doi":"10.1080/07853890.2026.2640457","year":2026,"isNew":true,"title":"Preclinical advances and mechanistic insights of CAR-T therapy for acute myeloid leukemia: from target iteration to microenvironment regulation"},{"pmid":"41784271","doi":"10.1080/15476286.2026.2639017","year":2026,"isNew":true,"title":"lncRNAs: key player in Aβ deposition"},{"pmid":"42212122","doi":"10.3389/fimmu.2026.1820785","year":2026,"isNew":true,"title":"Post-translational modifications in retinoblastoma: mechanisms, immune regulation, and therapeutic opportunities"}],"trialsShown":[{"nct":"NCT05650749","phase":"phase 1","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"GPC2 CAR T Cells for Relapsed or Refractory Neuroblastoma and Metastatic Retinoblastoma"},{"nct":"NCT01109394","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Comprehensive Omics Analysis of Pediatric and Adult Solid Tumors and Establishment of a Repository for Related Biological Studies"},{"nct":"NCT07633756","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"A Phase 1b, Open-Label Study Of REC-617, A Selective CDK7 Inhibitor, In Patients With Metastatic Or Unresectable RB1-Negative Leiomyosarcoma"},{"nct":"NCT04040205","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Abemaciclib for Bone and Soft Tissue Sarcoma With Cyclin-Dependent Kinase (CDK) Pathway Alteration"},{"nct":"NCT03567642","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study of the Combination of Osimertinib, Platinum and Etoposide for Patients With Metastatic EGFR Mutant Lung Cancers"},{"nct":"NCT03655223","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Early Check: Expanded Screening in Newborns"},{"nct":"NCT01783535","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma"},{"nct":"NCT03050268","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Familial Investigations of Childhood Cancer Predisposition"}],"usage":{"input":8157,"output":5975},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"retinoblastoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"retinoblastoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41782059","PMID:41571571","PMID:42301768","PMID:42187002","PMID:42053427","PMID:41953235","PMID:41918250","PMID:41800605","PMID:41784271","PMID:42212122","NCT05650749","NCT01109394","NCT07633756","NCT04040205","NCT03567642","NCT03655223","NCT01783535","NCT03050268"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787151868694","cycle":17,"visit":1,"ts":"2026-08-19T15:04:28.694Z","cancer":{"key":"medulloblastoma","name":"medulloblastoma","mondo":{"id":"MONDO:0007959","name":"medulloblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise MYC/MYCN-amplification-gated replication-stress therapy (PLX038, NCT06161519) plus ODC1 blockade (DFMO, NCT04696029) for Group 3/4 medulloblastoma, and use the new fractionated-CSI mouse platform (PMID:42502578) to test radiosensitisers such as atovaquone rather than testing them under fo","confidence":0.42,"notebook":"**Visit 1 — programme initiation.** The pack is trial-heavy and review-heavy; only two papers carry primary mechanistic data (P5, P10). I therefore anchor the programme on subgroup-specific vulnerabilities where a trial already exists, and I record the KG's germline/somatic labels as unreliable: ELP1 and SUFU are established **germline** predisposition alleles in SHH-MB, not somatic drivers, while CTNNB1 activation in WNT-MB is **somatic** exon-3 hotspot, not germline ([KNOWN]; Monarch's assignments are inverted here). No citable MB primary data in this pack touches ELP1/SUFU/GPR161, so no lead is opened on them.\n\nLead L1 (MYC/MYCN-amplified Group 3/4): NCT06161519 tests PLX038, a PEGylated SN-38 prodrug, selected *by MYC/MYCN amplification* in primary CNS tumours — an explicit replication-stress/TOP1 synthetic-lethality bet, since MYC amplification raises origin firing and transcription–replication conflict ([INFERRED] from the trial's biomarker-gated design; [KNOWN] for the MYC–replication-stress biology). NCT04337177 (oral irinotecan VAL-413 + temozolomide) is the pragmatic comparator arm and a source of pediatric TOP1 tolerability data. Expected resistance: ABCG2/ABCB1 efflux, SLFN11 loss, TDP1 upregulation.\n\nLead L2: DFMO maintenance (NCT04696029) in molecular high/very-high-risk and relapsed MB — ODC1 is a direct MYC transcriptional target, so polyamine depletion is a MYC-pathway-adjacent, orally available maintenance strategy [KNOWN]; the trial's molecular-risk stratification makes it the highest-priority readout to track.\n\nLead L3: P10 is the only new MB mechanism paper — brefeldin A destabilises CD133 structurally in Group 3 lines, collapsing stem-like phenotype and PI3K/AKT/mTOR signalling, with FDA/EMA-approved mimetics identified only *in silico*. Mechanistically this is secretory-pathway/ARF1-GBF1 disruption rather than CD133 targeting per se [INFERRED]; BFA itself is not developable (GBF1 is essential in normal secretory tissue). Opened at low confidence pending named compounds and orthotopic data.\n\nLead L4: radiosensitisation. P5 delivers a fractionated CSI mouse platform across seven MB models showing focal/whole-brain irradiation fails to control spinal disease — the first honest preclinical substrate for testing radiosensitisers; NCT06624371 (atovaquone + RT) supplies the clinical-stage OXPHOS/complex-III hypoxia-reoxygenation candidate. P8 (reduced CTV_2340 volume) shows the field is simultaneously de-escalating dose volume, which raises the value of tumour-selective sensitisation.\n\nLead L5 (speculative, delivery): P1 establishes WNT7a/b–β-catenin–GPR124/RECK/SOX17 as the BBB differentiation programme; WNT-MB's aberrantly permeable vasculature is the mirror image of this [KNOWN/INFERRED], predicting subgroup-differential CNS drug exposure — a testable explanation for why WNT-MB responds to conventional chemotherapy and why Group 3/4 may need delivery engineering.\n\nNegatives recorded: selpercatinib (NCT04320888) and savolitinib (NCT03598244) are basket trials with negligible RET/MET alteration prevalence in MB — low prior, do not re-propose. Immunotherapy in this pack (P3, P4, P9) is review-level only; NCT06514898 tracked, not yet a lead.","leadChanges":[{"id":"L1","title":"TOP1-directed replication-stress payloads in MYC/MYCN-amplified Group 3/4 MB","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"Polyamine depletion (DFMO/ODC1) as molecular-risk-stratified maintenance","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"Secretory-pathway (ARF1/GBF1) disruption destabilises CD133 and collapses Group 3 MB stem cells","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L4","title":"Metabolic radiosensitisation tested under clinically faithful fractionated craniospinal irradiation","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L5","title":"Subgroup-differential BBB integrity as the determinant of CNS drug exposure in MB","level":"LEAD","status":"NEW","confidence":0.2}],"unverifiedCitations":0,"openQuestions":["Is there primary evidence that ELP1-mutant [GERMLINE] SHH-MB carries a tRNA-modification/proteostasis or translational-stress vulnerability that could be drugged (e.g. ISR, GCN2, HSP90)?","Which MYC-amplified Group 3 dependency is more tractable — replication stress (TOP1/ATR/PARP/CHK1) or transcription-CDK (CDK7/CDK9/CDK12) — and does any dataset compare them head-to-head in vivo?","Do the in-silico-nominated FDA/EMA-approved brefeldin-A mimetics have named identities, CNS penetration and orthotopic activity, and is the target GBF1/ARF1 rather than CD133?","Are the immunotherapy strategies reviewed in the pack (CAR-T/NK, DC-RNA vaccines, ICI) backed by any primary MB efficacy data, and what antigens (GD2, B7-H3, HER2) are actually validated in MB rather than glioma?","Does molecular subgroup predict measurable intratumoural drug exposure/BBB permeability in MB, and can Group 3/4 exposure be raised without generalised barrier disruption?","Which radiosensitisers besides atovaquone have been tested under fractionated CSI rather than focal irradiation, and did any show spinal-relapse control?"],"nextQueries":["(\"medulloblastoma\") AND (ELP1 OR SUFU OR \"germline predisposition\") AND (vulnerability OR dependency OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"medulloblastoma\" AND (\"Group 3\" OR MYC)) AND (\"replication stress\" OR ATR OR CHK1 OR PARP OR CDK7 OR \"transcriptional addiction\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"medulloblastoma\") AND (\"CAR T\" OR \"CAR-NK\" OR GD2 OR B7-H3 OR \"immune checkpoint\") AND (xenograft OR \"clinical trial\" OR \"first-in-human\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42007489","doi":"10.1080/07853890.2026.2657638","year":2026,"isNew":true,"title":"Role of the WNT signalling pathway in physiological and pathological blood-brain barrier"},{"pmid":"41885448","doi":"10.1080/14756366.2026.2636394","year":2026,"isNew":true,"title":"PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators"},{"pmid":"41758201","doi":"10.1080/07853890.2026.2635774","year":2026,"isNew":true,"title":"Opportunities and challenges for cancer immunotherapy based on antigen cross-presentation"},{"pmid":"41491954","doi":"10.1080/2162402x.2025.2608436","year":2026,"isNew":true,"title":"Unlocking the therapeutic potential of immuno-radiotherapy: insights from preclinical and clinical research"},{"pmid":"42502578","doi":"10.1016/j.adro.2026.102114","year":2026,"isNew":true,"title":"Establishing a Clinically Relevant Radiation Therapy Method for Preclinical Medulloblastoma Research"},{"pmid":"42524270","doi":"10.1210/jcemcr/luag177","year":2026,"isNew":true,"title":"Challenges in managing endocrine and metabolic dysfunction in a child with Prader-Willi syndrome and medulloblastoma"},{"pmid":"42431280","doi":"10.1016/j.bbcan.2026.189660","year":2026,"isNew":true,"title":"Mapping epigenetic alterations across brain tumor hallmarks"},{"pmid":"42425418","doi":"10.1016/j.radonc.2026.111685","year":2026,"isNew":true,"title":"Strategic modulation to avoid radiation toxicities for brain integrity (SMART-BRAIN)"},{"pmid":"42346637","doi":"10.3390/jpm16060326","year":2026,"isNew":true,"title":"Immune Cell Therapy Promises More Effective Cure for Medulloblastoma"},{"pmid":"42443895","doi":"10.1186/s12935-026-04398-w","year":2026,"isNew":true,"title":"CD133 structural instability as a gateway to medulloblastoma vulnerability"}],"trialsShown":[{"nct":"NCT06161519","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"PLX038 in Primary Central Nervous System Tumors Containing MYC or MYCN Amplifications"},{"nct":"NCT04696029","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"DFMO as Maintenance Therapy for Molecular High/Very High Risk and Relapsed Medulloblastoma"},{"nct":"NCT05057702","phase":"NA","status":"RECRUITING","isNew":true,"title":"Individualized Treatment Plan in Children and Young Adults With Relapsed Medulloblastoma and Ependymoma"},{"nct":"NCT06514898","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Adoptive T Cell Therapy, DC Vaccines, and Hematopoietic Stem Cells Combined With Immune checkPOINT Blockade in Patients With Medulloblastoma"},{"nct":"NCT04320888","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediat"},{"nct":"NCT06624371","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Atovaquone Combined With Radiation in Children With Malignant Brain Tumors"},{"nct":"NCT04337177","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With Temozolomide for Treatment of Recurrent Pediatric Solid Tumors"},{"nct":"NCT03598244","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Savolitinib in Treating Patients With Recurrent or Refractory Primary CNS Tumors"}],"usage":{"input":8283,"output":6127},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"medulloblastoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"medulloblastoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42007489","PMID:41885448","PMID:41758201","PMID:41491954","PMID:42502578","PMID:42524270","PMID:42431280","PMID:42425418","PMID:42346637","PMID:42443895","NCT06161519","NCT04696029","NCT05057702","NCT06514898","NCT04320888","NCT06624371","NCT04337177","NCT03598244"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787151659454","cycle":16,"visit":1,"ts":"2026-08-19T15:00:59.454Z","cancer":{"key":"neuroblastoma","name":"neuroblastoma","mondo":{"id":"MONDO:0005072","name":"neuroblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Anti-GD2 failure in high-risk neuroblastoma is largely effector-cell and tumour-state driven, so the highest-value near-term test is ex vivo expanded UCB-NK cells plus dinutuximab stratified by FCGR3A genotype and baseline NK infiltration, with epigenetic ADRN re-differentiation as the shared enable","confidence":0.55,"notebook":"Programme opens. The pack is ~50% off-target (Lyme vaccines P3, rabies circRNA P4, varroacidal spider peptides P8, melanoma MITF P5, generic GSH/H₂S P6, opaganib P7, BMX P10 — none carry neuroblastoma data; logged as noise so the desk does not mine them again). Four NB-relevant items plus five NB-relevant trials support four founding leads.\n\nThe strongest mechanistic thread is that anti-GD2 efficacy is effector-cell-limited, not antibody-limited. P9 (PMID:42216567) shows intratumoral NK infiltration correlates with anti-GD2 response in clinical samples, that induction chemotherapy depletes patient PB NK cells, and that ex vivo expanded UCB NK cells are more cytotoxic, more persistent and exhaustion-resistant, with anti-GD2 driving a \"high activating–low inhibitory\" phenotype; two R/R patients had CR/PR without added toxicity (n=2, uncontrolled — hypothesis-generating only). P1 (PMID:41827873) supplies the counterweight: MDSC/TAM infiltration, checkpoint and metabolic barriers, FcγR polymorphisms, and GD2 heterogeneity are all plausible failure routes. Lead 1 therefore proposes UCB-NK + dinutuximab/hu14.18K322A backbones (NCT06172296, NCT07549321) with FCGR3A-158V/F genotype and baseline NK infiltration as prespecified stratifiers.\n\nP1's second axis — MYCN-amplified tumours downregulate MHC-I and carry low TMB [SOMATIC] — argues that T-cell-intrinsic recognition is structurally weak, favouring antibody/CAR modalities over checkpoint monotherapy. That motivates Lead 2: multi-antigen CAR against GD2-independent surface targets, anchored on GPC2 CAR-T (NCT05650749) and B7-H3 CAR-T co-delivered with dTβRII-armoured antigen-specific T cells (NCT07172958) — the latter is the only asset in the pack that directly neutralises TGF-β, the dominant immunosuppressive node P1 names.\n\nP2 (PMID:41977421) reframes NTRK biology in NB: not a fusion/mutation disease but an epigenetically governed axis where PRC2/EZH2, promoter methylation and MYCN silence TrkA/TrkC (adrenergic, differentiation-competent) while BDNF–TrkB autocrine loops mark mesenchymal, therapy-resistant states. Lead 3: EZH2 (tazemetostat [KNOWN, approved]) ± DNMT inhibition to re-impose ADRN identity, deliberately paired with a pan-Trk inhibitor to pre-empt the predicted TrkB escape route. [INFERRED] the same ADRN→MES switch should erode GD2 and SLC6A2/NET expression, coupling this lead to both immunotherapy and radiopharmaceutical failure.\n\nLead 4 is that coupling made concrete: [²¹¹At]MABG (NCT07767630) delivers α-particles via NET, so ADRN-state dependence is an on-target liability; SSTR2 α-therapy (NCT06479811, non-NB indications) is the state-orthogonal hedge.\n\nNext I need quantitative co-expression of GD2/GPC2/B7-H3/NET across ADRN-MES states, evidence that EZH2i restores MHC-I or ST8SIA1, and ALK/lorlatinib data absent from this pack.","leadChanges":[{"id":"L1","title":"Allogeneic umbilical-cord-blood NK cells to restore ADCC on an anti-GD2 backbone","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"Multi-antigen CAR-T against GPC2/B7-H3 with TGF-beta blockade for MHC-I-low MYCN-amplified disease","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L3","title":"EZH2/DNMT-mediated reactivation of TrkA/TrkC differentiation with pre-emptive TrkB blockade","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L4","title":"Alpha-emitter radiopharmaceuticals and the ADRN-state dependence of NET-mediated uptake","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["What is the quantitative single-cell co-expression of GD2 (ST8SIA1), GPC2, B7-H3 and SLC6A2/NET across ADRN versus MES neuroblastoma states, and does any pair cover both states?","Does EZH2 or DNMT inhibition restore MHC-I and GD2 synthase expression in MYCN-amplified models, i.e. can one epigenetic agent enable both immunotherapy and re-differentiation?","Is there controlled (beyond n=2) or randomised evidence that adoptive NK infusion adds benefit over anti-GD2 alone, and does FCGR3A-158V/F genotype predict it?","What ALK-inhibitor (lorlatinib) data exist in ALK-mutant/amplified neuroblastoma and what are the reported resistance mutations? No ALK evidence appeared in this pack despite ALK being a KG anchor.","Which myeloid-directed intervention (CSF1R, CD47, adenosine axis) most reliably reverses MDSC/TAM-mediated anti-GD2 resistance in neuroblastoma models?","Are LIN28B, LMO1, HACE1 or PHOX2B tractable as anything other than lineage/predisposition markers, and are any germline versus somatic?"],"nextQueries":["\"neuroblastoma\" AND (ALK OR lorlatinib OR crizotinib) AND (resistance OR mutation OR trial) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"neuroblastoma\" AND (\"adrenergic\" OR \"mesenchymal\" OR \"ADRN\" OR \"plasticity\") AND (\"GD2\" OR \"MHC class I\" OR \"antigen loss\" OR \"EZH2\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"neuroblastoma\" AND (\"GPC2\" OR \"B7-H3\" OR \"CAR T\" OR \"NK cell\") AND (\"clinical trial\" OR \"phase 1\" OR \"phase 2\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41827873","doi":"10.3390/cells15050441","year":2026,"isNew":true,"title":"Factors Influencing Immunotherapy Response in Neuroblastoma: From Tumor Microenvironment to Combination Strategies"},{"pmid":"41977421","doi":"10.3390/ijms27073238","year":2026,"isNew":true,"title":"Epigenetic Regulation of Trk Receptors and Neurotrophic Signalling in Neuroblastoma: Mechanisms, Plasticity, and Therapeutic Opportunities"},{"pmid":"42324826","doi":"10.1080/21505594.2026.2690805","year":2026,"isNew":true,"title":"The current landscape and future directions of Lyme disease vaccines"},{"pmid":"42308359","doi":"10.1080/21505594.2026.2690777","year":2026,"isNew":true,"title":"mmu_circ_0012122/mmu-miR-1843-5p/Sertad2 axis: A novel regulatory pathway in rabies virus infection"},{"pmid":"42290218","doi":"10.1080/15384101.2026.2684937","year":2026,"isNew":true,"title":"MITF-Driven melanoma plasticity as a core mechanism of therapy resistance: integrating microenvironmental signaling, mechanotransduction, and metabolic reprogramming"},{"pmid":"42275298","doi":"10.1080/13510002.2026.2687238","year":2026,"isNew":true,"title":"Significance of GSH and H&lt;sub&gt;2&lt;/sub&gt;S regulation for cancer: an intricate interplay between diet, microbiota, metabolic reprogramming, and immune health"},{"pmid":"42256552","doi":"10.1016/j.pscia.2026.100125","year":2026,"isNew":true,"title":"Therapeutic potential of the sphingosine kinase 2 inhibitor opaganib"},{"pmid":"42253431","doi":"10.1038/s44386-026-00050-9","year":2026,"isNew":true,"title":"Spider venom peptides Ht1a and Gg1a are toxic to honeybee parasite &lt;i&gt;Varroa destructor&lt;/i&gt; by topical application"},{"pmid":"42216567","doi":"10.1080/2162402x.2026.2679315","year":2026,"isNew":true,"title":"Umbilical cord blood natural killer cells improve anti-GD2 antibody efficacy in neuroblastoma: from mouse to human"},{"pmid":"42212521","doi":"10.1080/14756366.2026.2677282","year":2026,"isNew":true,"title":"Targeting the BMX in cancer: molecular mechanisms and emerging therapeutic strategies"}],"trialsShown":[{"nct":"NCT06172296","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Dinutuximab With Chemotherapy, Surgery and Stem Cell Transplantation for the Treatment of Children With Newly Diagnosed High Risk Neuroblast"},{"nct":"NCT07767630","phase":"EARLY_phase 1","status":"RECRUITING","isNew":true,"title":"Safety, Tolerability, and Preliminary Efficacy of [211At]MABG in Patients With Relapsed or Refractory Neuroblastoma"},{"nct":"NCT06479811","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"[212Pb]VMT-Alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive Gastrointestinal Neuroendocrine Tumors, Pheochromocytoma/Par"},{"nct":"NCT04755205","phase":"n/a","status":"RECRUITING","isNew":true,"title":"A Natural History Study of Children and Adults With Olfactory Neuroblastoma"},{"nct":"NCT01005654","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Prospective Comprehensive Molecular Analysis of Endocrine Neoplasms"},{"nct":"NCT07549321","phase":"phase 2/phase 3","status":"RECRUITING","isNew":true,"title":"A Safety and Efficacy Study of hu14 in High-Risk Neuroblastoma Patients"},{"nct":"NCT05650749","phase":"phase 1","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"GPC2 CAR T Cells for Relapsed or Refractory Neuroblastoma and Metastatic Retinoblastoma"},{"nct":"NCT07172958","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Selective Antigen Specific T Cells and CAR T Cells in Subjects With Relapsed/Refractory Embryonal Tumors (SABRE)"}],"usage":{"input":8424,"output":5760},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"neuroblastoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"neuroblastoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41827873","PMID:41977421","PMID:42324826","PMID:42308359","PMID:42290218","PMID:42275298","PMID:42256552","PMID:42253431","PMID:42216567","PMID:42212521","NCT06172296","NCT07767630","NCT06479811","NCT04755205","NCT01005654","NCT07549321","NCT05650749","NCT07172958"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787151462730","cycle":15,"visit":1,"ts":"2026-08-19T14:57:42.730Z","cancer":{"key":"adrenocortical carcinoma","name":"adrenocortical carcinoma","mondo":{"id":"MONDO:0006639","name":"adrenal cortex carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise the OTSSP167 (RSK1)/adavosertib WEE1-inhibitor combination as a TP53-mutant-selective synthetic-lethal strategy in ACC, and test cortisol-secretion status as the modifier of VEGFR-TKI plus PD-1 response.","confidence":0.42,"notebook":"Programme opens. The pack is mostly off-target noise: sodium thiosulphate (PMID:41490376), CXCR4/CYP11B2 and renalase aldosterone biology in aldosterone-producing adenoma (PMID:42290661, PMID:41495987) — benign adenoma physiology, not ACC maintenance — and pan-cancer TCGA mining where ACC appears only as one bar in a plot (CHRNA7, PMID:42292701; GLUT10/SLC2A10, PMID:42595549; PMID:42057949, PMID:42180999). Logged as dead ends; do not re-propose.\n\nTwo real signals. First, PMID:42601067 gives the only mechanistic in vivo package: the multikinase inhibitor OTSSP167 (nominally MELK-directed; here RSK1 identified as the direct in vitro target) shrank TP53-WT (CUACC1) and TP53-mutant (H295R, CUACC9) PDX/CDX tumours via caspase-dependent apoptosis and G2/M arrest independent of TP53 status, with added DNA damage and translational suppression selectively in TP53-mutant lines. Critically, WEE1 induction was an early adaptive response in all models, and adding adavosertib/AZD1775 potentiated cytotoxicity and tumour control in TP53-mutant ACC. This is textbook adaptive-checkpoint synthetic lethality: TP53 is the top somatic anchor in ACC [SOMATIC], p53-null cells depend on the G2/M checkpoint after DNA damage [KNOWN], so a WEE1 inhibitor should convert OTSSP167-induced damage into mitotic catastrophe. Highest-value lead. Caveats: OTSSP167 is promiscuous and MELK-directed agents have a poor clinical record [KNOWN]; RSK1 attribution rests on in vitro assays in the abstract; adavosertib myelosuppression bounds the combination window.\n\nSecond, the clinic is converging on VEGFR/MET TKI plus PD-1 blockade: NCT06900595 (cabozantinib + cemiplimab) is the registrational-intent version, with pembrolizumab/ipilimumab/lenvatinib producing a durable RECIST partial response in a TMB-high (11.6/Mb), MSS, GNAS/HSD11B2-altered cortisol-secreting ACC (PMID:42158873). Anti-angiogenic normalisation plus checkpoint release is the mechanism [INFERRED]; single-agent PD-1 in ACC has been weak historically [KNOWN], consistent with NCT02721732/NCT03333616 being basket-level.\n\nThird, derived lead: cortisol as the dominant immune-evasion axis. PMID:42590935 reports single-cell interplay between steroidogenic cancer populations and immunity; the case report's response coincided with resolution of Cushing's and induction of adrenal insufficiency. Hypothesis: selective GR antagonism (relacorilant, NCT03604198) or steroidogenesis blockade restores intratumoral T-cell function and should be tested as an immunotherapy enabler. Note the tension: NCT05286814 co-administers dexamethasone with PDS01ADC (IL-12 immunocytokine) + HAIP floxuridine, which by this logic could blunt the immune arm — a testable contradiction.\n\nNext: quantify whether cortisol-secretion status predicts checkpoint failure, and find human WEE1/RSK data in ACC.","leadChanges":[{"id":"L1","title":"Adaptive WEE1 induction as the actionable vulnerability of TP53-mutant ACC after RSK1/multikinase inhibition","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"VEGFR/MET TKI plus PD-1 blockade as the practical immunotherapy backbone in advanced ACC","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"Tumour-derived cortisol as a targetable immune-evasion axis: GR antagonism to enable checkpoint therapy","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Is the OTSSP167 effect genuinely RSK1-dependent, or MELK/off-target polypharmacology — and does any clinically developable agent reproduce the WEE1-induction phenotype in TP53-mutant ACC?","Does cortisol-secreting status (or GNAS/HSD11B2 alteration) predict failure of PD-1-based therapy in ACC cohorts larger than n=1?","Do published single-cell/spatial ACC datasets show WEE1, RSK1 or CDK1 pathway dependency confined to particular molecular subtypes (steroid-high vs proliferative)?","The KG anchors ZNRF3 and CTNNB1 (WNT activation) generated no leads this visit — is there any 2023-2026 evidence for tractable WNT-pathway or porcupine/TNKS targeting in ACC, and does WNT activation drive T-cell exclusion here?","Which resistance mechanism dominates after VEGFR-TKI/PD-1 combination in ACC, and are there on-treatment biopsy data from NCT06900595 or its predecessors?","Does concurrent glucocorticoid administration (as in NCT05286814) measurably blunt immunotherapy efficacy in ACC?"],"nextQueries":["(\"adrenocortical carcinoma\" AND (WEE1 OR adavosertib OR RSK1 OR MELK OR \"cell cycle checkpoint\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"adrenocortical carcinoma\" AND (cortisol OR hypercortisolism OR glucocorticoid) AND (immunotherapy OR \"PD-1\" OR \"checkpoint\" OR \"T cell\")) AND SRC:MED","(\"adrenocortical carcinoma\" AND (ZNRF3 OR CTNNB1 OR \"Wnt\" OR beta-catenin) AND (inhibitor OR target OR dependency)) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"papersShown":[{"pmid":"41490376","doi":"10.1080/07853890.2025.2611464","year":2026,"isNew":true,"title":"Advances in the clinical applications of sodium thiosulphate"},{"pmid":"42290661","doi":"10.1016/j.gendis.2025.101956","year":2026,"isNew":true,"title":"CXCR4 reduces aldosterone synthesis via regulating CYP11B2 expression"},{"pmid":"41495987","doi":"10.1080/14756366.2025.2610034","year":2026,"isNew":true,"title":"Renalase stimulates aldosterone production via PMCA4b/cAMP in NCI-H295R cells"},{"pmid":"42292701","doi":"10.1016/j.bbrep.2026.102649","year":2026,"isNew":true,"title":"Pan-cancer expression, methylation, and prognostic significance of α7 nicotinic acetylcholine receptor in tumor immunology"},{"pmid":"42180999","doi":"10.1016/j.gendis.2025.101979","year":2026,"isNew":true,"title":"Ammonia-induced cell death patterns in glioblastoma: Immune landscape, prognostic signature, and therapeutic target identification"},{"pmid":"42057949","doi":"10.1016/j.gendis.2025.101960","year":2026,"isNew":true,"title":"Integrative pan-cancer analysis identifies CCHCR1 as a prognostic biomarker and therapeutic target driving EMT in hepatocellular carcinoma via PI3K/AKT activation"},{"pmid":"42601067","doi":"10.1210/endocr/bqag091","year":2026,"isNew":true,"title":"Comprehensive Profiling of OTSSP167 Action in Adrenocortical Carcinoma"},{"pmid":"42595549","doi":"10.3760/cma.j.cn112152-20251018-00521","year":2026,"isNew":true,"title":"[Expression characteristics of GLUT10 in breast cancer and its mechanism in mediating cisplatin resistance]"},{"pmid":"42590935","doi":"10.1097/med.0000000000000974","year":2026,"isNew":true,"title":"Single-cell resolution in adrenocortical carcinoma: from pathogenesis to treatment"},{"pmid":"42158873","doi":"10.3389/fimmu.2026.1819473","year":2026,"isNew":true,"title":"Case Report: triple therapy with pembrolizumab, ipilimumab, and lenvatinib in mitotane- and radiation-refractory, cortisol-secreting stage IV adrenocortical carcinoma: a genomicall"}],"trialsShown":[{"nct":"NCT06487481","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Study of Preoperative Radiation Therapy in Participants With Resectable Recurrent Abdominal Adrenocortical Carcinoma"},{"nct":"NCT03604198","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Extension Study to Evaluate the Safety of Long-Term Use of Relacorilant in Patients With Cushing Syndrome"},{"nct":"NCT06900595","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Testing the Addition of an Anti-Cancer Drug, Cabozantinib to the Immunotherapy Drug Cemiplimab (REGN2810), in Adolescents and Adults With Ad"},{"nct":"NCT03333616","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Nivolumab Combined With Ipilimumab for Patients With Advanced Rare Genitourinary Tumors"},{"nct":"NCT02867592","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumor"},{"nct":"NCT02721732","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Pembrolizumab in Treating Patients With Rare Tumors That Cannot Be Removed by Surgery or Are Metastatic"},{"nct":"NCT03583710","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Mitotane With or Without Cisplatin and Etoposide After Surgery in Treating Patients With Stage I-III Adrenocortical Cancer With High Risk of"},{"nct":"NCT05286814","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"PDS01ADC in Combination With Hepatic Artery Infusion Pump (HAIP) and Systemic Therapy for Subjects With Metastatic Colorectal Cancer, Intrah"}],"usage":{"input":7680,"output":4427},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"adrenocortical carcinoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"adrenocortical carcinoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41490376","PMID:42290661","PMID:41495987","PMID:42292701","PMID:42180999","PMID:42057949","PMID:42601067","PMID:42595549","PMID:42590935","PMID:42158873","NCT06487481","NCT03604198","NCT06900595","NCT03333616","NCT02867592","NCT02721732","NCT03583710","NCT05286814"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787151279171","cycle":14,"visit":1,"ts":"2026-08-19T14:54:39.171Z","cancer":{"key":"head and neck squamous cell carcinoma","name":"head and neck squamous cell carcinoma","mondo":{"id":"MONDO:0010150","name":"head and neck squamous cell carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise high-avidity HPV16 E6* (aa49-110)-directed TCR-T for HPV+ OPSCC over the clinically advancing low-avidity E7_11-19 TCR, whose clone was lost in metastasis, and test PI3K/AKT blockade plus platinum in FOXA2/LAMC2-high or PTEN-null HNSCC.","confidence":0.5,"notebook":"Visit 1 opens the programme. The pack is thin on target biology and heavy on health economics; I record P1 and P2 as context only — finotonlimab+chemo is not cost-effective in China at $112,384/QALY (PMID:42574211), and neoadjuvant/adjuvant pembrolizumab on top of surgery+SOC is now the LA-HNSCC backbone by KEYNOTE-689 EFS (PMID:42565346). Notebook rule for future visits: do not propose another me-too PD-1 monotherapy or PD-1+platinum doublet; the incremental space is combination partners layered onto a pembrolizumab backbone. P5 (TNBC), P7 (prostate lncRNA), P8 (pancreatic UBE2C) are off-target for this disease and are not citable support for HNSCC claims.\n\nFour leads open. The strongest is antigen-defined cell therapy in HPV+ OPSCC. PMID:42503644 isolates and functionally validates (NFAT-luciferase Jurkat) nine HPV16 E6/E7-specific TCRs and shows that high-avidity receptors against an alternatively spliced E6 region (E6*, aa49–110) persisted in a lung metastasis sampled three years after curative therapy, whereas lower-avidity clones — including an E7_11-19 TCR currently in clinical development — were lost. That is a directional, partly contradicting datum for E7_11-19 TCR-T and an argument that avidity plus epitope choice (E6*) governs durability. n=4 single-cell, one longitudinal pair: hypothesis-generating, not proof. Therapeutic window is the best in this disease [INFERRED]: E6/E7 are viral, absent from normal tissue, so off-tumour toxicity risk is HLA-restricted cross-reactivity, not lineage toxicity. Expected escape: HLA-A LOH, B2M loss, E6* splice-isoform downregulation, exhaustion of transferred cells.\n\nSecond, resistance mechanics. PMID:42319071 nominates FOXA2 as the sole cisplatin-resistance gene with survival association in TCGA-HNSCC and maps FOXA2→LAMC2 (direct promoter binding, ChIP+luciferase, PDO validation) with PI3K/AKT activation. This converges with the KG anchor PTEN [SOMATIC, correlated] — two independent routes into PI3K/AKT as the chemoresistance node, which makes AKT/PI3K inhibition plus platinum a testable repurposing arm in FOXA2/LAMC2-high or PTEN-null tumours. Third, PMID:42540626 reports apatinib binding IRF9 and driving RAN-dependent nuclear import with JAK-STAT output; Oroxin B reverses resistance. Single paper, in vitro, natural-product tool compound — low confidence, flagged for kill-testing. Fourth, myeloid/innate re-direction of cetuximab: NCT06508606 (anti-CD47 AK117 + cetuximab) and NCT06806852 (BI 770371 + pembrolizumab ± cetuximab) both test macrophage-axis potentiation, with MTDH's CCL18–macrophage paracrine loop (PMID:42294496) as mechanistic rationale. MTDH itself I will not nominate as a direct target — scaffold protein, no ligandable pocket asserted [INFERRED].\n\nNext visit must attack: whether E6* TCR-T has any clinical footprint; whether AKT inhibitor + platinum has HNSCC data; PTEN-null synthetic lethality; and TNFRSF10B/DR5 [GERMLINE-likely anchor] which currently has zero citable support.","leadChanges":[{"id":"L1","title":"High-avidity HPV16 E6* (aa49-110)-directed TCR-T for HPV+ oropharyngeal SCC; deprioritise E7_11-19","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L2","title":"PI3K/AKT blockade to resensitise cisplatin-resistant HNSCC in FOXA2/LAMC2-high or PTEN-null tumours","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"Macrophage/innate-checkpoint potentiation of cetuximab-mediated ADCP in R/M HNSCC","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L4","title":"IRF9 nuclear translocation as a reversible node of apatinib (VEGFR2 TKI) resistance","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Is there any clinical or preclinical footprint for E6*(aa49-110)-directed TCR-T or TCR-mimic bispecifics in HPV+ OPSCC, and has the E7_11-19 TCR-T trial reported outcomes that corroborate or refute the avidity/persistence hypothesis?","Does any HNSCC-specific dataset support AKT or PI3K inhibition plus platinum, and does PTEN-null status stratify response - i.e. is there a synthetic-lethal partner (PI3Kbeta, SGK1, PARP) for PTEN loss in this disease?","TNFRSF10B (DR5) and ING1 are the Monarch causal/germline-likely anchors and have zero citable support in this pack - is DR5 agonism (with a caspase-8-intact requirement) a real HNSCC lead, and does ING1 loss create any exploitable dependenc","What resistance mechanisms are reported for the pembrolizumab neoadjuvant backbone (KEYNOTE-689), since every combination lead must now be layered onto it?","Which myeloid-axis or CD47 combination has actually shown ADCP-dependent responses in EGFR-driven tumours, and does cetuximab remain necessary given HPV status?","Is LAMC2/laminin-332-integrin alpha6beta4 signalling independently druggable in HNSCC, separate from the PI3K/AKT readout?"],"nextQueries":["(\"head and neck\" OR oropharyngeal) AND (\"TCR-T\" OR \"T cell receptor\" OR \"adoptive cell therapy\") AND (HPV16 OR E6 OR E7) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"head and neck squamous cell carcinoma\" AND (PTEN OR \"PIK3CA\" OR capivasertib OR alpelisib OR \"AKT inhibitor\") AND (cisplatin OR platinum OR \"synthetic lethality\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"head and neck squamous cell carcinoma\" AND (TNFRSF10B OR \"death receptor 5\" OR TRAIL OR ING1 OR \"caspase-8\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"papersShown":[{"pmid":"42574211","doi":"10.1080/21645515.2026.2713808","year":2026,"isNew":true,"title":"Cost-effectiveness analysis of finotonlimab in the treatment of advanced recurrent metastatic head and neck squamous cell carcinoma in China"},{"pmid":"42565346","doi":"10.1080/13696998.2026.2712763","year":2026,"isNew":true,"title":"Cost-effectiveness of pembrolizumab as neoadjuvant therapy and in combination with standard of care (SOC) as adjuvant therapy for stage III-IVA resectable locally advanced head and"},{"pmid":"42503644","doi":"10.1080/2162402x.2026.2707808","year":2026,"isNew":true,"title":"Characterization of persistent HPV-specific activated T cells in head and neck squamous cell carcinoma"},{"pmid":"42294496","doi":"10.1016/j.jdsr.2026.05.003","year":2026,"isNew":true,"title":"Metadherin: A pivotal oncogene and therapeutic target in head and neck cancer - a systematic review"},{"pmid":"42247481","doi":"10.1080/15384047.2026.2683942","year":2026,"isNew":true,"title":"The tumor microenvironment in triple negative breast cancer and a strategy to improve responses to immunotherapy using cryoablation and immunostimulants"},{"pmid":"42211773","doi":"10.1016/j.jdsr.2026.05.001","year":2026,"isNew":true,"title":"Diagnostic accuracy of HPV DNA in oral gargle and rinse samples for Head and neck squamous cell carcinoma: A systematic review and meta-analysis"},{"pmid":"42187002","doi":"10.1080/15384047.2026.2678636","year":2026,"isNew":true,"title":"Diagnostic and prognostic value of lncSPATA8-AS1 in prostate cancer and its regulatory effect on tumor progression"},{"pmid":"42157383","doi":"10.1080/15384101.2026.2668450","year":2026,"isNew":true,"title":"UBE2C promotes pancreatic cancer progression through PI3K/Akt/mTOR signaling pathway"},{"pmid":"42319071","doi":"10.1111/cbdd.70328","year":2026,"isNew":true,"title":"Revealing the Action Mechanism of the FOXA2-LAMC2 Axis in Driving Cisplatin Resistance of Head and Neck Squamous Cell Carcinoma via Based Multi-Omic Analysis and Experimental Valid"},{"pmid":"42540626","doi":"10.1016/j.isci.2026.116444","year":2026,"isNew":true,"title":"Apatinib resistance mediated by IRF9 nuclear translocation in head and neck squamous cell carcinoma"}],"trialsShown":[{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT06508606","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"AK117 (Anti-CD47 mAb) Plus Cetuximab or AK104 (Anti-PD-1/CTLA-4 bsAb) as Second-Line Therapy in Recurrent/Metastatic Head and Neck Squamous "},{"nct":"NCT04958239","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Test BI 765179 Alone and in Combination With Ezabenlimab in Patients With Advanced Cancer (Solid Tumors) and BI 765179 in Combina"},{"nct":"NCT07241039","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"A Study to Assess the Adverse Events, Change in Disease Activity, and How Oral ABBV-711 Tablets Move Through the Body as a Monotherapy and i"},{"nct":"NCT02734537","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Radiation Therapy With or Without Cisplatin in Treating Patients With Stage III-IVA Squamous Cell Carcinoma of the Head and Neck Who Have Un"},{"nct":"NCT06995508","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Olanzapine for Managing Anorexia in Head and Neck Cancer Patients Undergoing Chemoradiation, MACRO Trial"},{"nct":"NCT05136196","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"BiCaZO: A Study Combining Two Immunotherapies (Cabozantinib and Nivolumab) to Treat Patients With Advanced Melanoma or Squamous Cell Head an"},{"nct":"NCT06806852","phase":"phase 1","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Test Whether Treatment With BI 770371 in Combination With Pembrolizumab With or Without Cetuximab Helps People With Head and Neck"}],"usage":{"input":9069,"output":6063},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"head and neck squamous cell carcinoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"head and neck squamous cell carcinoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42574211","PMID:42565346","PMID:42503644","PMID:42294496","PMID:42247481","PMID:42211773","PMID:42187002","PMID:42157383","PMID:42319071","PMID:42540626","NCT07115043","NCT06508606","NCT04958239","NCT07241039","NCT02734537","NCT06995508","NCT05136196","NCT06806852"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787151075174","cycle":13,"visit":1,"ts":"2026-08-19T14:51:15.174Z","cancer":{"key":"mesothelioma","name":"mesothelioma","mondo":{"id":"MONDO:0005065","name":"mesothelioma"}},"control":false,"modelLabel":"SCIENCE","summary":"In pleural mesothelioma, NF2 copy-number loss drives cavity-restricted CAR-T/anti-PD-1 resistance through retinoic-acid- and chemokine-dependent recruitment of CRIg+ macrophages, making TEAD inhibition (or retinoic-acid/chemokine blockade) a rational sensitiser to add to mesothelin-directed CAR T ce","confidence":0.52,"notebook":"Visit 1 opens the programme. Seven of ten pack items are off-target (Alzheimer nanomedicine P1, gut-microbiome ICI biomarkers P2, Castleman P4, MITF melanoma P5, in-vivo CAR-T preconditioning P6, endocrine irAEs P8) — logged as non-informative for mesothelioma so the desk does not re-mine them. Two papers carry the visit.\n\nP10 (PMID:42208538) is the highest-value item: in diffuse pleural mesothelioma models, acquired resistance to mesothelin-directed CAR T cells tracked with reduced NF2 [SOMATIC]; enforced NF2 depletion conferred resistance to CAR T and anti-PD-1 **only in the pleural cavity**, not subcutaneously, via tumour-secreted chemokines and retinoic acid recruiting immunosuppressive CRIg+ macrophages. Chemokine ablation, retinoic-acid inhibition, or TEAD inhibition restored CAR-T sensitivity; in two patient cohorts NF2 copy-number loss (not mutation) associated with higher infiltration. Mechanistically this converts NF2 tumour-suppressor loss from an undruggable event into a Hippo-dependent, microenvironment-mediated immune-evasion programme — i.e. a combination hypothesis, not a monotherapy one [INFERRED]. It pairs directly with the active anti-mesothelin TNaive/SCM hYP218 CAR-T trial (NCT06885697), which supplies the T-cell backbone. Caveat: abstract does not name the TEAD inhibitor, dose, or whether CNV-loss/mutation discordance reflects allele dosage versus a passenger effect. Window argument: P7 shows YAP1/TEAD1 sustains SLC7A5–leucine–mTOR and protects renal tubular epithelium from ferroptosis, so systemic TEAD blockade carries a plausible renal-tubular toxicity axis — intracavitary or intermittent dosing deserves modelling. P3 (YAP–TEAD4 peptide, AML) is only a chemical-tool datapoint, not mesothelioma evidence.\n\nP9 (PMID:42257802) restates the epigenetic axis: BAP1 loss [SOMATIC; germline in the predisposition setting per NCT03830229/NCT04431024] correlates with high EZH2, and EZH2 inhibitors (tazemetostat, valemetostat, tulmimetostat, GSK126) are in preclinical/early clinical testing. It is a review, so no new efficacy data — [KNOWN] single-agent tazemetostat in BAP1-deficient mesothelioma gave disease control without meaningful response rates, so I open this lead at modest confidence and explicitly as a combination scaffold. NCT04104776 (tulmimetostat, solid tumours/lymphoma) is the nearest live vehicle.\n\nThird lead: the CRIg+ macrophage / retinoic-acid niche itself as a cavity-restricted immunosuppression target, separable from Hippo blockade because the intervention (RAR antagonism, chemokine-receptor blockade) differs and may spare renal YAP function [SPECULATIVE].\n\nWT1 [causal/GERMLINE-likely per KG] has no pack citation this visit; parked as a question, not a lead. LAG-3 (NCT07234058) and peritoneal atezolizumab/bevacizumab (NCT05001880) are watch items.\n\nNext visit must resolve: which TEAD inhibitor and schedule, whether BAP1 and NF2 loss co-segregate, and whether EZH2 inhibition alters the same macrophage niche.","leadChanges":[{"id":"L1","title":"TEAD inhibition to reverse NF2-loss-driven resistance to mesothelin CAR T cells in pleural mesothelioma","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L2","title":"BAP1-loss-associated EZH2 dependency as a combination scaffold, not monotherapy","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"CRIg+ macrophage / retinoic-acid niche as a cavity-specific immunosuppression target","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["Which TEAD inhibitor, dose and route were used in PMID:42208538, and does the effect require tumour-cell-intrinsic YAP/TAZ or macrophage-intrinsic Hippo signalling?","Do NF2 copy-number loss and BAP1 loss co-occur or are they mutually exclusive in pleural mesothelioma cohorts, and does BAP1 status modify CAR-T/anti-PD-1 resistance?","Which specific chemokine(s) and retinoic-acid receptor isoform mediate CRIg+ macrophage recruitment, and is there an approved antagonist (e.g. a CCR2/CCR5 or RARalpha agent) to repurpose?","Does EZH2 inhibition alter the pleural myeloid niche or MHC-I/antigen presentation in BAP1-null mesothelioma, i.e. is an EZH2i + PD-1 or EZH2i + CAR-T combination mechanistically supported?","Is WT1 [GERMLINE-likely per KG anchor] tractable as a mesothelioma immunotherapy target (vaccine or TCR) in current literature, and what is the somatic-versus-predisposition split?","Does LAG-3 blockade (fianlimab, NCT07234058) address the same macrophage-mediated resistance or a distinct T-cell-intrinsic mechanism?"],"nextQueries":["(\"mesothelioma\" OR \"diffuse pleural mesothelioma\") AND (\"NF2\" OR \"TEAD\" OR \"YAP\") AND (inhibitor OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"mesothelioma\" AND (\"BAP1\" AND (\"EZH2\" OR tazemetostat OR \"synthetic lethal\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"mesothelioma\" AND (mesothelin AND (\"CAR T\" OR \"chimeric antigen receptor\")) AND (macrophage OR \"tumor microenvironment\" OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41863079","doi":"10.1080/10717544.2026.2645830","year":2026,"isNew":true,"title":"Overcoming the blood‒brain barrier: nanomedicine strategies for targeted delivery and multimodal therapy in Alzheimer's disease"},{"pmid":"42026803","doi":"10.1080/19490976.2026.2662690","year":2026,"isNew":true,"title":"Gene-level gut microbiome signatures as predictive biomarkers for response to immune checkpoint inhibitors across multiple cancer types"},{"pmid":"41800759","doi":"10.1080/14756366.2026.2633822","year":2026,"isNew":true,"title":"Screening of peptide inhibitors targeting YAP-TEAD4 interaction: affinity evaluation and anti-AML cell activity"},{"pmid":"42310940","doi":"10.1080/0886022x.2026.2671463","year":2026,"isNew":true,"title":"Successful treatment of idiopathic multicentric Castleman disease with TAFRO and kidney involvement: case report and literature review"},{"pmid":"42290218","doi":"10.1080/15384101.2026.2684937","year":2026,"isNew":true,"title":"MITF-Driven melanoma plasticity as a core mechanism of therapy resistance: integrating microenvironmental signaling, mechanotransduction, and metabolic reprogramming"},{"pmid":"42088834","doi":"10.1016/j.synbio.2026.04.012","year":2026,"isNew":true,"title":"Remodeling memory T cells with chemotherapy and immune checkpoint inhibitors as host pre-conditioning to empower in vivo CAR-T therapy"},{"pmid":"41833934","doi":"10.1080/13510002.2026.2643967","year":2026,"isNew":true,"title":"The hippo-YAP1/TEAD1-SLC7A5 axis: uncovering a novel therapeutic target for oxalate-induced renal tubular ferroptosis"},{"pmid":"41800705","doi":"10.1080/21645515.2026.2638068","year":2026,"isNew":true,"title":"Real world incidence, predictors and outcomes of endocrine immune-related adverse events following immune checkpoint inhibitors"},{"pmid":"42257802","doi":"10.1007/s11912-026-01754-x","year":2026,"isNew":true,"title":"The Role of EZH2 ın Malıgnant Pleural Mesothelıoma and Beyond: Current Practıce and Future Perspectıves"},{"pmid":"42208538","doi":"10.1016/j.medj.2026.101149","year":2026,"isNew":true,"title":"Loss of tumor suppressor NF2 mediates resistance to CAR T cell and anti-PD-1 therapy: Strategies to restore immunotherapy sensitivity"}],"trialsShown":[{"nct":"NCT04104776","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas"},{"nct":"NCT00242723","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Evaluation of Cell Changes in Blood and Tissue in Cancers of the Lung, Esophagus and Lung Lining"},{"nct":"NCT03830229","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Long Term Follow-Up of Patients With Mesothelioma and Individuals With Germline Mutations in BAP1"},{"nct":"NCT05001880","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Chemotherapy With or Without Immunotherapy for Peritoneal Mesothelioma"},{"nct":"NCT04431024","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Prospective Evaluation of High Resolution Dual Energy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and Minimally Invasive Su"},{"nct":"NCT00715611","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Pleurectomy/Decortication (Neo) Adjuvant Chemotherapy and Intensity Modulated Radiation Therapy to the Pleura in Patients With Locally Advan"},{"nct":"NCT07234058","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Trial Assessing Fianlimab Plus Cemiplimab Plus Chemotherapy or Cemiplimab Plus Chemotherapy in Patients With Pleural Mesothelioma"},{"nct":"NCT06885697","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Anti-Mesothelin TNaive/SCM hYP218 (TNhYP218) CAR T Cells in Participants With Mesothelin-Expressing Solid Tumors Including Mesothelioma"}],"usage":{"input":8951,"output":5288},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"mesothelioma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"mesothelioma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41863079","PMID:42026803","PMID:41800759","PMID:42310940","PMID:42290218","PMID:42088834","PMID:41833934","PMID:41800705","PMID:42257802","PMID:42208538","NCT04104776","NCT00242723","NCT03830229","NCT05001880","NCT04431024","NCT00715611","NCT07234058","NCT06885697"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787150880659","cycle":12,"visit":1,"ts":"2026-08-19T14:48:00.659Z","cancer":{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"}},"control":true,"modelLabel":"SCIENCE","summary":"CML programme anchored on somatic BCR-ABL1 kinase inhibition, with the tractable frontier being residual-clone eradication — test orthosteric+allosteric (asciminib) combinations and TKI+venetoclax BCL2 co-targeting, while treating the USP28–BCR-ABL–IFITM3 resistance axis as unreplicated.","confidence":0.62,"notebook":"Visit 1 opens the CML programme. The pack is largely off-target (CRC NK biology P4, ccRCC ENPP3 P5, XPT review P3, hyperleukocytosis epidemiology P2, acute leukaemia in pregnancy P6) — noted and not built on. Four items carry CML signal.\n\nThe KG anchor needs correcting before anything else: BCR-ABL1 is the somatic disease-defining fusion [SOMATIC]; Monarch's \"causal ABL1\" is a germline-annotation artefact (ABL1 developmental syndrome), not CML predisposition [KNOWN]. RUNX1 [SOMATIC] mutations are blast-crisis/progression events, not chronic-phase drivers [KNOWN]. So the programme's spine is direct inhibition of an activated fusion kinase — the paradigm case — and the real open problems are (i) residual leukaemic stem cells that survive kinase inhibition, (ii) resistance beyond kinase-domain mutation, (iii) toxicity/stewardship.\n\nFour leads open. L1: dual targeting of the ATP site plus the myristoyl pocket. NCT03906292 (frontline asciminib + imatinib/nilotinib/dasatinib, phase 2) tests exactly the allosteric-plus-orthosteric pincer that should suppress single-site escape mutants and possibly deepen responses toward treatment-free remission [INFERRED]. Expected resistance: compound mutations spanning both sites, A337V/P465S-type myristoyl-pocket changes [KNOWN].\nL2: BCL2 co-dependence of the residual clone. NCT02689440 (dasatinib + venetoclax, early chronic phase) is the actionable readout; mechanistically BCR-ABL1→STAT5 sustains BCL2/MCL1, so LSCs may be primed but not killed by TKI alone [KNOWN/INFERRED]. Predicted escape: MCL1/BCL-xL switching. Window argument: venetoclax's normal-tissue liability is platelet-sparing but neutropenic; dose/duration-limited exposure is the design lever.\nL3: BCR-ABL1-independent resistance via the USP28–BCR-ABL–IFITM3 axis (PMID:42582078). IFITM3 knockout plus ponatinib in a ginger-lipid nanocarrier reversed K562R resistance in vitro and in xenografts. Single-laboratory, single resistant line, CRISPR cargo — nowhere near clinic; IFITM3 is an interferon-inducible antiviral effector in normal cells, so systemic loss has an infection-risk cost [INFERRED]. Kept as a low-confidence mechanistic lead worth independent replication, and it reframes ponatinib dose-limiting toxicity as a combination problem.\nL4 (stewardship/tox): nilotinib QTc prolongation via hERG was aggravated by curcumin and mitigated by nicorandil in telemetered rats (PMID:42474156) — a testable herb–drug interaction hypothesis, rat-only, no human data.\n\nNotebook negatives, so the desk never re-proposes them: the kinase-inactive ABL1 in-frame exon 4 deletion (p.L184_K274del) explains slow molecular response without conferring true resistance in 7 patients — do not treat it as grounds for TKI switching (PMID:42517020). Pregnancy CML remains an access/counselling problem, not a target (PMID:42604095).","leadChanges":[{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","level":"LEAD","status":"NEW","confidence":0.7},{"id":"L2","title":"BCL2 co-dependence of the TKI-persistent CML clone: dasatinib + venetoclax","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L3","title":"USP28–BCR-ABL–IFITM3 axis as a BCR-ABL-kinase-independent resistance node permitting lower-dose ponatinib","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L4","title":"Modifiable hERG-mediated QTc risk during nilotinib therapy (curcumin aggravates, nicorandil protects)","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Does frontline asciminib + ATP-site TKI (NCT03906292) actually increase MR4.5/TFR rates versus TKI alone, and what mutational spectrum emerges at relapse?","Has TKI + venetoclax produced measurable CD34+CD38- LSC clearance in any reported CML cohort, and does MCL1 upregulation explain non-responders?","Is the USP28-BCR-ABL-IFITM3 resistance axis reproduced by any independent group, and is USP28 pharmacologically inhibitable in CML models?","Which BCR-ABL1-kinase-independent LSC dependencies (STAT3, Wnt/beta-catenin, autophagy, PPARgamma/pioglitazone, arachidonate/interferon) have the strongest recent human data for repurposing?","What immune determinants (NK cell number/function, PD-1 on CD8 T cells) predict successful treatment-free remission, and can approved immunomodulators enhance it?","In blast-crisis transformation, do RUNX1 [SOMATIC] and other cooperating mutations define actionable non-ABL1 targets?"],"nextQueries":["\"chronic myeloid leukemia\" AND (\"leukemic stem cell\" OR \"leukaemic stem cell\") AND (persistence OR quiescence OR eradication) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"chronic myeloid leukemia\" AND (\"treatment-free remission\" OR discontinuation) AND (NK OR immune OR predictor) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(asciminib OR \"myristoyl pocket\" OR \"compound mutation\") AND \"BCR-ABL\" AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41956548","doi":"10.1080/21645515.2026.2654318","year":2026,"isNew":true,"title":"Second primary cancers following hematologic malignancies: Epidemiology, pathobiology and clinical management"},{"pmid":"41761903","doi":"10.1080/07853890.2026.2636347","year":2026,"isNew":true,"title":"Can hyperleukocytosis be caused by a non-hematologic condition? A 10-year retrospective tertiary-care center cohort study"},{"pmid":"41758201","doi":"10.1080/07853890.2026.2635774","year":2026,"isNew":true,"title":"Opportunities and challenges for cancer immunotherapy based on antigen cross-presentation"},{"pmid":"41742461","doi":"10.1080/2162402x.2026.2636311","year":2026,"isNew":true,"title":"TNF-α deficiency underlies NK cell dysfunction in colorectal cancer"},{"pmid":"41715305","doi":"10.1080/15384047.2026.2632995","year":2026,"isNew":true,"title":"ENPP3 drives ccRCC progression by cGAMP hydrolysis and STING-IFN suppression"},{"pmid":"41706499","doi":"10.1080/07853890.2026.2626141","year":2026,"isNew":true,"title":"Acute leukemia during pregnancy: a single center experience with 23 cases, 2012-2022 and literature review"},{"pmid":"42474156","doi":"10.36721/pjps.2026.39.10.277.1","year":2026,"isNew":true,"title":"Effects of curcumin and nicorandil on nilotinib-induced QT interval prolongation in rats: A telemetry-based study"},{"pmid":"42604095","doi":"10.1016/j.crwh.2026.e00846","year":2026,"isNew":true,"title":"Therapeutic challenges in the management of chronic myeloid leukemia during pregnancy: A report of two cases"},{"pmid":"42582078","doi":"10.3389/fphar.2026.1852978","year":2026,"isNew":true,"title":"Targeted nanoparticle-mediated Co-delivery of IFITM3 KO and ponatinib reverses TKI resistance in chronic myeloid leukemia"},{"pmid":"42517020","doi":"10.1002/jha2.70361","year":2026,"isNew":true,"title":"Characteristics of Clinical Response in Patients With Chronic Myeloid Leukemia With an &lt;i&gt;ABL1&lt;/i&gt; In-Frame Exon 4 Deletion: A Multicenter Retrospective Study"}],"trialsShown":[{"nct":"NCT02689440","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myeloge"},{"nct":"NCT06904066","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Mali"},{"nct":"NCT06566742","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Phase 2 Study Evaluating Olutasidenib in Patients With IDH1-mutated Clonal Cytopenia of Undetermined Significance and Lower-risk Myelodysp"},{"nct":"NCT03147612","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Ac"},{"nct":"NCT05600894","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloprolifer"},{"nct":"NCT03906292","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Frontline Asciminib Combination in Chronic Phase CML"},{"nct":"NCT07033598","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia"},{"nct":"NCT06001385","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Proph"}],"usage":{"input":9009,"output":4796},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"chronic myeloid leukemia\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"chronic myeloid leukemia\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41956548","PMID:41761903","PMID:41758201","PMID:41742461","PMID:41715305","PMID:41706499","PMID:42474156","PMID:42604095","PMID:42582078","PMID:42517020","NCT02689440","NCT06904066","NCT06566742","NCT03147612","NCT05600894","NCT03906292","NCT07033598","NCT06001385"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787150692617","cycle":11,"visit":1,"ts":"2026-08-19T14:44:52.617Z","cancer":{"key":"hepatocellular carcinoma","name":"hepatocellular carcinoma","mondo":{"id":"MONDO:0007256","name":"hepatocellular carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Open the HCC programme with ABHD17C-mediated depalmitoylation as a tractable lenvatinib-resistance modifier and GPC3-directed cellular/antigen immunotherapy as the lead immune axis, while formally retiring ablation-modality substitution and unpriced PD-1+VEGF first-line proposals.","confidence":0.42,"notebook":"Programme opens. The pack is thin on mechanism and heavy on care-delivery: I log three items as terminal-for-now so the desk never re-proposes them. Cryoablation offers a higher initial complete-ablation rate and less intraprocedural pain than RFA but no PFS or OS advantage, with I²>85% heterogeneity for the survival endpoints (PMID:42595456) — modality substitution in locoregional therapy is not a survival lever. Finotonlimab+bevacizumab beats sorafenib clinically but is not cost-effective at a $27,906/QALY threshold in China (ICER $51,899/QALY, negative INMB) (PMID:42505057), so future first-line PD-1+VEGF proposals must carry a price/duration argument, not just an HR. Canine OATP1A2 downregulation (PMID:42441046), Dutch SES surgical access (PMID:42358902), postoperative symptom networks (PMID:42358731) and a mitochondria-targeted chlorambucil prodrug (PMID:42518555, no HCC-specific target rationale) are off-programme.\n\nFour mechanistic threads are worth opening. First, ABHD17C: a serine hydrolase depalmitoylase whose overexpression blunts lenvatinib effect in cell lines, xenografts and patient-derived organoids, and whose scRNA-seq correlate is CD8-poor, exhaustion-high TME (PMID:42358063). [KNOWN] ABHD17 family enzymes depalmitoylate N-Ras and PSD95; loss of S-acylation cycling alters membrane RAS/MAPK output, which is a credible route to TKI escape and worth testing directly. [SPECULATIVE] ABHD17 inhibition (palmostatin-class tool compounds) plus lenvatinib. Second, FAM117B–NAT10 reciprocal stabilisation feeding JAK–STAT3 (PMID:42595291) — NAT10 is the only ac4C writer [KNOWN] and is chemically tractable (remodelin); the actionable test is whether NAT10 loss phenocopies FAM117B knockdown and whether a JAK1/2 inhibitor is epistatic. Third, antigen-directed immunotherapy: GPC3 is oncofetal and largely absent from adult hepatocytes [KNOWN], making GPC3 CAR-T (AZD5851, NCT06084884) a real-window asset, and a carrier-free fluorinated-CpG/neoantigen nanovaccine expanded antigen-specific CD8/memory T cells in Hepa1-6 (PMID:42491306) — antigen escape and GPC3-low subclones are the named resistance route. Fourth, PD-L1×VEGF bispecific pumitamig ± ipilimumab first-line (NCT07291076) is the field's attempt to compress atezo/bev+CTLA-4 into one axis; the P3 economics make its differentiation question sharper. Sorafenib resistance via PI3K/AKT-driven ABCG2 efflux (PMID:42599637) is mechanistically plausible but the agent is a flavonoid with CETSA/DARTS-only target validation; I open it at low confidence and will kill it unless independent PI3K-pathway-plus-TKI data appear.\n\nUntouched: the KG anchors carry the two most druggable HCC lesions — DNAJB1–PRKACA fusion [SOMATIC] in fibrolamellar and AXIN1/CTNNB1 Wnt activation [SOMATIC in tumours, some germline reports] with its documented immune-exclusion phenotype. No pack citation supports either yet; both become next-visit queries.","leadChanges":[{"id":"L1","title":"ABHD17C depalmitoylase as a lenvatinib-resistance modifier in HCC","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L2","title":"GPC3/neoantigen-directed antigen-specific immunotherapy for HCC","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L3","title":"FAM117B-NAT10 ac4C loop driving JAK-STAT3 as an epitranscriptomic target","level":"LEAD","status":"NEW","confidence":0.28},{"id":"L4","title":"PD-L1xVEGF bispecific (pumitamig) +/- ipilimumab as first-line HCC, priced against existing IO+VEGF","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L5","title":"PI3K/AKT-driven ABCG2 efflux as a reversible sorafenib-resistance mechanism","level":"LEAD","status":"NEW","confidence":0.2}],"unverifiedCitations":0,"openQuestions":["Is the ABHD17C lenvatinib-resistance effect hydrolase-activity dependent, and which palmitoylated substrates (N-RAS? MET? EGFR?) mediate it — i.e. is there a druggable enzyme step rather than an expression biomarker?","Does ABHD17C-high status also cause the CD8-poor microenvironment it correlates with, making ABHD17C inhibition a TKI-plus-IO sensitiser in immunocompetent models?","For the DNAJB1-PRKACA fusion [SOMATIC] in fibrolamellar HCC, what current evidence exists for direct PKA-catalytic or downstream (e.g. Aurora, mTOR) inhibition, and can the desk cite it?","Does AXIN1/CTNNB1-mutant [SOMATIC] Wnt activation predict resistance to PD-L1xVEGF bispecifics as it does to PD-1+VEGF, and is there a tractable co-target (Porcupine, TCF/beta-catenin, TEAD)?","In GPC3-directed cell therapy, what is the observed on-target hepatic toxicity and the GPC3 expression floor for activity, and do GPC3-negative subclones drive relapse?","Are TSC1/TSC2-altered [SOMATIC] HCCs an mTORC1-inhibitor-sensitive subset with any recent clinical or organoid evidence?"],"nextQueries":["(\"DNAJB1-PRKACA\" OR \"fibrolamellar\") AND (inhibitor OR target OR \"protein kinase A\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"hepatocellular carcinoma\") AND (CTNNB1 OR AXIN1 OR \"Wnt\") AND (\"immune evasion\" OR \"immunotherapy resistance\" OR \"checkpoint\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"hepatocellular carcinoma\") AND (palmitoylation OR depalmitoylation OR ZDHHC OR ABHD17) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42595456","doi":"10.1080/02656736.2026.2713200","year":2026,"isNew":true,"title":"Cryoablation versus radiofrequency ablation for hepatocellular carcinoma: a systematic review and meta-analysis"},{"pmid":"42518555","doi":"10.1016/j.pscia.2026.100132","year":2026,"isNew":true,"title":"A visualizable mitochondrial-targeted Chlorambucil prodrug for enhancing anti-hepatoma efficacy"},{"pmid":"42505057","doi":"10.1080/21645515.2026.2707849","year":2026,"isNew":true,"title":"Cost-effectiveness of finotonlimab plus bevacizumab versus sorafenib as first-line therapy in unresectable hepatocellular carcinoma in China"},{"pmid":"42491306","doi":"10.1016/j.ijpx.2026.100606","year":2026,"isNew":true,"title":"A Self-assembly Carrier-Free Nanovaccine based on Fluorinated CpG and Neoantigen Peptides for Hepatocellular Carcinoma Immunotherapy"},{"pmid":"42441046","doi":"10.1002/vro2.70038","year":2026,"isNew":true,"title":"OATP1A2 mRNA downregulation in canine hepatocellular carcinoma"},{"pmid":"42358902","doi":"10.1016/j.puhip.2026.100818","year":2026,"isNew":true,"title":"Impact of COVID-19 pandemic on surgical cancer care disparities according to socioeconomic status"},{"pmid":"42358731","doi":"10.1016/j.apjon.2026.100960","year":2026,"isNew":true,"title":"Longitudinal symptom dynamics in postoperative patients with liver cancer: A cross-lagged panel network analysis"},{"pmid":"42358063","doi":"10.1080/15384047.2026.2693350","year":2026,"isNew":true,"title":"ABHD17C regulates the efficacy of lenvatinib in suppressing hepatocellular carcinoma"},{"pmid":"42595291","doi":"10.1016/j.yexcr.2026.115151","year":2026,"isNew":true,"title":"FAM117B Promotes Malignant Progression of Hepatocellular Carcinoma by Forming a Bidirectional Regulatory Loop with NAT10 and Activating the JAK-STAT3 Pathway"},{"pmid":"42599637","doi":"10.1007/s12033-026-01588-9","year":2026,"isNew":true,"title":"Tectochrysin Attenuates the Chemoresistance of Hepatocellular Carcinoma Cells to Sorafenib by Inhibiting the PI3K/AKT Signaling Pathway and ABCG2 Expression"}],"trialsShown":[{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT06084884","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Phase I/II Study to Evaluate AZD5851 in GPC3+ Advanced/Recurrent Hepatocellular Carcinoma"},{"nct":"NCT06979219","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Streamlining Radioembolization for Small HCC"},{"nct":"NCT06764316","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"A First-in-human Study to Learn About the Safety of BAY 3547926 and How Well it Works in Participants With Advanced Liver Cancer"},{"nct":"NCT07727759","phase":"n/a","status":"RECRUITING","isNew":true,"title":"CT Volumetry and Hepatic Vascular Deformation Mapping to Predict Post-Hepatectomy Liver Failure"},{"nct":"NCT07291076","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study to Evaluate the Safety and Tolerability of Pumitamig Alone or In Combination With Ipilimumab in Participants With First-Line Advance"},{"nct":"NCT07620574","phase":"phase 3","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Long-Term Extension Study for Participants Previously Enrolled in an Exelixis-Sponsored Study"},{"nct":"NCT06944483","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Same-day Radioembolization for Large HCC"}],"usage":{"input":9372,"output":6634},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"hepatocellular carcinoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"hepatocellular carcinoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42595456","PMID:42518555","PMID:42505057","PMID:42491306","PMID:42441046","PMID:42358902","PMID:42358731","PMID:42358063","PMID:42595291","PMID:42599637","NCT07636785","NCT06084884","NCT06979219","NCT06764316","NCT07727759","NCT07291076","NCT07620574","NCT06944483"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787150479623","cycle":10,"visit":1,"ts":"2026-08-19T14:41:19.623Z","cancer":{"key":"gastric cancer","name":"gastric cancer","mondo":{"id":"MONDO:0001056","name":"gastric cancer"}},"control":false,"modelLabel":"SCIENCE","summary":"Open the gastric programme on chemoresistance nodes: prioritise RPRD1B(CREPT)-TOPBP1-driven DDR amplification as a 5-FU-resistance target testable with PARP1-selective/ATR combinations in intramuscular PDX models.","confidence":0.42,"notebook":"**Visit 1 — programme initialisation, gastric cancer.** Pack is noisy: P4, P5, P6, P8 are off-target (Dutch SES surgical access, liver-cancer symptom networks, DHFR antibacterials, gynaecologic ferroptosis) and are logged as non-evidence for this desk. P7 (MSS colorectal chemoimmunotherapy, OS HR 0.58, PMID:42322272) is cross-indication only; it is mechanistically congruent with the gastric MSS question being tested by PARAMUNE (nivolumab + paclitaxel, NCT06203600) but I will not build a lead on borrowed histology this visit. P3 (PMID:42466845) is infrastructure, not a hypothesis: intramuscular PDX engraftment 71.7% with WES-defined fast-growth genes (KMT2C, APOB, CDK12, MSH2) vs slow (TP53, CHD3, TET2) — CDK12 and MSH2 enrichment in aggressive grafts is a DDR/immunogenicity hook worth pursuing [INFERRED]. I adopt this platform as the preferred in vivo test bed for every lead below.\n\nFour leads open, one exploratory. The strongest mechanistic novelty is RPRD1B (CREPT) transcriptionally driving TOPBP1 via Pol II recruitment to confer 5-FU resistance, reversible by AAV-delivered anti-RPRD1B (PMID:42542502). This makes GC chemoresistance a DDR-amplification state, which is directly actionable with the ATR/PARP axis: AZD5305 (PARP1-selective) is already partnered with paclitaxel, carboplatin and T-DXd in NCT04644068, an obvious combinatorial read-out. Therapeutic-window argument: TOPBP1/ATR signalling is required in normal proliferating crypt and marrow cells [KNOWN], so I favour lowering the RPRD1B input rather than blocking TOPBP1 itself; RPRD1B is low in most adult tissues [KNOWN, needs verification]. Second: SNHG15/miR-451a/CAV1 rewires fatty-acid β-oxidation to sustain oxaliplatin resistance (PMID:41972796) — a metabolic, repurposable node (CPT1 inhibition; ranolazine/etomoxir-class) [SPECULATIVE]. Third: the YWHAZ(14-3-3ζ)–G3BP1 stress-granule module retaining Bax in cytoplasm (PMID:42507757) predicts apoptotic priming defects and BH3-mimetic/stress-granule combination sensitisation; evidence is review-grade only, so this enters at low confidence. Fourth, distinct axis: chemoprevention — SIRT1 declines progressively along the H. pylori cascade, and resveratrol/lactoferrin/fucoidan nanocarriers eradicate H. pylori while reversing intestinal metaplasia via SIRT1-dependent autophagy (PMID:42569414); relevant to CDH1 [GERMLINE] carriers and IL1B/IL1RN [SOMATIC/correlated] inflammatory anchors.\n\nGermline discipline note: MUTYH [GERMLINE] is base-excision, not homologous-recombination, repair; PARP-sensitivity in MUTYH carriers is unproven, and NCT04550494 (talazoparib in DNA-repair variants) is the right place to check rather than assume. Recorded so the desk never re-proposes MUTYH→PARPi as settled. KRAS [causal anchor] G12D is now degradable (ARV-806, NCT07023731) — no gastric-specific data in pack; parked as a watch item, not a lead. AZD6750 target undisclosed in pack (NCT07115043); do not speculate.","leadChanges":[{"id":"L1","title":"RPRD1B(CREPT)-TOPBP1 axis as the druggable node of 5-FU resistance in gastric cancer","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"CAV1-driven fatty-acid beta-oxidation as a metabolic vulnerability in oxaliplatin-resistant gastric cancer","level":"LEAD","status":"NEW","confidence":0.33},{"id":"L3","title":"YWHAZ(14-3-3zeta)-G3BP1 stress-granule module sequesters Bax and sets apoptotic resistance in gastric cancer","level":"LEAD","status":"NEW","confidence":0.25},{"id":"L4","title":"SIRT1 restoration plus H. pylori eradication to reverse precancerous intestinal metaplasia","level":"LEAD","status":"NEW","confidence":0.3},{"id":"L5","title":"Biomarker question, not yet a lead: PARP inhibitor sensitivity in DNA-repair-altered gastric cancer including MUTYH carriers","level":"LEAD","status":"NEW","confidence":0.2}],"unverifiedCitations":0,"openQuestions":["Is RPRD1B expression low enough in normal gastric/marrow/crypt epithelium to give a therapeutic window, and does RPRD1B loss sensitise GC to ATR inhibitors and PARP1-selective agents as well as to 5-FU?","Does the FAO/CAV1 oxaliplatin-resistance axis replicate in independent GC models, and is CPT1 inhibition additive with platinum in PDX at tolerable cardiac exposure?","Is there gastric-specific evidence that the G3BP1-14-3-3zeta complex (not total 14-3-3) governs Bax localisation and BH3-mimetic sensitivity?","Does chemoimmunotherapy benefit in MSS colorectal cancer (PMID:42322272) extend to MSS/immune-cold gastric cancer, and what does PARAMUNE (NCT06203600) predict for taxane+PD-1 in that subset?","Which gastric molecular subsets are enriched in CDK12/MSH2 alterations (fast-growing PDX signature), and do they define a PARP- or ICI-tractable stratum?","Is SIRT1 loss a reproducible stage biomarker of H. pylori-driven intestinal metaplasia in independent human cohorts, and can eradication plus SIRT1 agonism reverse OLGIM stage?"],"nextQueries":["(\"gastric cancer\" OR \"gastric adenocarcinoma\") AND (RPRD1B OR CREPT OR TOPBP1 OR \"ATR inhibitor\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"gastric cancer\" AND (\"fatty acid oxidation\" OR CPT1A OR CAV1 OR \"lipid metabolism\") AND (oxaliplatin OR cisplatin OR resistance) AND SRC:MED","\"gastric cancer\" AND (\"microsatellite stable\" OR \"immune cold\") AND (\"chemoimmunotherapy\" OR \"PD-1\" OR nivolumab OR paclitaxel) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"papersShown":[{"pmid":"42569414","doi":"10.1016/j.bioactmat.2026.07.030","year":2026,"isNew":true,"title":"Eradicating &lt;i&gt;Helicobacter pylori&lt;/i&gt; and reversing precancerous intestinal metaplasia by gastric epithelial cells-localizable oral nanomedicines"},{"pmid":"42507757","doi":"10.1080/15384047.2026.2710413","year":2026,"isNew":true,"title":"Stress-specific 14-3-3-client modules in digestive cancers: an evidence-graded review of adaptive survival and therapy resistance"},{"pmid":"42466845","doi":"10.1080/07853890.2026.2680340","year":2026,"isNew":true,"title":"Intramuscular patient-derived xenografts achieve high engraftment rates in gastric cancer: implications for pharmacodynamic testing and genomic biomarker discovery"},{"pmid":"42358902","doi":"10.1016/j.puhip.2026.100818","year":2026,"isNew":true,"title":"Impact of COVID-19 pandemic on surgical cancer care disparities according to socioeconomic status"},{"pmid":"42358731","doi":"10.1016/j.apjon.2026.100960","year":2026,"isNew":true,"title":"Longitudinal symptom dynamics in postoperative patients with liver cancer: A cross-lagged panel network analysis"},{"pmid":"42343149","doi":"10.1080/14756366.2026.2690351","year":2026,"isNew":true,"title":"Design, synthesis, and antibacterial activity study of pyrroloquinazoline diamine derivatives"},{"pmid":"42322272","doi":"10.1080/2162402x.2026.2671491","year":2026,"isNew":true,"title":"Pooled analysis of 2 clinical trials of first-line chemoimmunotherapy for metastatic microsatellite stable colorectal cancer MEDITREME and METIMMOX studies"},{"pmid":"42318797","doi":"10.1080/07853890.2026.2688328","year":2026,"isNew":true,"title":"Research progress of ferroptosis in gynecological diseases"},{"pmid":"41972796","doi":"10.1158/1541-7786.mcr-25-0154","year":2026,"isNew":true,"title":"The SNHG15/miR-451a/Caveolin-1 Axis Promotes Oxaliplatin Resistance in Gastric Cancer Cells by Regulating Fatty Acid β-Oxidation"},{"pmid":"42542502","doi":"10.1007/s13402-026-01227-0","year":2026,"isNew":true,"title":"Targeting RPRD1B overcomes chemoresistance in gastric cancer by suppressing the TOPBP1-mediated DNA damage repair pathway"}],"trialsShown":[{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT07646574","phase":"n/a","status":"ENROLLING_BY_INVITATION","isNew":true,"title":"Non-surgical Management After NIT for dMMR/MSI-H GC"},{"nct":"NCT06203600","phase":"phase 2/phase 3","status":"RECRUITING","isNew":true,"title":"Adding Nivolumab to Usual Treatment for People With Advanced Stomach or Esophageal Cancer, PARAMUNE Trial"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04550494","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations"},{"nct":"NCT07001748","phase":"phase 2/phase 3","status":"RECRUITING","isNew":true,"title":"Testing the Addition of Paclitaxel Administered Into the Abdominal Cavity Combined With Chemotherapy for Patients With Gastric Cancer Spread"},{"nct":"NCT04644068","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies"},{"nct":"NCT05203627","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Telehealth for the Self-Management of Dietary Quality of Life in Patients After Stomach Cancer Surgery"}],"usage":{"input":9205,"output":6532},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"gastric cancer\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"gastric cancer\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42569414","PMID:42507757","PMID:42466845","PMID:42358902","PMID:42358731","PMID:42343149","PMID:42322272","PMID:42318797","PMID:41972796","PMID:42542502","NCT07115043","NCT07646574","NCT06203600","NCT07023731","NCT04550494","NCT07001748","NCT04644068","NCT05203627"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787150269771","cycle":9,"visit":1,"ts":"2026-08-19T14:37:49.771Z","cancer":{"key":"esophageal cancer","name":"esophageal cancer","mondo":{"id":"MONDO:0007576","name":"esophageal cancer"}},"control":false,"modelLabel":"SCIENCE","summary":"Prioritise KLF4 re-induction as a pharmacologically reversible MHC-I/antigen-presentation defect that resensitises esophageal cancer to PD-1 blockade, with allosteric SHP2 inhibition (BGC1201-class) plus RTK blockade and Lactobacillus-D-lactate/STAT3-K631-lactylation-gated ferroptosis sensitisation ","confidence":0.46,"notebook":"**Visit 1 — programme opened.** The pack is mostly noise (perioperative opioid protocol P1, discharge-readiness qualitative work P6, generic CRBN-ligand chemistry P2, GSH/H₂S review P5, PDT review P8 — the last only confirming what is [KNOWN], that PDT is established for early/obstructive esophageal lesions). Three items carry real mechanistic weight, and the KG anchors are largely unhelpful: DCC, LZTS1, WWOX, TGFBR2, RNF6 are [GERMLINE]-leaning tumour-suppressor/fragile-site loci — not directly druggable; only ERBB2 [SOMATIC] is an actionable node, and P10 explicitly concedes that targeted therapy in EC has lagged immunotherapy, with TKIs, CDK4/6, PI3K–AKT–mTOR and epigenetic agents still aspirational.\n\nLead A (highest value): KLF4 loss as a *reversible* antigen-presentation defect. P9 (PMID:42493491) reports that KLF4 downregulation closes chromatin at MHC-I loci, blocks enhanceosome assembly, depletes CD8⁺ infiltration, drives PD-1 resistance in allografts, and that pharmacological KLF4 induction restores presentation and rescues PD-1 efficacy. This is a defect-restoration hypothesis, not a new target class, and it slots directly onto existing backbones (NCT06780111 KEYMAKER-U06 pembrolizumab combinations; NCT06203600 nivolumab/paclitaxel). The abstract does not name the inducing agent — that is the first thing to resolve; [KNOWN] HDAC/BET inhibitors and APTO-253 raise KLF4, but attributing the P9 result to any of them is [SPECULATIVE]. Therapeutic window argument: KLF4 is a normal squamous-differentiation factor, so induction is pro-differentiation rather than gain-of-function, but KLF4 is context-dependently oncogenic in some epithelia [KNOWN].\n\nLead B: allosteric SHP2 inhibition. BGC1201 (PMID:42388521) is nanomolar on SHP2-WT, low hERG, spares HUVEC, and gives dose-dependent growth inhibition in the ESCC line KYSE-520 with on-target p-ERK suppression in tumour. SHP2 is the convergence node for EGFR/ERBB2/FGFR signalling, the one anchor gene with somatic relevance. Single-agent activity in one xenograft is weak evidence; the real hypothesis is SHP2i + EGFR/ERBB2 blockade in RTK-amplified ESCC. Expected resistance: RAS-GTP reloading, MAPK reactivation via MYC/CCND1, PTPN11 pocket mutations. Window: SHP2 is required for haematopoiesis and cytokine signalling — thrombocytopenia/edema are the on-target liabilities [KNOWN].\n\nLead C: microbe-driven ferroptosis resistance. P4 (PMID:42281240) defines *L. reuteri* D-lactate → STAT3 K631 lactylation → GPX4/FTH1 upregulation, genetically validated by *ldhD* mutant and STAT3-K631R. Predicts that Lactobacillus-high ESCC is GPX4-inhibitor/cyst(e)ine-deprivation sensitive only after decolonisation — a testable stratification biomarker.\n\nAnti-lead recorded: TFPI2 (PMID:42216563) is bidirectional across the metastatic cascade; do not nominate it as a target.","leadChanges":[{"id":"L1","title":"KLF4 re-induction to reopen MHC-I chromatin and rescue PD-1 blockade in esophageal cancer","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L2","title":"Allosteric SHP2 inhibition as the drug-tractable node downstream of ERBB2/EGFR in ESCC","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L3","title":"Decolonisation-gated ferroptosis sensitisation: intratumour Lactobacillus D-lactate/STAT3-K631 lactylation as a resistance switch","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L4","title":"B7-H3-directed ADC plus PD-1 blockade in esophageal cancer","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Which pharmacological agent induced KLF4 in PMID:42493491, at what exposure, and is the MHC-I/CD8 rescue strictly KLF4-dependent (KLF4-null and B2M-null controls)?","Does KLF4-low / MHC-I-low status prospectively predict PD-1 failure in esophageal cohorts, and is it enriched in ESCC vs EAC?","Is there a genotype that confers SHP2 dependency in esophageal cancer (EGFR/ERBB2 amplification, NF1 loss, KEAP1/NFE2L2), and does SHP2i + anti-ERBB2/EGFR give synergy rather than additivity?","What fraction of ESCC tumours carry Lactobacillus/D-lactate-high niches, and does decolonisation or ldhD blockade restore GPX4-inhibitor or chemoradiation-induced ferroptosis in immunocompetent models?","Is STAT3 K631 lactylation detectable as a clinical-grade biomarker, and does it overlap with the KLF4-low immune-cold phenotype?","What is B7-H3/CD276 prevalence and intensity in ESCC vs EAC, and does it co-segregate with antigen-presentation loss?"],"nextQueries":["(\"KLF4\" AND (\"MHC class I\" OR \"antigen presentation\" OR \"immune evasion\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"esophageal squamous cell carcinoma\" AND (SHP2 OR PTPN11 OR \"ERBB2 amplification\") AND (inhibitor OR combination OR resistance)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","((lactylation OR \"D-lactate\" OR \"intratumor microbiota\") AND (ferroptosis OR GPX4) AND (esophageal OR ESCC)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42525825","doi":"10.1080/07853890.2026.2707864","year":2026,"isNew":true,"title":"Protocol for a cohort study: evaluating the effect of neoadjuvant immunochemotherapy on intraoperative remifentanil consumption during IoC2-guided anesthesia in elderly patients wi"},{"pmid":"42418534","doi":"10.1080/14756366.2026.2700038","year":2026,"isNew":true,"title":"Evolving CRBN ligands enhance the drug-like properties of protein degraders"},{"pmid":"42388521","doi":"10.1016/j.pscia.2026.100128","year":2026,"isNew":true,"title":"BGC1201: A potent allosteric SHP2 inhibitor with broad antitumor activity in lung, pancreatic, and esophageal cancer xenografts"},{"pmid":"42281240","doi":"10.1080/19490976.2026.2685912","year":2026,"isNew":true,"title":"Intratumor &lt;i&gt;Lactobacillus&lt;/i&gt; drives ferroptosis resistance via D-lactate-STAT3 K631 lactylation in esophageal squamous cell carcinoma"},{"pmid":"42275298","doi":"10.1080/13510002.2026.2687238","year":2026,"isNew":true,"title":"Significance of GSH and H&lt;sub&gt;2&lt;/sub&gt;S regulation for cancer: an intricate interplay between diet, microbiota, metabolic reprogramming, and immune health"},{"pmid":"42265983","doi":"10.1080/17482631.2026.2686490","year":2026,"isNew":true,"title":"A qualitative study exploring discharge readiness experiences among patients with esophageal cancer undergoing esophagectomy"},{"pmid":"42216563","doi":"10.1080/15384047.2026.2678642","year":2026,"isNew":true,"title":"TFPI2 in tumor metastasis: a double-edged sword with clinical implications"},{"pmid":"42157432","doi":"10.4103/mgr.medgasres-d-25-00315","year":2026,"isNew":true,"title":"Photodynamic therapy: research progress and paradigm evolution from mechanism innovation to clinical breakthrough in cancers"},{"pmid":"42493491","doi":"10.1038/s41392-026-02854-7","year":2026,"isNew":true,"title":"Krüppel-like factor 4 downregulation during esophageal cancer formation facilitates immune evasion and impairs immunotherapy"},{"pmid":"42425097","doi":"10.1097/cm9.0000000000004194","year":2026,"isNew":true,"title":"Molecular mechanisms, current therapeutics, and emerging strategies in esophageal cancer: A comprehensive review"}],"trialsShown":[{"nct":"NCT06203600","phase":"phase 2/phase 3","status":"RECRUITING","isNew":true,"title":"Adding Nivolumab to Usual Treatment for People With Advanced Stomach or Esophageal Cancer, PARAMUNE Trial"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT06748911","phase":"NA","status":"RECRUITING","isNew":true,"title":"Navicam for Detection of Barrett's Esophagus"},{"nct":"NCT00242723","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Evaluation of Cell Changes in Blood and Tissue in Cancers of the Lung, Esophagus and Lung Lining"},{"nct":"NCT07222657","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Liquid Nitrogen Spray Cryotherapy Prior to Neoadjuvant Systemic Therapy in Esophageal Adenocarcinoma"},{"nct":"NCT07182149","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"A Phase 1 Study of NRM-823 in Participants With Locally Advanced or Metastatic Refractory Solid Tumors"},{"nct":"NCT07217171","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"A Study Evaluating the Safety, Efficacy, and Pharmacokinetics (PK) of EVOLVE104 in Participants With Advanced Urothelial and Squamous Cell C"},{"nct":"NCT06780111","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Substudy 06E: Umbrella Study of Combination Therapies in Esophageal Cancer (MK-3475-06E/KEYMAKER-U06)"}],"usage":{"input":8413,"output":6233},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"esophageal cancer\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"esophageal cancer\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42525825","PMID:42418534","PMID:42388521","PMID:42281240","PMID:42275298","PMID:42265983","PMID:42216563","PMID:42157432","PMID:42493491","PMID:42425097","NCT06203600","NCT07023731","NCT06748911","NCT00242723","NCT07222657","NCT07182149","NCT07217171","NCT06780111"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787150062060","cycle":8,"visit":2,"ts":"2026-08-19T14:34:22.060Z","cancer":{"key":"small cell lung cancer","name":"small cell lung cancer","mondo":{"id":"MONDO:0008433","name":"small cell lung carcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Relapsed SCLC generates a YAP1-positive drug-tolerant persister state that loses DLL3/SEZ6 and gains B7-H3/TROP2, so DLL3-engager programmes should be designed with paired-biopsy antigen mapping and pre-planned B7-H3/TROP2 ADC coverage, plus CD2-based costimulation to widen the engager dose window i","confidence":0.55,"notebook":"**Visit 2 notebook.**\n\nThe pack's one primary research article does the real work. PMID:42019833 shows that YAP1 is essentially absent from treatment-naive pure SCLC and instead emerges at relapse as a drug-tolerant persister population — senescent, stem-like, plastic — that abandons SCLC identity for an LCNEC-like state and, critically, **loses DLL3 and SEZ6 while gaining B7-H3 and TROP2**. This answers open question 1 in a specific and unwelcome way: the dominant escape route from DLL3-directed therapy is predicted to be lineage/state drift with coordinate antigen loss, not simple DLL3 downregulation, and it is not a subtype that exists to be selected for at baseline — it is generated by treatment. It also answers question 3 without needing a separate hunt: the engager-escape state has its own surfaceome, and B7-H3 and TROP2 are the covering antigens. Three concurrent reviews (PMID:41411619, PMID:41824576, PMID:41220942) frame the same plasticity axis as epigenetically encoded, which is the only stated handle for reversibility [INFERRED from review-level claims; no SCLC-specific pharmacological reversal data in this pack].\n\nL1 moves to CANDIDATE. New, independent literature supports it in two directions: PMID:42271190 states tarlatamab is the only classical CD3 engager with marketing approval in solid tumours — external validation of the modality, not just of two trials — while PMID:42019833 defines its resistance ceiling. Confidence rises only modestly (0.6→0.62) because the same paper that validates the axis predicts antigen escape.\n\nTwo new leads. L3: sequence B7-H3- or TROP2-directed ADCs against the post-engager YAP1-emergent state, with paired-biopsy/CTC antigen mapping as the enabling assay rather than a bolt-on — this is a scheduling hypothesis, and its failure mode is heterogeneous coexistence of DLL3+ and YAP1+ compartments requiring concurrent, not sequential, coverage. L4: costimulatory rescue of the engager window. PMID:42271190 shows a non-blocking CD2 agonist bispecific restores cytotoxicity of a sub-efficacious CD3-engager dose, compensates for tumour CD58 loss, and recruits CD28-negative CD8 T cells prevalent in elderly patients — mechanistically the most relevant proposal yet for the PS 2/fitness-reserve question (NCT07203053), where cytokine toxicity caps dose. 4-1BB agonists (PMID:41645963) are the alternative costimulatory axis with a worse hepatotoxicity history [KNOWN].\n\nNotebook negatives: nothing in this pack addresses RB1/TP53 synthetic lethality (question 4 remains unanswered and un-citable); AZD6750's target is still undisclosed in NCT07115043; PMID:42163062 (tebentafusp) and PMID:41427927 are off-target pack noise. PMID:41869709 nominates Bcl-2 in cisplatin resistance — review-level only, parked, not a lead.\n\nL2 (belinostat/UGT1A1) unchanged, no new evidence.","leadChanges":[{"id":"L1","title":"DLL3xCD3 T-cell engagers as lineage-restricted therapy in neuroendocrine SCLC","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.62},{"id":"L3","title":"Sequenced B7-H3 / TROP2 ADC coverage of the YAP1-emergent post-engager escape state","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L4","title":"CD2-based tumour-dependent costimulation to widen the DLL3 engager dose window in unfit SCLC","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L5","title":"Epigenetic blockade of subtype plasticity to prevent, not chase, antigen loss","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Is the YAP1-positive persister state (PMID:42019833) pharmacologically preventable or reversible, or only avoidable by antigen switching - and does any citable SCLC experiment show restoration of DLL3/SEZ6 after LSD1/EZH2 or Notch modulatio","In relapsed SCLC, do DLL3+ and YAP1+/B7-H3+ compartments coexist spatially in the same lesion (mandating concurrent DLL3-engager + B7-H3 ADC) or replace each other temporally (permitting sequencing)?","Does the NCT07203053 PS 2 read-out show efficacy loss or toxicity-driven discontinuation - i.e. is the engager ceiling in unfit patients set by cytokine toxicity/T-cell fitness (CD28-null, CD58 loss) or by tumour biology?","What is the CD58 expression status of SCLC and of the YAP1-emergent state, and is CD58 loss an independent engager-resistance route in this disease?","Is there any citable synthetic-lethal handle for RB1/TP53-null SCLC (Aurora A/B, CHK1, WEE1, PARP+temozolomide) - still wholly unaddressed after two visits?","What is AZD6750's molecular target, and does NCT07115043 (with rilvegostomig) enrol SCLC at all?"],"nextQueries":["(\"SCLC\" OR \"small cell lung\") AND (\"B7-H3\" OR CD276 OR \"ifinatamab\" OR TROP2 OR \"sacituzumab\") AND (relapsed OR resistance OR \"antibody-drug conjugate\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"small cell lung\" AND (LSD1 OR KDM1A OR EZH2 OR \"Notch\") AND (\"DLL3\" OR plasticity OR \"subtype switch\" OR persister)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","((\"RB1\" AND \"TP53\") AND (\"synthetic lethal\" OR AURKA OR AURKB OR CHK1 OR WEE1 OR \"PARP\") AND (\"small cell lung\" OR SCLC)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41645963","doi":"10.1080/19420862.2026.2622746","year":2026,"isNew":true,"title":"Expanding the horizons of cancer therapy with next-generation 4-1BB agonists: a review of molecular and clinical strategies to maximize efficacy and ensure safety"},{"pmid":"41869709","doi":"10.1080/07853890.2025.2601401","year":2026,"isNew":true,"title":"Application and mechanistic research of novel therapeutic strategies in cisplatin-resistant small cell lung cancer"},{"pmid":"41411619","doi":"10.1158/0008-5472.can-25-1483","year":2026,"isNew":true,"title":"Small Cell Lung Cancer Classification: Unraveling Heterogeneity to Enable Personalized Treatments"},{"pmid":"41824576","doi":"10.1126/sciadv.aea6225","year":2026,"isNew":true,"title":"Subtype-specific dependencies and therapeutic opportunities in small cell lung cancer"},{"pmid":"42019833","doi":"10.1016/j.jtho.2026.103730","year":2026,"isNew":true,"title":"YAP1 Defines an Emergent, Plastic Population of Relapsed SCLC"},{"pmid":"41220942","doi":"10.3389/fonc.2025.1657441","year":2025,"isNew":true,"title":"Intratumoral heterogeneity and potential treatment strategies in small cell lung cancer"},{"pmid":"42271190","doi":"10.1080/19420862.2026.2684378","year":2026,"isNew":true,"title":"Combination therapy with a novel CD2-targeted costimulatory bispecific antibody overcomes limitations of CD3 T cell engager treatment for solid tumors"},{"pmid":"42163062","doi":"10.1080/21645515.2026.2675068","year":2026,"isNew":true,"title":"Tebentafusp (IMCgp100), a first in class immune-mobilizing monoclonal T-cell receptors against cancer (ImmTAC) for HLA-A*02:01 positive uveal melanoma: Product review"},{"pmid":"41700001","doi":"10.1080/2162402x.2026.2632421","year":2026,"isNew":true,"title":"Trial Watch - bispecific T cell engagers and higher-order multispecific immunotherapeutics"},{"pmid":"41427927","doi":"10.1080/19490976.2025.2606477","year":2026,"isNew":true,"title":"Impact of gut microbiota on host stem cells across the gastrointestinal tract"}],"trialsShown":[{"nct":"NCT07774520","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Randomized Study to Evaluate the Efficacy of a Reduced Starting Dose of Lazertinib (Leclaza) and Preemtive Magnesium Supplementation to Pr"},{"nct":"NCT07203053","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A Trial of Tarlatamab in Patients With Pretreated Extensive-stage Small Cell Lung Cancer (ES-SCLC) and ECOG PS 2"},{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT04181060","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"Osimertinib With or Without Bevacizumab as Initial Treatment for Patients With EGFR-Mutant Lung Cancer"},{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT07472517","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"DAREON ® -Lung-1: A Study in People With Advanced Small Cell Lung Cancer to Compare Obrixtamig Plus Atezolizumab, Carboplatin, and Etoposide"},{"nct":"NCT06194448","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"To Evaluate the Efficacy/Safety of Osimertinib Prior to CRT and Maintenance of it With Stage III, Unresectable NSCLC With EGFR Mutations"},{"nct":"NCT06406465","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"A UGT1A1 Genotype-Directed Study of Belinostat Pharmacokinetics and Toxicity"}],"usage":{"input":9487,"output":6467},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"DLL3\" OR \"tarlatamab\" OR \"obrixtamig\") AND (resistance OR \"antigen loss\" OR plasticity) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"SCLC\" AND (\"ASCL1\" OR \"NEUROD1\" OR \"POU2F3\" OR \"YAP1\") AND (subtype OR plasticity OR vulnerability)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41645963","PMID:41869709","PMID:41411619","PMID:41824576","PMID:42019833","PMID:41220942","PMID:42271190","PMID:42163062","PMID:41700001","PMID:41427927","NCT07774520","NCT07203053","NCT07115043","NCT04181060","NCT07636785","NCT07472517","NCT06194448","NCT06406465"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787149848793","cycle":7,"visit":2,"ts":"2026-08-19T14:30:48.793Z","cancer":{"key":"cholangiocarcinoma","name":"cholangiocarcinoma","mondo":{"id":"MONDO:0019087","name":"cholangiocarcinoma"}},"control":false,"modelLabel":"SCIENCE","summary":"In FGFR2-fusion cholangiocarcinoma, co-occurring CDKN2A/B or PTEN loss — not only kinase-domain mutation — drives short pemigatinib PFS, so the actionable next step is FGFRi + CDK4/6 (or PI3K) combination stratified by baseline co-alteration NGS; meanwhile unselected PARPi/PD-1 maintenance in BTC is","confidence":0.6,"notebook":"Visit 2 reshapes two of four leads and opens three.\n\nFGFR2 (L1). Two real-world/agnostic cohorts sharpen the resistance question I posed. P7 (n=158, single centre) confirms fusions as the privileged allele class — ORR 45.9%, mPFS 7.3 mo, mOS 19.7 mo — but shows second-line FGFRi salvage is weak (ORR 13.6% vs 47.6% on first exposure), which undercuts the \"futibatinib after pemigatinib rescues everyone\" framing; only the subset with a covalent-sensitive kinase-domain allele plausibly benefits [INFERRED]. P2 relocates much of the variance to *primary* resistance by co-alteration: 44.4% of pemigatinib-treated FGFR2+ CCA carried concomitant GAs, with CDKN2A mutation conferring PFS 4.79 vs 8.66 mo, plus BAP1 (11%), TP53, CDKN2B, PTEN. Mechanistically this predicts FGFR2-fusion tumours with CDKN2A/B loss escape via RB1-pathway-independent cycling and should be co-treated with a CDK4/6 inhibitor, and PTEN-null tumours with PI3K/AKT blockade — testable, repurposable, and now the primary stratification I want in NCT06439485 and any futibatinib cohort. P9 (n=1) is weak but consistent with a class-toxicity/window difference: pemigatinib-induced grade-severe nail disease improved on switch to futibatinib. L1 strengthened, 0.75.\n\nPARP (L2). BilT-02 (P10) is the high-value negative: rucaparib + nivolumab maintenance after platinum in advanced BTC missed its primary endpoint (4-mo PFS 54.8% vs 63% null; 2/31 PR). The desk should not re-propose unselected PARPi/PD-1 maintenance in BTC. However, the 4-month PFS rate was 83.3% in DDR-mutant (BRCA2 n=3, ATM n=2, FANCA n=1) and 100% in IDH1-mutant (n=3) subsets — directionally supportive of the BRCAness hypothesis but n=9, hypothesis-generating only. Net: L2 weakened to 0.48 and narrowed to biomarker-selected monotherapy (NCT03212274), with the concurrent-versus-sequential ivosidenib question unaddressed.\n\nNew. P4 supplies an orthogonal route to the same synthetic lethality: azacitidine or DNMT3B knockdown impairs HR via OGFR signalling and sensitises TFK-1/RBE to niraparib — induced BRCAness with two approved-class agents, addressing the rarity of BRCA1/2 alteration in BTC. P1 nominates TNK1 from unbiased multiomic/phosphoproteomic clustering with in vivo TP-5801 validation in cluster-matched PDX — the first non-genomic, cluster-directed target this programme has seen. P3 gives tinengotinib (Aurora A/B + FGFR1-3 + VEGFR2 + JAK1/2): CCA ORR 13.0% (n=23) in an unselected refractory phase Ib/II, low hyperphosphataemia/ocular toxicity, hypertension-dominant; plausible post-FGFRi option requiring FGFR2-fusion enrichment to be credible.","leadChanges":[{"id":"L1","title":"Covalent pan-FGFR inhibition (futibatinib) and combination FGFR/VEGF/PD-L1 blockade in FGFR2-fusion cholangiocarcinoma","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.75},{"id":"L2","title":"IDH1/2-mutant BRCAness: PARP inhibition, sequenced rather than combined with IDH inhibitors","level":"LEAD","status":"WEAKENED","confidence":0.48},{"id":"L5","title":"Epigenetically induced BRCAness: azacitidine (DNMT3B axis) plus PARP inhibitor in biliary tract cancer","level":"LEAD","status":"NEW","confidence":0.42},{"id":"L6","title":"TNK1 as a cluster-directed kinase target in cholangiocarcinoma (TP-5801)","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L7","title":"Tinengotinib (Aurora A/B + FGFR1-3 + VEGFR2 + JAK1/2) in FGFR-inhibitor-refractory cholangiocarcinoma","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["Does adding a CDK4/6 inhibitor to pemigatinib or futibatinib restore PFS in FGFR2-fusion CCA with CDKN2A/CDKN2B loss, and is CDKN2A loss prognostic or genuinely predictive of FGFRi failure?","In post-FGFRi FGFR2-fusion CCA, what fraction of progression is kinase-domain-mutant (covalent-inhibitor-addressable) versus bypass/EMT, and does tinengotinib's activity segregate by that split?","Can azacitidine-induced HR impairment (DNMT3B/OGFR axis) be reproduced in BTC organoids/PDX with a functional RAD51 readout, and is priming-then-PARPi superior to concurrent dosing?","Are the DDR (BRCA2/ATM/FANCA) and IDH1 subgroup signals from BilT-02 reproducible in a prospective biomarker-selected PARPi cohort, and were those BRCA2 events germline or somatic?","Does the multiomic CCA cluster assignment and its TNK1 dependency replicate in an independent cohort, and is there an FFPE-deployable classifier?","Do the KG correlated anchors ROS1 (fusion) and PTPN3 represent recurrent druggable events in CCA, or small-series artefacts — still unresolved after two visits?"],"nextQueries":["(\"cholangiocarcinoma\" OR \"biliary tract cancer\") AND (\"CDKN2A\" OR \"CDK4/6\" OR palbociclib OR abemaciclib) AND (FGFR2 OR pemigatinib OR futibatinib) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"biliary tract cancer\" OR cholangiocarcinoma) AND (azacitidine OR decitabine OR DNMT OR \"induced BRCAness\") AND (\"PARP inhibitor\" OR niraparib OR olaparib) AND SRC:MED","cholangiocarcinoma AND (TNK1 OR \"proteogenomic\" OR \"phosphoproteome\" OR \"molecular subtype\" OR ROS1 fusion OR PTPN3) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41020779","doi":"10.1097/hep.0000000000001535","year":2026,"isNew":true,"title":"Multiomics combined with machine learning defines unique molecular subtypes of cholangiocarcinoma and identifies TNK1 as a therapeutic target"},{"pmid":"42494243","doi":"10.1111/liv.70813","year":2026,"isNew":true,"title":"Prognostic Impact of Concomitant Genomic Alterations in FGFR2-Positive Cholangiocarcinoma Treated With Pemigatinib"},{"pmid":"42489683","doi":"10.1158/1078-0432.ccr-26-1076","year":2026,"isNew":true,"title":"Multikinase Inhibition with Tinengotinib in Advanced Solid Tumors: Results from a Multicenter Phase Ib/II Trial"},{"pmid":"41463187","doi":"10.3390/cancers17243936","year":2025,"isNew":true,"title":"DNMT3B Knockdown Enhances PARP Inhibitor Sensitivity in Biliary Tract Cancer Cells via Opioid Growth Factor Receptor-Mediated Homologous Recombination Impairment"},{"pmid":"42050803","doi":"10.1080/15384047.2026.2664327","year":2026,"isNew":true,"title":"Parthenolide inhibits the progression of intrahepatic cholangiocarcinoma by promoting ferroptosis through inhibiting UBD"},{"pmid":"41592786","doi":"10.1080/19336918.2026.2616948","year":2026,"isNew":true,"title":"NCEH1 promotes breast cancer progression by regulating NRP1 and activating the TNF-α/NF-κB signalling pathway"},{"pmid":"42330567","doi":"10.1016/j.ejca.2026.116900","year":2026,"isNew":true,"title":"Outcomes of patients treated by FGFR inhibitors according to alteration types: An agnostic monocentric retrospective cohort"},{"pmid":"42543673","doi":"10.5582/bst.2026.01104","year":2026,"isNew":true,"title":"Comparison of current global guidelines and consensus on the management of patients with cholangiocarcinoma: A 2026 update"},{"pmid":"42491302","doi":"10.1007/s13691-026-00857-3","year":2026,"isNew":true,"title":"Severe nail toxicity induced by FGFR inhibitor in &lt;i&gt;FGFR2&lt;/i&gt;-rearranged cholangiocarcinoma"},{"pmid":"42489677","doi":"10.1158/1078-0432.ccr-25-1114","year":2026,"isNew":true,"title":"A phase 2 multicenter trial of rucaparib and nivolumab as maintenance therapy in patients with advanced biliary tract cancer: BilT-02"}],"trialsShown":[{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04645160","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Evaluating Efficacy of Tivozanib (AV-951) in Biliary Tract Cancers"},{"nct":"NCT01915225","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Obtaining Solid Tumor Tissue From People Having Biopsy or Surgery for Certain Types of Cancer"},{"nct":"NCT03212274","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations"},{"nct":"NCT07043387","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Streamlining Radioembolization for CCC and Metastatic Liver Cancer"},{"nct":"NCT06048133","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of Gemcitabine, Cisplatin, AB680 and AB122 During First Line Treatment of Advanced Biliary Tract Cancers (QUIC)"},{"nct":"NCT04891289","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Gemcitabine and Oxaliplatin Chemotherapy With or Without a Floxuridine and Dexamethasone Pump in People With Cholangiocarcinoma That Cannot "},{"nct":"NCT06439485","phase":"phase 1/phase 2","status":"RECRUITING","isNew":false,"title":"Phase I/II Trial of Pemigatinib in Combination With Atezolizumab and Bevacizumab for Treatment of Advanced Cholangiocarcinoma With FGFR2 Fus"}],"usage":{"input":11687,"output":8283},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"cholangiocarcinoma\" AND (\"FGFR2\" AND (resistance OR \"acquired mutation\" OR futibatinib OR ctDNA)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"cholangiocarcinoma\" OR \"biliary tract cancer\") AND (\"IDH1\" OR \"homologous recombination\" OR \"PARP inhibitor\" OR BRCAness) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"evidenceIds":["PMID:41020779","PMID:42494243","PMID:42489683","PMID:41463187","PMID:42050803","PMID:41592786","PMID:42330567","PMID:42543673","PMID:42491302","PMID:42489677","NCT07023731","NCT04645160","NCT01915225","NCT03212274","NCT07043387","NCT06048133","NCT04891289","NCT06439485"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787149620178","cycle":6,"visit":2,"ts":"2026-08-19T14:27:00.178Z","cancer":{"key":"pancreatic cancer","name":"pancreatic cancer","mondo":{"id":"MONDO:0009831","name":"malignant pancreatic neoplasm"}},"control":false,"modelLabel":"SCIENCE","summary":"Independent reproduction of bacterial CDD-mediated gemcitabine inactivation plus a GSH-cleavable tobramycin–gemcitabine conjugate elevates intratumoral-bacteria-directed gemcitabine rescue to a CANDIDATE, with tumour-restricted antibiotic delivery (not systemic antibiotics) as the lead translational","confidence":0.5,"notebook":"The pack's one primary paper is decisive for L1. PMID:42302584 independently reproduces the core premise — CDD-expressing intratumoral bacteria blunt gemcitabine — in a different lab, different model (Panc02, bacteria-colonised tumours), and solves the objection I raised at visit 1 about microbiome collateral damage: a tobramycin–SS–gemcitabine conjugate that is stable in plasma and cleaved by high tumour GSH, delivering aminoglycoside and antimetabolite in the same compartment. It also adds an immunological arm I had not attributed to bacterial clearance: DC maturation and increased CD8+ infiltration accompanying debulking of intratumoral bacteria, i.e. the microbe is both a drug sink and an immune modulator. Three reviews (PMID:41963781, PMID:41758194, PMID:42345004) place microbial metabolic inactivation of antimetabolites in a general framework and flag the unsolved item — proof of causation in patients and biomarker translation — which is exactly the human cdd_L prevalence question I left open. L1 accordingly moves to CANDIDATE. One counterweight, recorded so the desk does not over-read mouse data: PMID:42178725 shows laboratory mice carry non-physiological microbiomes and that sustained Gram-negative environmental colonisation drives Treg/IL-10 expansion; effect sizes for antibiotic potentiation in SPF KPC mice may not transfer, and systemic Gram-negative ablation could perturb immunoregulatory tone in either direction. Tumour-restricted delivery (AiDC) is therefore preferred over systemic ciprofloxacin, and this is now the primary translational branch.\n\nFor L2 the pack is review-only (PMID:41598808, PMID:41924551, PMID:41423807) — no efficacy data, so no promotion. Mechanistically useful nonetheless: G12D is described as preferentially routing to PI3K/AKT and as an immune-exclusion driver, which reprioritises my pre-specified combinations — PI3K/AKT (or mTOR) blockade should sit alongside SHP2/SOS1, not behind it — and the tri-complex/pan-RAS(ON) modality (RMC-9805 class) is offered as a distinct answer to wild-type-RAS bypass, with claims of TME remodelling and delayed resistance. I split that off as its own lead rather than diluting L2, because the two make opposite bets on the therapeutic window: allele-selective degradation preserves wild-type RAS in crypt and marrow, pan-RAS(ON) deliberately does not.\n\nNew trial-anchored lead: AZD0171 (anti-LIF) + durvalumab + gemcitabine/nab-paclitaxel (NCT04999969). LIF is a stromal/CAF-derived STAT3 signal in PDAC [KNOWN]; this is the only combination in the pack pairing stromal signalling blockade with the standard backbone, and it is a plausible partner for any strategy that also restores gemcitabine exposure. L3, L4, L5 unchanged — no new evidence bears on them.","leadChanges":[{"id":"L1","title":"cdd_L+ intratumoral Enterobacter as an antibiotic-reversible driver of gemcitabine inactivation","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.65},{"id":"L2","title":"KRAS G12D targeted degradation (ARV-806) in PDAC","level":"LEAD","status":"STRENGTHENED","confidence":0.5},{"id":"L6","title":"Pan-RAS(ON) tri-complex inhibition as the wild-type-bypass-proof alternative to allele-selective G12D therapy","level":"LEAD","status":"NEW","confidence":0.4},{"id":"L7","title":"LIF neutralisation (AZD0171) plus PD-L1 blockade on the gemcitabine/nab-paclitaxel backbone","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["What fraction of human PDAC resections carry cdd/cdd_L+ Gammaproteobacteria, and does carriage predict neoadjuvant gemcitabine non-response?","Does tumour-restricted antibiotic delivery (GSH-cleavable antibiotic–drug conjugate) achieve the same gemcitabine rescue as systemic Gram-negative antibiotics with less microbiome-wide perturbation, and is the immune activation (DC maturati","Are preclinical antibiotic-potentiation effect sizes inflated by non-physiological SPF mouse microbiomes, and do they persist in environmentally colonised or humanised-microbiome PDAC models?","For KRAS G12D, does PI3K/AKT rather than MAPK rebound dominate on-treatment escape, and does adding a PI3K/AKT inhibitor to degradation deepen pERK/pS6 suppression without crypt toxicity?","Does pan-RAS(ON) tri-complex inhibition outperform mutant-selective degradation on duration of response and resistance-clone spectrum, and at what cost to the wild-type-RAS-dependent window?","Does LIF blockade lower intratumoral pSTAT3 in PDAC patients on gemcitabine/nab-paclitaxel, and is IL-6/OSM redundancy the escape?"],"nextQueries":["(\"pancreatic ductal adenocarcinoma\" AND (\"pan-RAS\" OR \"RMC-6236\" OR \"RMC-9805\" OR \"tri-complex\") AND (resistance OR trial OR response)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"pancreatic\" AND (\"cytidine deaminase\" OR cdd OR Gammaproteobacteria) AND (\"human\" OR resection OR cohort OR biomarker) AND gemcitabine) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"pancreatic\" AND (LIF OR \"leukemia inhibitory factor\" OR STAT3) AND (durvalumab OR \"immune checkpoint\" OR stroma)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"41598808","doi":"10.3390/jcm15020873","year":2026,"isNew":true,"title":"KRAS Inhibition in Pancreatic Ductal Adenocarcinoma"},{"pmid":"41953725","doi":"10.1016/j.gendis.2025.101963","year":2026,"isNew":true,"title":"Intra-tumoral microbiota: Key modulators of tumor immunity and therapeutic potential"},{"pmid":"41924551","doi":"10.2147/dddt.s559325","year":2026,"isNew":true,"title":"Key Considerations for Targeting &lt;i&gt;KRAS&lt;/i&gt; in Pancreatic Cancer: Potential Impact on the Treatment Paradigm"},{"pmid":"41423807","doi":"10.1111/1759-7714.70203","year":2025,"isNew":true,"title":"Targeting KRAS G12D: Advances in Inhibitor Design"},{"pmid":"42302584","doi":"10.1016/j.biomaterials.2026.124368","year":2026,"isNew":true,"title":"Antibiotic-drug conjugates: Enhancing chemo-immunotherapy of gemcitabine for pancreatic cancer by eliminating intratumoral bacteria"},{"pmid":"42178725","doi":"10.1080/19490976.2026.2675089","year":2026,"isNew":true,"title":"Soil-derived microbiota induces T regulatory cells and protect against mouse colitis, metabolic disease, and sepsis"},{"pmid":"41963781","doi":"10.1080/19490976.2026.2651930","year":2026,"isNew":true,"title":"Microbiota as a modulator of drug response: targeting microbial-drug crosstalk in cancer therapy"},{"pmid":"41758194","doi":"10.1080/19490976.2026.2638009","year":2026,"isNew":true,"title":"Exploring the gut microbiome and metabolomic interactions of antimetabolite drugs to optimize therapy"},{"pmid":"42326066","doi":"10.1016/j.mtbio.2026.103330","year":2026,"isNew":true,"title":"Modeling cancer with bacteria-integrated tumor microenvironments using biomaterials: Emerging concepts and opportunities"},{"pmid":"42345004","doi":"10.1002/mco2.70825","year":2026,"isNew":true,"title":"Intratumoral Microbiota in Tumor: Current Understandings and Future Perspectives"}],"trialsShown":[{"nct":"NCT04999969","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic "},{"nct":"NCT05692323","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Supervised Prehabilitation Program for Patients With Pancreatic Cancer"},{"nct":"NCT07226154","phase":"n/a","status":"RECRUITING","isNew":false,"title":"Prediction of Neoadjuvant Chemotherapy Response in Pancreatic Cancer"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04550494","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations"},{"nct":"NCT04644068","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies"},{"nct":"NCT03454035","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Ulixertinib/Palbociclib in Patients With Advanced Pancreatic and Other Solid Tumors"},{"nct":"NCT01174121","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer"}],"usage":{"input":11831,"output":6211},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(\"pancreatic\" AND (\"intratumoral microbiome\" OR \"intratumour bacteria\" OR \"cytidine deaminase\" OR Gammaproteobacteria) AND (gemcitabine OR resistance)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"pancreatic ductal adenocarcinoma\" AND (\"KRAS G12D\" OR \"KRAS degrader\" OR PROTAC OR SOS1 OR SHP2) AND (resistance OR combination)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"evidenceIds":["PMID:41598808","PMID:41953725","PMID:41924551","PMID:41423807","PMID:42302584","PMID:42178725","PMID:41963781","PMID:41758194","PMID:42326066","PMID:42345004","NCT04999969","NCT05692323","NCT07226154","NCT07023731","NCT04550494","NCT04644068","NCT03454035","NCT01174121"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787149413895","cycle":5,"visit":2,"ts":"2026-08-19T14:23:33.895Z","cancer":{"key":"glioblastoma","name":"glioblastoma","mondo":{"id":"MONDO:0018177","name":"glioblastoma"}},"control":false,"modelLabel":"SCIENCE","summary":"Promote lactate-flux blockade + bevacizumab to CANDIDATE on three independent 2026 lactate-lactylation reviews, and reframe LonP1 as an ATF4/UPRmt adaptive effector whose biguanide-combination arm is retired on exposure grounds.","confidence":0.42,"notebook":"This visit's pack was largely off-target: two of ten records concern bacterial RNA decay and fire blight, three concern kidney/adipocyte/alcohol mitochondrial biology, and no primary GBM paper arrived. The trial list is unchanged from visit 1 (NCT06816927, NCT06860594, NCT02977780, NCT03212274, NCT04047264 all persist; T1/T5/T8 are imaging/device arms that add no new mechanism), so no lead moves on trial evidence.\n\nTwo things did change. First, PMID:42462827 gives me the ATF4 node for L1: complex I inhibition by metformin induces UPRmt with *Lonp1* upregulation, ATF4-dependently, and ISRIB abrogates it. Mechanistically this reframes LonP1 not as a standalone protease but as an ATF4/ISR-driven adaptive effector [INFERRED], which predicts that OXPHOS-directed agents will *raise* LonP1 and thereby self-limit — so the visit-1 speculative \"biguanide + LonP1i\" arm is retired in that form and replaced by the sharper test: does ATF4/LonP1 induction constitute the adaptive resistance route to OXPHOS inhibitors in GBM, i.e. is LonP1 inhibition (or ATF4/ISR modulation) an anti-adaptation partner rather than a co-cytotoxin? Two hard caveats: 10 mM metformin is orders above achievable plasma/CSF exposure [KNOWN], and this is adipocyte, not glioma, tissue. Combined with the dedicated LONP1 query returning zero GBM-relevant or medicinal-chemistry hits, open question 1 stays unanswered and L1 is weakened, not killed — the chemical-matter gap is now the rate-limiter.\n\nSecond, three independent 2026 reviews (PMID:42058190, PMID:41593811, PMID:42002813) converge on the lactate–lactylation axis as a druggable node: MCT/LDHA/writer-eraser inhibition, lactylation-stabilised PD-L1, M2/Treg-driven immunosuppression, and — explicitly — adaptive resistance and immunosuppression as the failure mode of conventional anti-angiogenics (PMID:41593811), which is exactly the L2 clinical phenotype. This is review-level, not new primary GBM in vivo data, so I promote L2 to CANDIDATE with restrained confidence and record that the decisive experiment (MCT1/4 or LDHA blockade + bevacizumab in orthotopic GBM, with H3K18la/BMAL1-K123 readouts) still does not exist in the literature I can cite.\n\nPMID:42058190's claim that lactylation supports DNA-damage repair and stemness bridges L2 to L4 and justifies one new lead: lactate-supply blockade as a hypoxia-core radiosensitiser, mechanistically consonant with HIF-1α degradation lowering SMUG1/LIG4 (PMID:42523098). Next visit I need primary GBM data, not reviews: in vivo MCT/LDHA experiments, LonP1 chemical matter with brain exposure, and any measured intratumoral PK.","leadChanges":[{"id":"L1","title":"LonP1 inhibition to resensitise glioblastoma to temozolomide (MGMT-independent)","level":"LEAD","status":"WEAKENED","confidence":0.42},{"id":"L2","title":"Block glycolytic lactate flux to reverse BMAL1-lactylation-driven bevacizumab resistance","level":"CANDIDATE","status":"STRENGTHENED","confidence":0.48},{"id":"L6","title":"Lactate-supply blockade as a hypoxia-core radiosensitiser in glioblastoma","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does any LonP1 inhibitor with documented brain exposure exist, and does LONP1 loss sensitise MGMT-methylated as well as unmethylated orthotopic GBM to TMZ in vivo?","Is ATF4-driven LONP1/UPRmt induction the adaptive resistance route to TMZ and to OXPHOS inhibitors in GBM cells, and does ISR modulation phenocopy LONP1 loss?","Is there any primary in vivo GBM experiment (not review, not in silico) showing MCT1/MCT4 or LDHA blockade reverses bevacizumab resistance and lowers H3K18la at the BMAL1 promoter?","Does lactylation measurably support DNA repair in GBM specifically — i.e. does lactate or LDHA blockade alter SMUG1/LIG4/RAD51 and gammaH2AX resolution under hypoxia?","Is there experimental GBM evidence that CCL2/CCR2 or TIMP1/CD63 blockade improves PD-1 or LAG-3 efficacy, and does lactate-driven PD-L1 stabilisation offer a cleaner intervention on the same niche?","Which current GBM resistance targets have measurable intratumoral exposure by microdialysis or paired-tissue PK — which hypotheses are delivery-limited rather than biology-limited?"],"nextQueries":["(\"MCT1\" OR \"MCT4\" OR SLC16A1 OR SLC16A3 OR LDHA) AND (glioma OR glioblastoma) AND (orthotopic OR xenograft OR \"in vivo\" OR radiotherapy) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(LONP1 OR \"Lon protease\") AND (inhibitor OR CDDO OR obtusilactone OR \"blood-brain barrier\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(ATF4 OR \"integrated stress response\" OR ISRIB OR UPRmt) AND (glioblastoma OR glioma) AND (temozolomide OR radioresistance OR OXPHOS) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"41633353","doi":"10.1080/0886022x.2026.2620218","year":2026,"isNew":true,"title":"Targeting mitochondrial quality control in diabetic kidney disease: emerging therapeutic opportunities"},{"pmid":"42058190","doi":"10.3389/fimmu.2026.1772701","year":2026,"isNew":true,"title":"The glycolysis-lactylation axis: a metabolic-epigenetic driver of immunosuppression and therapy resistance in cancer"},{"pmid":"41593811","doi":"10.1186/s40364-026-00898-z","year":2026,"isNew":true,"title":"Lactate-lactylation in tumor angiogenesis and progression: mechanisms, biomarker potential, and therapeutic implications"},{"pmid":"42002813","doi":"10.1186/s13578-026-01572-5","year":2026,"isNew":true,"title":"Lactate metabolic reprogramming and lactylation modification: molecular mechanisms reshaping the tumor immunosuppressive microenvironment"},{"pmid":"42167936","doi":"10.1080/15476286.2026.2678028","year":2026,"isNew":true,"title":"Identification of proteins interacting with the N-terminal half of endoribonuclease RNase E in &lt;i&gt;Escherichia coli&lt;/i&gt;"},{"pmid":"42118848","doi":"10.1080/15592294.2026.2670909","year":2026,"isNew":true,"title":"A relative methylation ordering biomarker of lactylation-related genes predicts prognosis and therapeutic response in cutaneous melanoma"},{"pmid":"42035484","doi":"10.1080/21505594.2026.2664987","year":2026,"isNew":true,"title":"Pathogenicity and virulence of &lt;i&gt;Erwinia amylovora&lt;/i&gt;"},{"pmid":"41973649","doi":"10.1080/21623945.2026.2651605","year":2026,"isNew":true,"title":"The role and mechanism of UPRmt in adipocytes"},{"pmid":"42327979","doi":"10.1016/j.gendis.2025.101886","year":2026,"isNew":true,"title":"The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy"},{"pmid":"42462827","doi":"10.1016/j.bbamcr.2026.120191","year":2026,"isNew":true,"title":"Metformin triggers ATF4-mediated UPR&lt;sup&gt;mt&lt;/sup&gt; and COX-2 inflammation in adipocytes"}],"trialsShown":[{"nct":"NCT06108206","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Adaptive Radiotherapy and MRIs Based on Patients With Newly Diagnosed High-Grade Glioma"},{"nct":"NCT06816927","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Trial of Glioblastoma Immunotherapy Advancement With Nivolumab and Relatlimab"},{"nct":"NCT06860594","phase":"phase 1","status":"RECRUITING","isNew":false,"title":"Testing the Addition of an Anti-Cancer Drug, Triapine, to the Usual Radiation Therapy for Recurrent Glioblastoma or Astrocytoma"},{"nct":"NCT02977780","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"INdividualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT)"},{"nct":"NCT06556563","phase":"phase 3","status":"RECRUITING","isNew":false,"title":"EF-41/KEYNOTE D58: Phase 3 Study of Optune Concomitant With Temozolomide Plus Pembrolizumab in Newly Diagnosed Glioblastoma"},{"nct":"NCT04047264","phase":"NA","status":"RECRUITING","isNew":false,"title":"Feasibility of Intra- and Post-operative Microdialysis During Neurosurgery for Central Nervous System Lesions"},{"nct":"NCT03212274","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":false,"title":"Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations"},{"nct":"NCT06319027","phase":"phase 2","status":"RECRUITING","isNew":false,"title":"Identifying Findings on Brain Scans That Could Help Make Better Predictions About Brain Cancer Progression, The GABLE Trial"}],"usage":{"input":12131,"output":6514},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["(LONP1 OR \"Lon protease\") AND (glioma OR glioblastoma OR inhibitor) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","glioblastoma AND (lactylation OR \"MCT1\" OR \"MCT4\" OR LDHA OR bevacizumab resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:41633353","PMID:42058190","PMID:41593811","PMID:42002813","PMID:42167936","PMID:42118848","PMID:42035484","PMID:41973649","PMID:42327979","PMID:42462827","NCT06108206","NCT06816927","NCT06860594","NCT02977780","NCT06556563","NCT04047264","NCT03212274","NCT06319027"],"modelFamily":"Claude (Anthropic)","servedBy":"Claude Opus 5","effort":"high","maxTokens":32000}},{"id":"f1787146208507","cycle":4,"visit":1,"ts":"2026-08-19T13:30:08.507Z","cancer":{"key":"small cell lung cancer","name":"small cell lung cancer","mondo":{"id":"MONDO:0008433","name":"small cell lung carcinoma"}},"control":false,"modelLabel":"Claude","summary":"Prioritise DLL3xCD3 bispecific engagers (tarlatamab, obrixtamig) as SCLC's lead lineage-directed axis, with the PS 2 tarlatamab trial and the randomised first-line obrixtamig trial as the two decisive near-term read-outs; treat non-NE (POU2F3/YAP1) plasticity as the expected escape route to pre-empt","confidence":0.5,"notebook":"Visit 1 opens the SCLC programme against a low-yield pack: 8 of 10 papers are NSCLC or non-oncology noise (p-TLS in horses, radiomics, MET/EGFR reviews, gut butyrate), and 4 of 8 trials are EGFR-mutant NSCLC. Only two trials and one case report bear directly on SCLC. Recording this so the desk does not repeat the query: the string \"small cell lung cancer\" retrieves NSCLC by substring; next visit must use SCLC-specific lexicon (DLL3, ASCL1, NEUROD1, POU2F3, tarlatamab, \"extensive-stage\").\n\nGenomic frame [KNOWN]: SCLC is near-universally RB1/TP53-null; the Monarch anchor's RB1 [GERMLINE] signal reflects retinoblastoma-survivor predisposition and is not itself druggable, while TP53/TP73 [SOMATIC] loss likewise offers no direct handle. So the tractable axes this visit are surface-antigen redirection and chromatin/pharmacology, not the anchor genes.\n\nLead 1 (new): DLL3-directed T-cell redirection as the lineage-defining vulnerability. Two independent sponsors now run DLL3×CD3 bispecifics in ES-SCLC — tarlatamab in pretreated ECOG PS 2 patients (NCT07203053), a population systematically excluded from registration trials, and obrixtamig moving into randomised first-line against atezolizumab/carboplatin/etoposide (NCT07472517). Mechanistically [KNOWN/INFERRED]: ASCL1/NEUROD1-driven neuroendocrine SCLC aberrantly surfaces DLL3, an inhibitory Notch ligand normally sequestered in Golgi and near-absent in adult somatic tissue — that compartmental restriction *is* the therapeutic window, and explains why an antigen that failed as an ADC payload carrier succeeds as a synapse-forming engager. Named resistance routes: antigen loss with drift to DLL3-low POU2F3/YAP1 or inflamed non-NE states, T-cell exhaustion in a cold TP53/RB1-null tumour, and dose-limiting CRS/ICANS. The PS 2 trial is the key falsification test: if engagers require fitness reserve, the modality's real-world ceiling is much lower than trial data imply.\n\nLead 2 (new, weaker): genotype-directed HDAC inhibition on the platinum-etoposide backbone. NCT06406465 uses UGT1A1 genotype to steer belinostat PK/toxicity with cisplatin/etoposide. Rationale [INFERRED]: RB1/TP53-null SCLC is chromatin-addicted and topoisomerase-sensitive; belinostat's narrow index has historically sunk combinations, so pharmacogenomic dose individualisation attacks the actual failure mode rather than the target. Abstracts give no SCLC-specific efficacy signal — this is a tolerability-enabling hypothesis only.\n\nToxicity note for the notebook, not a lead: a RUCAM-8 severe cholestatic injury emerged five months into etoposide/carboplatin plus adebrelimab, well outside the labelled onset window (PMID:42559863). Late-onset hepatotoxicity constrains maintenance PD-L1 duration and will confound any engager-plus-checkpoint combination read-out. AZD6750/rilvegostomig (NCT07115043) is a watch item; the abstract does not confirm SCLC enrolment or the AZD6750 target, so I make no claim.","leadChanges":[{"id":"L1","title":"DLL3xCD3 T-cell engagers as lineage-restricted therapy in neuroendocrine SCLC","level":"LEAD","status":"NEW","confidence":0.6},{"id":"L2","title":"UGT1A1 genotype-directed belinostat with cisplatin/etoposide in RB1/TP53-null tumours","level":"LEAD","status":"NEW","confidence":0.25}],"unverifiedCitations":0,"openQuestions":["Does DLL3 antigen loss or ASCL1/NEUROD1-to-POU2F3/YAP1 lineage switching dominate acquired resistance to tarlatamab and obrixtamig, and is either reversible pharmacologically?","Do DLL3 engagers retain activity in ECOG PS 2 patients, or is the modality's real-world ceiling set by cytokine toxicity and fitness reserve (NCT07203053 read-out)?","Beyond DLL3, which surface antigens (SEZ6, CEACAM5, B7-H3) are enriched in non-NE SCLC subtypes and could cover the engager-escape state?","Is there any citable synthetic-lethal handle for RB1-loss/TP53-loss SCLC (Aurora A/B, CHK1, WEE1, PARP-plus-temozolomide) in current literature, given the anchor genes are otherwise undruggable?","How does late-onset (>5 month) checkpoint-inhibitor hepatotoxicity, as in the adebrelimab RUCAM-8 case, constrain maintenance duration and confound engager-plus-PD-L1 combination trials?","What is AZD6750's target and does NCT07115043 (with rilvegostomig) actually enrol SCLC?"],"nextQueries":["(\"DLL3\" OR \"tarlatamab\" OR \"obrixtamig\") AND (resistance OR \"antigen loss\" OR plasticity) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"SCLC\" AND (\"ASCL1\" OR \"NEUROD1\" OR \"POU2F3\" OR \"YAP1\") AND (subtype OR plasticity OR vulnerability)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"small-cell lung\" AND (\"RB1\" OR \"TP53\") AND (\"synthetic lethal\" OR \"Aurora\" OR \"CHK1\" OR \"WEE1\" OR \"PARP\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42564760","doi":"10.1016/j.vas.2026.100777","year":2026,"isNew":true,"title":"Intratumoral para-toluenesulfonamide as a tumor-ablative therapy for equine cutaneous tumors: a case series of three horses"},{"pmid":"42559863","doi":"10.1080/20565623.2026.2712209","year":2026,"isNew":true,"title":"Drug-Induced liver injury with adebrelimab: how to assess causality using the updated RUCAM?"},{"pmid":"42499996","doi":"10.1016/j.ibneur.2026.07.007","year":2026,"isNew":true,"title":"Pre-treatment cognitive impairment in patients with NSCLC: Prevalence and psychosocial factors"},{"pmid":"42480036","doi":"10.1080/17581966.2026.2696220","year":2026,"isNew":true,"title":"Cost of managing brain metastases in patients with ALK+ advanced NSCLC with first-line tyrosine kinase inhibitors in the UK"},{"pmid":"42474358","doi":"10.1080/15384047.2026.2683169","year":2026,"isNew":true,"title":"Bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide sensitizes ABCC2/ALDH3A1 overexpressing NSCLC cells to cisplatin"},{"pmid":"42454784","doi":"10.1080/19490976.2026.2699457","year":2026,"isNew":true,"title":"Dietary intervention through bacterial-derived butyrate elicits anti-tumor activity and increases anti-PD-1 response"},{"pmid":"42376198","doi":"10.1016/j.ejro.2026.100775","year":2026,"isNew":true,"title":"Contrast-enhanced CT based radiomics for prediction of 3-year disease progression in NSCLC patients after anti-PD-1-targeted therapy"},{"pmid":"42345355","doi":"10.1080/15384047.2026.2694136","year":2026,"isNew":true,"title":"Advances in SEC61G research: from ER translocon subunit to emerging pan-cancer oncogenic roles"},{"pmid":"42450152","doi":"10.3390/ijms27135883","year":2026,"isNew":true,"title":"Targeting MET in 2025: From Exon 14 Skipping to MET-Amplified Acquired Resistance in Non-Small Cell Lung Cancer"},{"pmid":"42483918","doi":"10.2174/0113816128474105260604054207","year":2026,"isNew":true,"title":"Exploring the Mechanism of Shenqi Fuzheng Injection on Alleviating EGFR-TKIs Resistance in Non-small Cell Lung Cancer: Integration of Clinical Observation, Network Pharmacology, an"}],"trialsShown":[{"nct":"NCT07774520","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Randomized Study to Evaluate the Efficacy of a Reduced Starting Dose of Lazertinib (Leclaza) and Preemtive Magnesium Supplementation to Pr"},{"nct":"NCT07203053","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A Trial of Tarlatamab in Patients With Pretreated Extensive-stage Small Cell Lung Cancer (ES-SCLC) and ECOG PS 2"},{"nct":"NCT07115043","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors"},{"nct":"NCT04181060","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"Osimertinib With or Without Bevacizumab as Initial Treatment for Patients With EGFR-Mutant Lung Cancer"},{"nct":"NCT07636785","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors"},{"nct":"NCT07472517","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"DAREON ® -Lung-1: A Study in People With Advanced Small Cell Lung Cancer to Compare Obrixtamig Plus Atezolizumab, Carboplatin, and Etoposide"},{"nct":"NCT06194448","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"To Evaluate the Efficacy/Safety of Osimertinib Prior to CRT and Maintenance of it With Stage III, Unresectable NSCLC With EGFR Mutations"},{"nct":"NCT06406465","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"A UGT1A1 Genotype-Directed Study of Belinostat Pharmacokinetics and Toxicity"}],"usage":{"input":8747,"output":4307},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"small cell lung cancer\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"small cell lung cancer\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42564760","PMID:42559863","PMID:42499996","PMID:42480036","PMID:42474358","PMID:42454784","PMID:42376198","PMID:42345355","PMID:42450152","PMID:42483918","NCT07774520","NCT07203053","NCT07115043","NCT04181060","NCT07636785","NCT07472517","NCT06194448","NCT06406465"],"modelFamily":"Claude (Anthropic)","effort":"high","maxTokens":32000}},{"id":"f1787146015759","cycle":3,"visit":1,"ts":"2026-08-19T13:26:55.759Z","cancer":{"key":"cholangiocarcinoma","name":"cholangiocarcinoma","mondo":{"id":"MONDO:0019087","name":"cholangiocarcinoma"}},"control":false,"modelLabel":"Claude","summary":"Anchor the cholangiocarcinoma programme on four leads — covalent pan-FGFR inhibition plus anti-angiogenic/IO combination in FGFR2-fusion disease, IDH-mutant BRCAness treated with PARP inhibition (sequenced, not concurrent, with ivosidenib), CD73/adenosine blockade added to chemo-IO, and KRAS G12D de","confidence":0.55,"notebook":"Visit 1 opens the programme. The pack is largely noise for this indication — P3 (diabetic wound ALDOA), P6 (prostate lncRNA), P7 (circRNA review), P4 (TNBC cryoablation), P5 (BMX) contain no cholangiocarcinoma-specific evidence and are not usable anchors; P8 (H19 in biliary atresia) is cholangiocyte-relevant but pre-neoplastic, and I will not launder it into a CCA lead. P1 (transplant oncology) is a locoregional/curative-intent context note, not a target hypothesis. P2 (opaganib/SphK2) is mechanistically interesting — ceramide accumulation, pERK/pAKT/NF-κB suppression — but the abstract never names CCA, so I park it as an unverified hypothesis rather than a lead.\n\nFour leads are defensible. First, FGFR2: P10 states futibatinib is an irreversible covalent pan-FGFR inhibitor retaining activity across FGFR2 kinase-domain resistance mutations, and P9 confirms FGFR2 fusions as a validated actionable class alongside IDH1/2, HER2, BRAF V600E. T8 adds the orthogonal idea that pemigatinib failure is partly non-genetic — VEGF/angiogenic and immune escape — hence pemigatinib + atezolizumab + bevacizumab. Expected resistance: FGFR2 gatekeeper V564F/N550K, and bypass via MET/EGFR or PI3K reactivation [KNOWN]; hyperphosphataemia is the class window-limiting toxicity because FGFR1 governs renal phosphate handling [KNOWN].\n\nSecond, an HRD/synthetic-lethality lead that the KG anchor independently nominates: BRCA1 and BRCA2 appear as correlated (somatic-likely) genes, and T4 tests olaparib specifically in IDH1/IDH2-mutant cholangiocarcinoma — the 2-HG-mediated homologous-recombination defect [KNOWN]. This makes a testable prediction of antagonism: ivosidenib, by depleting 2-HG, should restore HR and blunt PARP-inhibitor sensitivity, so sequential rather than concurrent dosing is the rational design [INFERRED].\n\nThird, the adenosine axis. T6 (QUIC) puts quemliclustat (CD73) plus zimberelimab on a gem/cis backbone; mechanistically chemotherapy-released ATP is hydrolysed by CD73 to adenosine, and A2AR signalling suppresses CD8/NK function — a plausible explanation for the modest absolute gains of chemo-IO in BTC [KNOWN].\n\nFourth, KRAS G12D. T1 (ARV-806) is a degrader rather than an occupancy inhibitor; CCA, particularly extrahepatic/gallbladder disease, carries a KRAS-mutant subset [KNOWN]. Degradation should blunt the RTK-driven RAS-reactivation rebound seen with reversible inhibitors [INFERRED]; expected resistance is MAPK reactivation and wild-type RAS/RTK bypass.\n\nROS1 and PTPN3 from the KG anchor remain uncorroborated by anything in this pack; I will not build on them until I see CCA-specific fusion-prevalence or functional data. T2 (tivozanib) and T7 (HAI FUDR) are logged as comparator context, not leads.","leadChanges":[{"id":"L1","title":"Covalent pan-FGFR inhibition (futibatinib) and combination FGFR/VEGF/PD-L1 blockade in FGFR2-fusion cholangiocarcinoma","level":"LEAD","status":"NEW","confidence":0.72},{"id":"L2","title":"IDH1/2-mutant BRCAness: PARP inhibition, sequenced rather than combined with IDH inhibitors","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L3","title":"CD73/adenosine blockade added to first-line chemo-immunotherapy in biliary tract cancer","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L4","title":"KRAS G12D degradation (ARV-806) in the KRAS-mutant, predominantly extrahepatic/gallbladder cholangiocarcinoma subset","level":"LEAD","status":"NEW","confidence":0.4}],"unverifiedCitations":0,"openQuestions":["What is the emergent resistance spectrum after futibatinib in FGFR2-fusion CCA — kinase-domain alleles versus non-genetic bypass (MET, EGFR, PI3K, EMT) — and does adding bevacizumab/atezolizumab alter it?","Does 2-HG depletion by ivosidenib antagonise PARP-inhibitor sensitivity in IDH-mutant CCA, making sequential dosing superior to concurrent?","What is the true prevalence and functional consequence of somatic versus germline BRCA1/BRCA2 alteration in cholangiocarcinoma, and do PARP inhibitors show activity outside IDH-mutant tumours?","Is there any CCA-specific evidence for CD73/adenosine-mediated resistance to chemo-immunotherapy, or only pan-tumour rationale?","What is the KRAS G12D allele frequency by anatomic subtype (intrahepatic vs perihilar vs distal vs gallbladder), and are there CCA patients in the ARV-806 cohort?","Are ROS1 fusions and PTPN3 mutations (KG correlated anchors) real, recurrent, druggable events in CCA or artefacts of small-series reporting?"],"nextQueries":["\"cholangiocarcinoma\" AND (\"FGFR2\" AND (resistance OR \"acquired mutation\" OR futibatinib OR ctDNA)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"cholangiocarcinoma\" OR \"biliary tract cancer\") AND (\"IDH1\" OR \"homologous recombination\" OR \"PARP inhibitor\" OR BRCAness) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"cholangiocarcinoma\" OR \"biliary tract cancer\") AND (\"CD73\" OR NT5E OR adenosine OR \"KRAS G12D\" OR \"ROS1 fusion\" OR PTPN3) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"papersShown":[{"pmid":"42311093","doi":"10.1080/20450923.2026.2689312","year":2026,"isNew":true,"title":"Advances in liver transplantation for hepatic malignancies"},{"pmid":"42256552","doi":"10.1016/j.pscia.2026.100125","year":2026,"isNew":true,"title":"Therapeutic potential of the sphingosine kinase 2 inhibitor opaganib"},{"pmid":"42255492","doi":"10.1016/j.reth.2026.101148","year":2026,"isNew":true,"title":"Adipose-derived mesenchymal stem cells promote diabetic wound healing through ALDOA secretion"},{"pmid":"42247481","doi":"10.1080/15384047.2026.2683942","year":2026,"isNew":true,"title":"The tumor microenvironment in triple negative breast cancer and a strategy to improve responses to immunotherapy using cryoablation and immunostimulants"},{"pmid":"42212521","doi":"10.1080/14756366.2026.2677282","year":2026,"isNew":true,"title":"Targeting the BMX in cancer: molecular mechanisms and emerging therapeutic strategies"},{"pmid":"42187002","doi":"10.1080/15384047.2026.2678636","year":2026,"isNew":true,"title":"Diagnostic and prognostic value of lncSPATA8-AS1 in prostate cancer and its regulatory effect on tumor progression"},{"pmid":"42148803","doi":"10.1080/15384101.2026.2630878","year":2026,"isNew":true,"title":"Circular RNAs in tumorigenesis: an insight into recent research in biogenesis and targeted tumor therapy"},{"pmid":"42130294","doi":"10.1080/07853890.2026.2654939","year":2026,"isNew":true,"title":"LncRNA H19 as a key regulator in biliary atresia: insights into pathogenesis and potential therapeutic targets"},{"pmid":"42146765","doi":"10.2147/ott.s593457","year":2026,"isNew":true,"title":"Research on Targeted Therapy for Malignant Tumors of the Biliary Tract"},{"pmid":"41869869","doi":"10.1080/17474124.2026.2649804","year":2026,"isNew":true,"title":"The evolving role of futibatinib for advanced cholangiocarcinoma"}],"trialsShown":[{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04645160","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Evaluating Efficacy of Tivozanib (AV-951) in Biliary Tract Cancers"},{"nct":"NCT01915225","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Obtaining Solid Tumor Tissue From People Having Biopsy or Surgery for Certain Types of Cancer"},{"nct":"NCT03212274","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations"},{"nct":"NCT07043387","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Streamlining Radioembolization for CCC and Metastatic Liver Cancer"},{"nct":"NCT06048133","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study of Gemcitabine, Cisplatin, AB680 and AB122 During First Line Treatment of Advanced Biliary Tract Cancers (QUIC)"},{"nct":"NCT04891289","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Gemcitabine and Oxaliplatin Chemotherapy With or Without a Floxuridine and Dexamethasone Pump in People With Cholangiocarcinoma That Cannot "},{"nct":"NCT06439485","phase":"phase 1/phase 2","status":"RECRUITING","isNew":true,"title":"Phase I/II Trial of Pemigatinib in Combination With Atezolizumab and Bevacizumab for Treatment of Advanced Cholangiocarcinoma With FGFR2 Fus"}],"usage":{"input":8104,"output":5819},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"cholangiocarcinoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"cholangiocarcinoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42311093","PMID:42256552","PMID:42255492","PMID:42247481","PMID:42212521","PMID:42187002","PMID:42148803","PMID:42130294","PMID:42146765","PMID:41869869","NCT07023731","NCT04645160","NCT01915225","NCT03212274","NCT07043387","NCT06048133","NCT04891289","NCT06439485"],"modelFamily":"Claude (Anthropic)","effort":"high","maxTokens":32000}},{"id":"f1787145817818","cycle":2,"visit":1,"ts":"2026-08-19T13:23:37.818Z","cancer":{"key":"pancreatic cancer","name":"pancreatic cancer","mondo":{"id":"MONDO:0009831","name":"malignant pancreatic neoplasm"}},"control":false,"modelLabel":"Claude","summary":"Prioritise intratumoral Enterobacter hormaechei cdd_L as a stratifying biomarker and antibiotic-reversible cause of gemcitabine failure in PDAC, alongside KRAS-G12D degrader and PARP1-selective genotype-directed leads.","confidence":0.53,"notebook":"Visit 1 establishes the programme. The pack is heavy on preclinical nanomedicine and light on outcome data, so I anchor leads where a mechanism meets an existing agent or trial.\n\nThe single most tractable new finding is microbial drug inactivation: intratumoral *Enterobacter hormaechei* expresses a long-isoform cytidine deaminase (cdd_L, Km 0.22 mM, kcat 194 s⁻¹) that converts gemcitabine to dFdU; cdd_L ablation fully restored sensitivity and antibiotic co-treatment potentiated gemcitabine, permitting 50% dose reduction in vivo (PMID:42099454). This is a host-extrinsic resistance mechanism, orthogonal to tumour genotype, and testable now with an approved-drug pair. [KNOWN] Gammaproteobacterial CDD-mediated gemcitabine degradation was previously described in colorectal models and is ciprofloxacin-reversible; [INFERRED] the actionable question is whether cdd_L carriage stratifies gemcitabine benefit prospectively, which NCT07226154's neoadjuvant response-prediction cohort could be nested against. Tumour-intrinsic gemcitabine resistance gets a parallel, non-competing mechanism: 14-3-3σ(SFN)–YAP1 driving ribonucleotide reductase expression (PMID:42507757, graded review, no new primary data) — filed as a biomarker question (RRM1/RRM2 protein readout), not yet a lead.\n\nGenotype-directed leads: ARV-806, a KRAS G12D-directed degrader now in ph1/2 (NCT07023731), addresses the dominant PDAC allele where occupancy-driven inhibition has been weak; expected escape is wild-type RAS/RTK-driven MAPK reactivation, secondary KRAS amplification, and YAP1 bypass. Separately, vertical MAPK+CDK blockade — ulixertinib (ERK1/2) plus palbociclib — matches the KRAS/CDKN2A co-alteration structure of the KG anchor (NCT03454035); therapeutic window is the concern (ERK is required in normal gut/skin epithelium; CDK4/6 in marrow). DDR: talazoparib in DDR-variant tumours (NCT04550494) and PARP1-selective AZD5305 (NCT04644068) matter because BRCA2/PALB2/BRCA1 in PDAC are overwhelmingly **germline** predisposition alleles with somatic LOH — I will keep that distinction explicit; PARP1 selectivity is the argument for combining with gemcitabine/platinum without dose-limiting cytopenia.\n\nMetabolic-immune: lactate efflux blockade with syrosingopine (MCT4) plus a pyroptosis/STING inducer converted cold tumours to PD-1-responsive in models (PMID:42335581), consistent with the lactate/glutamine/lipid reviews (PMID:42603919, PMID:42364496). Syrosingopine is an approved antihypertensive — repurposing-first — but the evidence is nanoformulated and preclinical only.\n\nRecorded as low-priority so the desk does not re-propose: TTFields+GnP for LAPC has an ICER of $387,300/QALY with only 0.34 QALY gain (PMID:42517235); HIFU+PD-1 is n=13 retrospective, palliative pain benefit only, no antitumour signal (PMID:42552867). Both are palliative/economic, not mechanistic leads. P4/P7 are non-actionable here.","leadChanges":[{"id":"L1","title":"cdd_L+ intratumoral Enterobacter as an antibiotic-reversible driver of gemcitabine inactivation","level":"LEAD","status":"NEW","confidence":0.55},{"id":"L2","title":"KRAS G12D targeted degradation (ARV-806) in PDAC","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"Vertical MAPK+CDK4/6 blockade (ulixertinib + palbociclib) for KRAS-mutant/CDKN2A-deleted PDAC","level":"LEAD","status":"NEW","confidence":0.35},{"id":"L4","title":"PARP1-selective inhibition and combination in germline BRCA1/2- and PALB2-associated PDAC","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L5","title":"Lactate efflux blockade (syrosingopine/MCT4) plus immunogenic cell death to sensitise PDAC to PD-1 blockade","level":"LEAD","status":"NEW","confidence":0.3}],"unverifiedCitations":0,"openQuestions":["Does cdd_L+ Enterobacter/Gammaproteobacteria carriage in resected or biopsied PDAC predict gemcitabine non-response, and what fraction of tumours carry it?","Can intratumoral gemcitabine:dFdU ratio serve as a clinical pharmacodynamic endpoint for antibiotic co-treatment, and which antibiotic minimises microbiome collateral damage?","What depth and duration of pERK suppression does KRAS-G12D degradation (ARV-806) achieve versus G12D occupancy inhibitors, and which bypass route dominates on-treatment ctDNA?","Is PARP1-selective inhibition (AZD5305) genuinely combinable with platinum/gemcitabine in germline BRCA2/PALB2 PDAC at doses that produce RAD51-foci loss?","Does the SFN(14-3-3sigma)-YAP1-ribonucleotide reductase axis provide a tumour-intrinsic gemcitabine-resistance biomarker (RRM1/RRM2) separable from microbial drug inactivation?","Can free syrosingopine (with or without metformin) lower intratumoral lactate enough to sensitise autochthonous PDAC to PD-1 blockade without nanocarrier delivery?"],"nextQueries":["(\"pancreatic\" AND (\"intratumoral microbiome\" OR \"intratumour bacteria\" OR \"cytidine deaminase\" OR Gammaproteobacteria) AND (gemcitabine OR resistance)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"pancreatic ductal adenocarcinoma\" AND (\"KRAS G12D\" OR \"KRAS degrader\" OR PROTAC OR SOS1 OR SHP2) AND (resistance OR combination)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"pancreatic\" AND (BRCA2 OR PALB2 OR \"homologous recombination deficiency\") AND (\"PARP1-selective\" OR AZD5305 OR talazoparib OR olaparib) AND (trial OR maintenance OR reversion)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42552867","doi":"10.1080/02656736.2026.2713171","year":2026,"isNew":true,"title":"Safety, feasibility, and palliative benefit of HIFU combined with PD-1 inhibitors for elderly patients with advanced pancreatic cancer: a real-world retrospective study"},{"pmid":"42517235","doi":"10.1080/13696998.2026.2707046","year":2026,"isNew":true,"title":"Estimating the cost-effectiveness of tumor treating fields for locally advanced pancreatic cancer patients"},{"pmid":"42507757","doi":"10.1080/15384047.2026.2710413","year":2026,"isNew":true,"title":"Stress-specific 14-3-3-client modules in digestive cancers: an evidence-graded review of adaptive survival and therapy resistance"},{"pmid":"42411636","doi":"10.1080/15384047.2026.2699508","year":2026,"isNew":true,"title":"Integrative single-cell and spatial transcriptomic approaches to decipher the tumor microenvironment and therapeutic resistance in pancreatic cancer"},{"pmid":"42364496","doi":"10.1016/j.biomaterials.2026.124406","year":2026,"isNew":true,"title":"Size switchable nanomodulator achieving ratio-precise dual-drug codelivery for synergistic glutamine metabolism modulation in pancreatic cancer"},{"pmid":"42361749","doi":"10.1016/j.biomaterials.2026.124385","year":2026,"isNew":true,"title":"Opposing intracellular redox modulation by a carrier-free diselenide nanosystem integrates antifibrosis and ferroptosis sensitization for fibrotic pancreatic cancer therapy"},{"pmid":"42358902","doi":"10.1016/j.puhip.2026.100818","year":2026,"isNew":true,"title":"Impact of COVID-19 pandemic on surgical cancer care disparities according to socioeconomic status"},{"pmid":"42335581","doi":"10.1016/j.biomaterials.2026.124401","year":2026,"isNew":true,"title":"A pH-responsive liposomal nanoplatform for reprogramming lactate metabolism and immunogenic activation in pancreatic cancer"},{"pmid":"42603919","doi":"10.1007/s10616-026-01052-1","year":2026,"isNew":true,"title":"Metabolic reprogramming in pancreatic cancer: interplay of glucose, lipid, and amino acid metabolism in tumor progression"},{"pmid":"42099454","doi":"10.1002/imt2.70126","year":2026,"isNew":true,"title":"Intratumoral &lt;i&gt;Enterobacter hormaechei&lt;/i&gt; drives gemcitabine resistance in pancreatic cancer via &lt;i&gt;cdd&lt;/i&gt; &lt;sub&gt;L&lt;/sub&gt;-mediated drug inactiv"}],"trialsShown":[{"nct":"NCT04999969","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic "},{"nct":"NCT05692323","phase":"NA","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Supervised Prehabilitation Program for Patients With Pancreatic Cancer"},{"nct":"NCT07226154","phase":"n/a","status":"RECRUITING","isNew":true,"title":"Prediction of Neoadjuvant Chemotherapy Response in Pancreatic Cancer"},{"nct":"NCT07023731","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"A Study to Evaluate ARV-806 in Adults With Advanced Cancer That Has the KRAS G12D Mutation"},{"nct":"NCT04550494","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations"},{"nct":"NCT04644068","phase":"phase 1/phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies"},{"nct":"NCT03454035","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Ulixertinib/Palbociclib in Patients With Advanced Pancreatic and Other Solid Tumors"},{"nct":"NCT01174121","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer"}],"usage":{"input":8933,"output":6347},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"pancreatic cancer\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"pancreatic cancer\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42552867","PMID:42517235","PMID:42507757","PMID:42411636","PMID:42364496","PMID:42361749","PMID:42358902","PMID:42335581","PMID:42603919","PMID:42099454","NCT04999969","NCT05692323","NCT07226154","NCT07023731","NCT04550494","NCT04644068","NCT03454035","NCT01174121"],"modelFamily":"Claude (Anthropic)","effort":"high","maxTokens":32000}},{"id":"f1787145608093","cycle":1,"visit":1,"ts":"2026-08-19T13:20:08.093Z","cancer":{"key":"glioblastoma","name":"glioblastoma","mondo":{"id":"MONDO:0018177","name":"glioblastoma"}},"control":false,"modelLabel":"Claude","summary":"Open the GBM programme on four leads, prioritising LonP1-driven OXPHOS as an MGMT-independent temozolomide-resistance target and lactate-BMAL1-VEGFA lactylation as a druggable bevacizumab-resistance axis, with all target hypotheses required to name a CNS-delivery route.","confidence":0.4,"notebook":"Visit 1 opens the programme; nothing to retire yet. The pack is delivery-heavy (P2–P5: magnetothermal hydrogel microspheres, platelet-borne sonodynamic fluorescein, membrane-coated metal nanoplatforms, microneedles) — engineering that addresses the BBB/BBTB and residual-cavity problems flagged as the core translational bottleneck (PMID:42573440), but none nominates a target. I log these as a cross-cutting constraint, not leads: any target hypothesis I write must state a CNS-exposure route. FL-SDT's mechanistic claim of HIF-1α degradation with downstream SMUG1/LIG4 loss (PMID:42523098) is the one delivery paper with a druggable-node readout — parked as a repair-axis observation. Trichodermin (PMID:42474259) is recorded as a dead end for the desk: trichothecenes are ribosome-peptidyl-transferase poisons [KNOWN], so \"p53 activation, G2/M arrest, TMZ synergy\" is expected of generic translational shutdown and the therapeutic window in brain is implausible — do not re-propose.\n\nFour mechanistic leads survive first pass. Strongest: LonP1 as a TMZ/O6-BG-resistance node driving OXPHOS-supported survival, causal in both directions (overexpression confers resistance, shRNA or pharmacologic inhibition restores TMZ sensitivity), and MGMT-independent, i.e. orthogonal to the only current resistance biomarker (PMID:42478633). Caveat from the abstract itself: rescue only \"partially\" supports specificity. Second: lactate→H3K18la at the BMAL1 promoter plus BMAL1 K123 lactylation→TUBA1C-dependent nuclear import→VEGFA, as bevacizumab resistance (PMID:41995718) — this makes glycolytic-flux blockade (MCT1/4, LDHA) a rational bevacizumab partner and converges with LonP1 on tumour metabolic state. Third, weakest: CCL2/TIMP1 as hub of a macrophage-rich, synapse-mimicry-low aggressive state (PMID:42454783) — in silico only, virtual knockout is not perturbation, but it gives a myeloid-axis hypothesis to pair with the LAG-3/PD-1 arm now recruiting (NCT06816927). Fourth: DDR/nucleotide-pool radiosensitisation, with triapine (ribonucleotide reductase) + IMRT in recurrence (NCT06860594) and CC-115 (DNA-PK/mTOR) inside INSIGhT (NCT02977780); separately, olaparib in IDH1/2-mutant glioma (NCT03212274) tests the 2-HG-induced homologous-recombination-defect synthetic lethality [KNOWN] — but WHO 2021 removed IDH-mutant tumours from \"glioblastoma\", so that lead is adjacent-disease and must be tagged as such. SEC61G (PMID:42345355) stays on the watchlist, not a lead: distinguishing an independent driver from an EGFR 7p11.2 co-amplification passenger needs isogenic dependency data I do not have.\n\nNext visit I need LonP1 chemical matter and CNS penetrance, whether MCT/LDHA inhibition actually reverses bev resistance in vivo, and whether CCL2/CCR2 blockade has any GBM perturbation evidence.","leadChanges":[{"id":"L1","title":"LonP1 inhibition to resensitise glioblastoma to temozolomide (MGMT-independent)","level":"LEAD","status":"NEW","confidence":0.5},{"id":"L2","title":"Block glycolytic lactate flux to reverse BMAL1-lactylation-driven bevacizumab resistance","level":"LEAD","status":"NEW","confidence":0.45},{"id":"L3","title":"CCL2/TIMP1 myeloid axis as the immunosuppressive barrier to checkpoint blockade in mesenchymal-like GBM","level":"LEAD","status":"NEW","confidence":0.28},{"id":"L4","title":"Nucleotide-pool and DNA-damage-response radiosensitisation in recurrent glioblastoma","level":"LEAD","status":"NEW","confidence":0.38},{"id":"L5","title":"PARP inhibition in IDH1/IDH2-mutant glioma (adjacent-entity synthetic lethality)","level":"LEAD","status":"NEW","confidence":0.35}],"unverifiedCitations":0,"openQuestions":["Does any LonP1 inhibitor with documented CNS penetrance exist, and does LonP1 loss sensitise MGMT-methylated as well as unmethylated orthotopic GBM to TMZ in vivo?","Does MCT1/MCT4 or LDHA blockade actually reverse bevacizumab resistance in vivo, and does it reduce H3K18la at the BMAL1 promoter and BMAL1 K123 lactylation?","Is there any experimental (not in silico) GBM evidence that CCL2/CCR2 or TIMP1/CD63 blockade improves PD-1 or LAG-3 checkpoint efficacy?","Is SEC61G an independent GBM dependency or an EGFR 7p11.2 co-amplification passenger — are there isogenic CRISPR dependency data separating the two?","Is HIF-1alpha a general upstream controller of SMUG1/LIG4 and repair capacity in hypoxic GBM, making hypoxia-directed agents rational radiosensitisers?","Which of the current GBM resistance targets have measurable intratumoral exposure by microdialysis or paired-tissue PK, i.e. which hypotheses are delivery-limited rather than biology-limited?"],"nextQueries":["(LONP1 OR \"Lon protease\") AND (glioma OR glioblastoma OR inhibitor) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","glioblastoma AND (lactylation OR \"MCT1\" OR \"MCT4\" OR LDHA OR bevacizumab resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","glioblastoma AND (CCL2 OR CCR2 OR TIMP1 OR \"tumor-associated macrophage\") AND (\"immune checkpoint\" OR LAG-3 OR PD-1) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"papersShown":[{"pmid":"42573440","doi":"10.1080/20565623.2026.2715646","year":2026,"isNew":true,"title":"Pathway dysregulation and therapeutic resistance in glioblastoma: molecular mechanisms and emerging therapeutic targets"},{"pmid":"42569466","doi":"10.1016/j.bioactmat.2026.07.043","year":2026,"isNew":true,"title":"Single-cell transcriptome-guided biomimetic magnetothermal hydrogel microspheres for multimodal eradication of residual glioblastoma"},{"pmid":"42523098","doi":"10.1080/10717544.2026.2708389","year":2026,"isNew":true,"title":"Ultrasound-triggered platelet vehicles loading fluorescein for targeted sonodynamic therapy of glioblastoma"},{"pmid":"42502435","doi":"10.1016/j.ijpx.2026.100612","year":2026,"isNew":true,"title":"Biomimetic membrane-coated metal nanoplatforms for enhanced BBB penetration and targeted glioblastoma therapy"},{"pmid":"42499529","doi":"10.1016/j.bioactmat.2026.07.013","year":2026,"isNew":true,"title":"Emerging bioactive microneedle platforms for disease management: From cutaneous disorders to systemic therapeutics"},{"pmid":"42474259","doi":"10.1080/14756366.2026.2694181","year":2026,"isNew":true,"title":"Trichodermin exhibits potent anti-glioblastoma activity by inducing cell cycle arrest and apoptosis, suppressing invasion, and enhancing temozolomide efficacy"},{"pmid":"42454783","doi":"10.1080/15384101.2026.2703934","year":2026,"isNew":true,"title":"Exploratory multi-omics links CCL2/TIMP1 axis to immunosuppressive TME in glioblastoma"},{"pmid":"42345355","doi":"10.1080/15384047.2026.2694136","year":2026,"isNew":true,"title":"Advances in SEC61G research: from ER translocon subunit to emerging pan-cancer oncogenic roles"},{"pmid":"42478633","doi":"10.1152/ajpcell.00145.2026","year":2026,"isNew":true,"title":"Deciphering LonP1's Role in Glioblastoma: An Alternative Mechanism of Treatment Resistance"},{"pmid":"41995718","doi":"10.1158/1078-0432.ccr-25-2352","year":2026,"isNew":true,"title":"Lactate-Induced Lactylation Enhances BMAL1 Transcription and Nuclear Translocation, Promoting Bevacizumab Resistance in Glioblastoma through VEGFA"}],"trialsShown":[{"nct":"NCT06108206","phase":"n/a","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Adaptive Radiotherapy and MRIs Based on Patients With Newly Diagnosed High-Grade Glioma"},{"nct":"NCT06816927","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Trial of Glioblastoma Immunotherapy Advancement With Nivolumab and Relatlimab"},{"nct":"NCT06860594","phase":"phase 1","status":"RECRUITING","isNew":true,"title":"Testing the Addition of an Anti-Cancer Drug, Triapine, to the Usual Radiation Therapy for Recurrent Glioblastoma or Astrocytoma"},{"nct":"NCT02977780","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"INdividualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT)"},{"nct":"NCT06556563","phase":"phase 3","status":"RECRUITING","isNew":true,"title":"EF-41/KEYNOTE D58: Phase 3 Study of Optune Concomitant With Temozolomide Plus Pembrolizumab in Newly Diagnosed Glioblastoma"},{"nct":"NCT04047264","phase":"NA","status":"RECRUITING","isNew":true,"title":"Feasibility of Intra- and Post-operative Microdialysis During Neurosurgery for Central Nervous System Lesions"},{"nct":"NCT03212274","phase":"phase 2","status":"ACTIVE_NOT_RECRUITING","isNew":true,"title":"Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations"},{"nct":"NCT06319027","phase":"phase 2","status":"RECRUITING","isNew":true,"title":"Identifying Findings on Brain Scans That Could Help Make Better Predictions About Brain Cancer Progression, The GABLE Trial"}],"usage":{"input":8723,"output":7025},"structured":true,"status":"PENDING REVIEW","provenance":{"desk":"oncolyst/0.1","sources":["europepmc","clinicaltrials.gov-v2","monarch-v3"],"queries":["\"glioblastoma\" AND (therapy OR treatment OR inhibitor OR immunotherapy OR \"targeted agent\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","\"glioblastoma\" AND (mechanism OR target OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"evidenceIds":["PMID:42573440","PMID:42569466","PMID:42523098","PMID:42502435","PMID:42499529","PMID:42474259","PMID:42454783","PMID:42345355","PMID:42478633","PMID:41995718","NCT06108206","NCT06816927","NCT06860594","NCT02977780","NCT06556563","NCT04047264","NCT03212274","NCT06319027"],"modelFamily":"Claude (Anthropic)","effort":"high","maxTokens":32000}}]