[{"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 <i>BRAF p.V600E, CDKN2A, TP53</i>, and <i>TERT</i> 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 <i>Nras</i> <sup>G12D</sup>-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 <i>Nf1</i> 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 <i>via</i> lncRNA ADPGK-AS1 downregulation"},{"pmid":"42275298","doi":"10.1080/13510002.2026.2687238","year":2026,"isNew":true,"title":"Significance of GSH and H<sub>2</sub>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<sup>6</sup>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<sub>2</sub>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 <i>Varroa destructor</i> 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 <i>ABL1</i> 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 <i>Helicobacter pylori</i> 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 <i>Lactobacillus</i> 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<sub>2</sub>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 <i>FGFR2</i>-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 <i>KRAS</i> 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 <i>Escherichia coli</i>"},{"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 <i>Erwinia amylovora</i>"},{"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<sup>mt</sup> 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 <i>Enterobacter hormaechei</i> drives gemcitabine resistance in pancreatic cancer via <i>cdd</i> <sub>L</sub>-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}}]