[{"key":"glioblastoma","name":"glioblastoma","mondo":{"id":"MONDO:0018177","name":"glioblastoma"},"genes":[{"label":"FGFR1","kind":"correlated"},{"label":"LZTR1","kind":"correlated"},{"label":"IDH1","kind":"correlated"},{"label":"PPARG","kind":"correlated"},{"label":"TP53","kind":"correlated"},{"label":"MGMT","kind":"correlated"},{"label":"NFKBIA","kind":"correlated"},{"label":"TACC1","kind":"correlated"},{"label":"SEPTIN14","kind":"correlated"},{"label":"ROS1","kind":"correlated"},{"label":"TACC3","kind":"correlated"}],"visits":4,"openQuestions":["Does any primary study report brain/tumour exposure of a CDDO-class or CC4-derived LonP1 inhibitor — and if a third targeted query fails, should L1 be reclassified as delivery-blocked pending a new chemotype rather than a therapeutic lead?","Is ONC201/ClpP-agonist cytotoxicity H3K27M-dependent or protease-expression-dependent in H3-wildtype GBM stem-like cells, and does CLPP/LONP1 expression stratify it?","Do KEAP1/NRF2 pathway status and GSH reserve determine whether LonP1/proteasome dual inhibition crosses the lethal ROS threshold in patient-derived GBM, and is the effect sex-dependent?","Are ClpP agonism and LonP1 inhibition synergistic or mutually buffering when applied together to the same GSC line?","Does any primary in vivo glioma experiment show MCT1/MCT4 or LDHA blockade improving bevacizumab, RT or anti-PD-1 efficacy (L2/L6, unanswered for three visits)?","Can the newly listed Optune+TMZ+pembrolizumab phase 3 (NCT06556563) serve as the myeloid-biomarker context for L3 alongside NCT06816927?"],"leads":[{"id":"L1","title":"LonP1 inhibition to resensitise glioblastoma to temozolomide (MGMT-independent)","mechanism":"LonP1 [SOMATIC] is overexpressed in high-grade astrocytoma, marks recurrence and poor survival, sustains mitochondrial proteostasis/OXPHOS and hypoxic tolerance, is elevated in TMZ- and O6-benzylguanine-resistant lines irrespective of MGMT status, and its knockdown restores TMZ sensitivity (PMID:42478633); dual LonP1 + chymotrypsin-like proteasome inhibition by BT317 (CC4-derived) kills malignant astrocytoma lines and patient-derived glioma stem-like cultures via ROS/apoptosis, with LonP1 necessary and sufficient for sensitivity (PMID:40088962, PMID:42573440, PMID:42462827). New this visit: the killing mechanism is threshold-dependent redox stress, where sub-lethal ROS is itself pro-tumorige","approach":"Priority 1 unchanged and now overdue: measure BT317/CDDO-class plasma:brain ratio, unbound brain fraction and P-gp/BCRP substrate status; use approved omaveloxolone as a CNS-exposed CDDO-class benchmark [KNOWN]; nest intratumoral measurement in the microdialysis protocol (NCT04047264). Priority 2: orthotopic MGMT-methylated vs unmethylated patient-derived GBM, BT317 or LonP1 knockdown +/- TMZ and +/- fractionated RT; readouts mitochondrial protein aggregation, mtDNA integrity, mitoSOX, Seahorse, gammaH2AX persistence, ATF4/LONP1/mtHSP70 as adaptation markers. New required covariates: KEAP1/NRF2 pathway status and NQO1/HMOX1 induction, plus sex-stratified cohorts. Do not claim TMZ synergy fro","level":"CANDIDATE","confidence":0.48,"citations":[{"kind":"PMID","id":"42478633","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42573440","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42462827","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40088962","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"38156441","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40305312","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT04047264","verified":true,"isNew":false,"addedVisit":3},{"kind":"PMID","id":"41881983","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42193972","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42278536","verified":true,"isNew":true,"addedVisit":4}],"corrobVisits":4,"createdVisit":1,"createdCycle":1,"lastVisit":4,"lastNote":"A dedicated pharmacokinetics query returned zero primary data on BT317/CC4/CDDO brain penetration, so Question 1 is unanswered after a targeted search; added class-toxicity and NRF2-buffering liabilities. Held at CANDIDATE on founding genetics but confidence cut from 0.56.","history":[{"visit":4,"cycle":138,"status":"WEAKENED","note":"A dedicated pharmacokinetics query returned zero primary data on BT317/CC4/CDDO brain penetration, so Question 1 is unanswered after a targeted search; added class-toxicity and NRF2-buffering liabilities. Held at CANDIDATE on founding genetics but confidence cut from 0.56."},{"visit":3,"cycle":59,"status":"STRENGTHENED","note":"Promoted: Question 1's chemical-matter prerequisite is met with a molecule tested in patient-derived glioma stem-like cells, plus two independent reviews of LonP1 inhibitor classes. Biguanide arm stays retired; partner is now CT-L proteasome inhibition. Brain exposure still unmeasured, and no in vivo orthotopic efficacy is citable yet, which caps confidence."},{"visit":2,"cycle":5,"status":"WEAKENED","note":"Targeted LONP1+glioma query returned no GBM-relevant or medicinal-chemistry hits; only orthogonal support is adipocyte UPRmt data at supratherapeutic metformin. Mechanism sharpened (ATF4 node), speculative biguanide combination retired, confidence down from 0.50."},{"visit":1,"cycle":1,"status":"NEW","note":"New this visit from PMID:42478633; bidirectional genetic plus pharmacologic evidence, but the authors state the rescue experiment only partially supports specificity, and no CNS-penetrant chemical matter is named in the abstract."}]},{"id":"L2","title":"Block glycolytic lactate flux to reverse BMAL1-lactylation-driven bevacizumab resistance","mechanism":"Lactate raises BMAL1 [SOMATIC] transcription via H3K18 lactylation at its promoter and lactylates BMAL1 K123, promoting TUBA1C binding, nuclear import, VEGFA output and bevacizumab resistance across lines, PDX, mouse and five clinical cohorts (PMID:41995718); reviews place lactylation at the centre of tumour angiogenesis, PD-L1 stabilisation, repair and stemness (PMID:41593811, PMID:42058190, PMID:42002813). New this visit, but extracranial: in gastric cancer H3K18la activates HAS2, driving c-MYC nuclear translocation and CD274/PD-L1 transcription, and 2-DG/oxamate or LDHA/LDHB double knockdown lowers H3K18la, suppresses growth and restores CD8+ cytotoxicity in vivo (PMID:42021123). [INFERRE","approach":"Unchanged core experiment: bevacizumab plus dual MCT1/MCT4 blockade (AZD3965-class, syrosingopine [KNOWN]) or LDHA inhibition in orthotopic GBM PDX; readouts H3K18la ChIP at the BMAL1 promoter, BMAL1 K123 lactylation, nuclear/cytoplasmic BMAL1, VEGFA, vessel normalisation, myeloid/CD8 composition. Added: assay HAS2, nuclear c-MYC and PD-L1 as a second, immunologically actionable output of the same lactylation node, which would make anti-PD-1 rather than bevacizumab the combination partner. Target lactate supply, not BMAL1 (core clock TF, poor window). Expected resistance: MCT1/MCT4 redundancy, vessel co-option, invasive escape, systemic lactataemia and retinal toxicity of MCT1 inhibitors [KN","level":"CANDIDATE","confidence":0.44,"citations":[{"kind":"PMID","id":"41995718","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41593811","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42058190","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42002813","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42021123","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":1,"lastVisit":3,"lastNote":"Weakened, not retired: a second consecutive dedicated query for primary in vivo glioma MCT1/MCT4/LDHA experiments returned nothing, so the decisive GBM experiment still does not exist and the corroboration remains review-level plus a non-CNS primary paper. Held at CANDIDATE because the founding GBM primary data stand.","history":[{"visit":3,"cycle":59,"status":"WEAKENED","note":"Weakened, not retired: a second consecutive dedicated query for primary in vivo glioma MCT1/MCT4/LDHA experiments returned nothing, so the decisive GBM experiment still does not exist and the corroboration remains review-level plus a non-CNS primary paper. Held at CANDIDATE because the founding GBM primary data stand."},{"visit":2,"cycle":5,"status":"STRENGTHENED","note":"Promoted on three independent NEW 2026 reviews converging on lactate transport/lactylation as druggable and on anti-angiogenic adaptive resistance specifically. Confidence held modest because the corroboration is review-level, not new primary GBM data, and the decisive in vivo MCT/LDHA + bevacizumab experiment still does not exist in citable form."},{"visit":1,"cycle":1,"status":"NEW","note":"New this visit; unusually complete mechanism (ChIP-qPCR, IP-MS, PDX, five cohorts) for a single paper, but no in vivo test of lactate-transport blockade plus bevacizumab is reported, which is the actionable gap."}]},{"id":"L3","title":"CCL2/TIMP1 myeloid axis as the immunosuppressive barrier to checkpoint blockade in mesenchymal-like GBM","mechanism":"A CCL2/TIMP1-centred signature marks TCGA-GBM patients surviving under one year, maps by scRNA-seq and spatial transcriptomics to inflammatory macrophage-enriched niches, and scores inversely with neuronal synapse-mimicry programmes; virtual knockout ranks both as network hubs (PMID:42454783). [INFERRED] CCL2-CCR2 recruits monocytic MDSC/TAM that would blunt PD-1/LAG-3 blockade; TIMP1 additionally signals through CD63 independent of MMP inhibition [KNOWN].","approach":"Use the ongoing nivolumab+relatlimab+RT/TMZ trial (NCT06816927) as the biomarker context: pre/post plasma and tissue CCL2/TIMP1, myeloid fraction, LAG-3+ T-cell exhaustion, testing whether high-CCL2 tumours are non-responders. Preclinically, CCR2 antagonism (approved-adjacent small molecules) plus anti-PD-1 in GL261/CT-2A. Normal tissue: CCR2 governs monocyte egress and infection control, so continuous blockade carries infectious risk; pulse dosing around checkpoint dosing. Expected resistance: CXCR2/CXCL8 and CSF1R-dependent myeloid compensation.","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"42454783","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06816927","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":1,"lastVisit":1,"lastNote":"New but deliberately low confidence: purely in silico/retrospective, virtual perturbation is not experimental knockout, and the authors themselves call for independent cohort validation.","history":[{"visit":1,"cycle":1,"status":"NEW","note":"New but deliberately low confidence: purely in silico/retrospective, virtual perturbation is not experimental knockout, and the authors themselves call for independent cohort validation."}]},{"id":"L4","title":"Nucleotide-pool and DNA-damage-response radiosensitisation in recurrent glioblastoma","mechanism":"GBM recurrence after RT/TMZ is repair-driven; depleting dNTP supply or crippling non-homologous end-joining should widen the radiation therapeutic ratio. Triapine inhibits ribonucleotide reductase (dNTP depletion, replication-stress-driven radiosensitisation) and is being added to IMRT at recurrence (NCT06860594); CC-115 (dual DNA-PK/mTORC1/2) is an active INSIGhT arm (NCT02977780). Independent support that lowering repair-enzyme abundance (SMUG1, LIG4) potentiates DNA-damaging therapy comes from the FL-sonodynamic work, where HIF-1alpha degradation suppressed both (PMID:42523098). [INFERRED] HIF-1alpha is therefore a candidate upstream regulator of repair capacity in hypoxic GBM cores.","approach":"Correlative arm on NCT06860594: intratumoral/interstitial pharmacokinetics (feasible via the microdialysis protocol NCT04047264) to prove RNR-inhibitor CNS exposure, plus RRM2/SMUG1/LIG4 and replication-stress markers on recurrence tissue. Normal tissue: RNR is required by all proliferating cells (myelosuppression; triapine causes methaemoglobinaemia [KNOWN]) and DNA-PK loss sensitises normal brain vasculature to RT — spatial confinement by focal IMRT is the window argument. Expected resistance: RRM2 amplification, ATR/CHK1-mediated fork protection (rational ATR-inhibitor combination), mTOR-pathway rebound.","level":"LEAD","confidence":0.38,"citations":[{"kind":"NCT","id":"NCT06860594","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT02977780","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42523098","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04047264","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":1,"lastVisit":1,"lastNote":"New this visit; assembled from two active trials plus an orthogonal mechanistic hint. Weakness: no efficacy data yet for either agent in GBM, and prior DNA-PK/mTOR inhibitors have been limited by CNS exposure and marrow toxicity.","history":[{"visit":1,"cycle":1,"status":"NEW","note":"New this visit; assembled from two active trials plus an orthogonal mechanistic hint. Weakness: no efficacy data yet for either agent in GBM, and prior DNA-PK/mTOR inhibitors have been limited by CNS exposure and marrow toxicity."}]},{"id":"L5","title":"PARP inhibition in IDH1/IDH2-mutant glioma (adjacent-entity synthetic lethality)","mechanism":"IDH1 [SOMATIC] is a KG-anchored correlate; mutant IDH1 R132H generates D-2-hydroxyglutarate, which inhibits alpha-ketoglutarate-dependent dioxygenases and produces a homologous-recombination-deficient 'BRCAness' state exploitable by PARP inhibition [KNOWN]. Olaparib is in phase 2 in IDH1/2-mutant glioma and other IDH-mutant tumours (NCT03212274).","approach":"Await/seek response and biomarker data from NCT03212274 (RAD51 foci, 2-HG levels, MGMT status). Explicit framing caveat: under WHO 2021, IDH-mutant tumours are astrocytoma, not glioblastoma, so this lead informs the GBM programme only as a mechanism template (2-HG-driven repair defect) and for the rare IDH-mutant tumour still labelled GBM in legacy cohorts. Normal tissue: PARP1 loss is tolerated outside HR-deficient cells; marrow toxicity dominates. Expected resistance: HR restoration, PARP1 mutation, drug efflux at the BBB (P-gp limits olaparib CNS exposure [KNOWN]).","level":"LEAD","confidence":0.35,"citations":[{"kind":"NCT","id":"NCT03212274","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":1,"lastVisit":1,"lastNote":"New this visit from the trial pack and the IDH1 KG anchor; held at low confidence and flagged as adjacent-entity so the desk does not mistake it for IDH-wildtype GBM biology.","history":[{"visit":1,"cycle":1,"status":"NEW","note":"New this visit from the trial pack and the IDH1 KG anchor; held at low confidence and flagged as adjacent-entity so the desk does not mistake it for IDH-wildtype GBM biology."}]},{"id":"L6","title":"Lactate-supply blockade as a hypoxia-core radiosensitiser in glioblastoma","mechanism":"[INFERRED] The hypoxic GBM core is the most glycolytic and most radioresistant compartment. Lactylation has been asserted to support DNA repair and stemness and to stabilise PD-L1 (PMID:42058190), and in GBM HIF-1alpha degradation lowered SMUG1 and LIG4 and potentiated DNA-damaging therapy (PMID:42523098). New this visit the only primary evidence tying LDHA blockade to a mechanistic output is immunological, not repair-related: LDHA/LDHB knockdown lowers H3K18la and restores CD8+ killing via HAS2/c-MYC/PD-L1 in gastric cancer (PMID:42021123). [INFERRED] the lactylation-DDR link remains unsupported by any primary experiment in any tumour, so the repair-capacity rationale for this lead is the w","approach":"Reprioritise: run the immunometabolic arm first — fractionated RT +/- LDHA or dual MCT1/4 inhibition in immunocompetent GL261/CT-2A with anti-PD-1, scoring H3K18la, HAS2, nuclear c-MYC, tumour PD-L1, CD8 infiltration/exhaustion and myeloid fraction. Retain the DDR readouts (SMUG1/LIG4/RAD51, 53BP1/gammaH2AX resolution, clonogenic survival at 21% vs 1% O2, pimonidazole/CAIX mapping) as a falsification test of the repair hypothesis rather than its premise. Nest correlatives in the recurrent-GBM RT platform (NCT06860594) and use microdialysis (NCT04047264) to confirm intratumoral lactate falls on drug. Normal tissue: MCT1/4 support erythrocyte, muscle and neuronal lactate shuttling — neuronal l","level":"LEAD","confidence":0.26,"citations":[{"kind":"PMID","id":"42058190","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42523098","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT06860594","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT04047264","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42021123","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41995718","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":5,"lastVisit":3,"lastNote":"Weakened: Question 4 unanswered for a second visit and the new primary lactylation paper points to immune evasion rather than DNA repair. Lead survives but is re-pointed at the immunometabolic axis, where citable primary mechanism now exists.","history":[{"visit":3,"cycle":59,"status":"WEAKENED","note":"Weakened: Question 4 unanswered for a second visit and the new primary lactylation paper points to immune evasion rather than DNA repair. Lead survives but is re-pointed at the immunometabolic axis, where citable primary mechanism now exists."},{"visit":2,"cycle":5,"status":"NEW","note":"New this visit; bridges the L2 metabolic axis to the L4 repair axis. Deliberately low confidence: the lactylation-DDR link is asserted in a review, not demonstrated in GBM, and the HIF-SMUG1/LIG4 evidence comes from a sonodynamic paradigm, not from lactate manipulation."}]},{"id":"L7","title":"ClpP hyperactivation (dordaviprone/ONC201) versus LonP1 inhibition — opposing mitochondrial protease modalities in H3-wildtype GBM","mechanism":"Mitochondrial AAA+/serine proteases (ClpP, LONP1) share ATP-driven substrate unfolding and can be pharmacologically blocked or hyperactivated (PMID:41655698). New this visit: ONC201 produced investigator-reported 1 CR and 1 PR among 5 patients with recurrent NON-midline (frontal/temporal/parietal) H3K27M-mutant cerebral gliomas, though blinded central review confirmed only 2 responses with one deemed non-measurable and one stable (PMID:38386699) — activity is therefore anatomically portable to the cerebral hemispheres but still tied to H3K27M. Independent reviews position ClpP agonism as the leading mitochondrial-directed strategy in high-grade glioma and link mitochondrial metabolism to epi","approach":"Decisive experiment: ONC201 dose-response in H3-wildtype patient-derived GBM stem-like cultures stratified by CLPP/LONP1 expression and by H3K27M isogenic knock-in/knock-out, versus H3K27M DMG controls; readouts respiratory-chain subunit loss, mitochondrial protein aggregation, ATF4/CHOP/mtHSP70, ROS, clonogenicity at 21% vs 1% O2, and H3K27me3/2-oxoglutarate-dependent demethylase output to test the metabolism-epigenetics link. Then ONC201 + BT317/CDDO combination to resolve synergy versus mutual buffering. If H3-wildtype activity is absent, retire the H3-wildtype extension and keep ClpP agonism only as a mechanism template. Normal tissue: ClpP and LONP1 required in heart, neurons, haematopo","level":"CANDIDATE","confidence":0.42,"citations":[{"kind":"PMID","id":"41655698","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40088962","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"38386699","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"41008904","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"41155556","verified":true,"isNew":true,"addedVisit":4}],"corrobVisits":2,"createdVisit":3,"createdCycle":59,"lastVisit":4,"lastNote":"Promoted: new independent clinical and review evidence this visit. Key reframing — non-midline responses show anatomy is not the constraint, so the open question is now mutation-dependence vs protease-dependence. Notebook caution recorded: n=5 with partial blinded-review discordance, not efficacy evidence.","history":[{"visit":4,"cycle":138,"status":"STRENGTHENED","note":"Promoted: new independent clinical and review evidence this visit. Key reframing — non-midline responses show anatomy is not the constraint, so the open question is now mutation-dependence vs protease-dependence. Notebook caution recorded: n=5 with partial blinded-review discordance, not efficacy evidence."},{"visit":3,"cycle":59,"status":"NEW","note":"New axis opened by the AAA+ protease review; repurposing-first because ONC201 is already an approved CNS agent. Deliberately low confidence — no GBM data yet on ClpP agonism outside H3K27M, and directionality (activate vs inhibit) is unresolved."}]},{"id":"L8","title":"DRP1 inhibition to rescue NK/CAR-NK effector function in the hypoxic glioblastoma core","mechanism":"Hypoxia (1% O2) reduces NK cell mitochondrial content and membrane potential, raises mitochondrial ROS, triggers broad stress-response transcriptional change and drastically impairs cytotoxicity against tumour lines and patient-derived organoids; CD70-CAR-IL-15 engineering does not prevent this, whereas pharmacological DRP1 inhibition or CRISPR-Cas9 DRP1 knockout preserves mitochondrial load and restores cytotoxic function (PMID:41706678). Tumour-side NK evasion routes (ligand modulation, immunosuppressive cytokines, metabolic disruption, exhaustion) are catalogued in PMID:41799416. [INFERRED] GBM is a paradigmatically hypoxic, NK-poor tumour, so effector-intrinsic mitochondrial fission bloc","approach":"Ex vivo: DRP1-knockout or mdivi-1/Drpitor1a-preconditioned [KNOWN] allogeneic NK and CAR-NK products assayed against GBM patient-derived organoids/GSC spheroids at 1% O2 and in lactate-rich, low-glucose medium (to combine with the L2/L6 lactate axis); readouts mitochondrial mass/membrane potential, mitoSOX, degranulation, serial killing. In vivo: orthotopic GBM PDX with intratumoral or intracavitary delivery of DRP1-modified NK cells, hypoxia mapping to test whether killing now extends into pimonidazole-positive regions. Normal tissue: DRP1 (DNM1L) is essential for mitochondrial fission in neurons and heart, and germline DNM1L variants cause encephalopathy [KNOWN][GERMLINE] — hence ex vivo p","level":"LEAD","confidence":0.24,"citations":[{"kind":"PMID","id":"41706678","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41799416","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":59,"lastVisit":3,"lastNote":"New: first citable mechanism in this programme addressing effector-cell rather than tumour-cell hypoxia adaptation, and it is genetically validated. Low confidence because no GBM model was tested and the source work is not a brain-tumour study.","history":[{"visit":3,"cycle":59,"status":"NEW","note":"New: first citable mechanism in this programme addressing effector-cell rather than tumour-cell hypoxia adaptation, and it is genetically validated. Low confidence because no GBM model was tested and the source work is not a brain-tumour study."}]},{"id":"L9","title":"KEAP1/NRF2 antioxidant capacity and host sex as the response determinant for ROS-generating mitochondrial therapy in GBM","mechanism":"Tumour cells sit at elevated basal ROS; moderate oxidative stress is pro-tumorigenic (DNA damage, genomic instability, survival signalling) while only supra-threshold ROS triggers apoptosis/ferroptosis, making the antioxidant reserve the pharmacodynamic gatekeeper (PMID:41881983). [KNOWN] CDDO-class triterpenoids are canonical KEAP1-modifying NRF2 activators, so the same warhead proposed for LonP1/proteasome inhibition simultaneously induces the antioxidant programme that buffers its own lethal ROS burst [INFERRED]. NRF2 signalling is further sex-dependent — higher target-gene output in females, androgen-mediated suppression in males, plus CYP3A and body-composition pharmacokinetic differenc","approach":"Stratification/falsification experiment rather than a new target: in isogenic GBM stem-like lines with KEAP1 knockout or NRF2 (NFE2L2) overexpression versus NRF2 knockdown, test whether BT317/CDDO and ONC201 killing tracks inversely with NQO1/HMOX1/GCLM induction and GSH/GSSG ratio; combine with GCLC inhibition (buthionine sulfoximine [KNOWN]) or system xc- blockade to force supra-threshold ROS. Run male and female host orthotopic cohorts with matched plasma/tumour exposure to test sex-dependent pharmacodynamics; score lipid peroxidation (4-HNE, C11-BODIPY) spatially against pimonidazole/CAIX. Normal tissue: NRF2 is protective in brain and heart — systemic NRF2 suppression is unacceptable, s","level":"LEAD","confidence":0.24,"citations":[{"kind":"PMID","id":"41881983","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"41921312","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"41008904","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"41952187","verified":true,"isNew":true,"addedVisit":4}],"corrobVisits":1,"createdVisit":4,"createdCycle":138,"lastVisit":4,"lastNote":"New this visit; opened deliberately as a stratification/falsification lead for L1 and L7 rather than a standalone target, because the CDDO warhead's NRF2 agonism is a self-limiting mechanism the programme had not previously scored. Low confidence: no GBM-specific primary data, all supporting material is review-level.","history":[{"visit":4,"cycle":138,"status":"NEW","note":"New this visit; opened deliberately as a stratification/falsification lead for L1 and L7 rather than a standalone target, because the CDDO warhead's NRF2 agonism is a self-limiting mechanism the programme had not previously scored. Low confidence: no GBM-specific primary data, all supporting material is review-level."}]}],"retired":[],"nextQueries":["(omaveloxolone OR bardoxolone OR CDDO OR \"triterpenoid\") AND (\"brain penetration\" OR \"plasma:brain\" OR \"P-glycoprotein\" OR pharmacokinetics) AND (glioma OR brain OR CNS) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(ONC201 OR dordaviprone OR ClpP) AND (\"H3 wildtype\" OR \"IDH-wildtype\" OR \"glioma stem\" OR glioblastoma) AND (sensitivity OR resistance OR expression OR biomarker) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(NFE2L2 OR NRF2 OR KEAP1) AND (glioblastoma OR \"glioma stem\") AND (temozolomide OR radioresistance OR \"reactive oxygen\" OR ferroptosis) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T22:05:24.430Z"},{"key":"pancreatic cancer","name":"pancreatic cancer","mondo":{"id":"MONDO:0009831","name":"malignant pancreatic neoplasm"},"genes":[{"label":"TP53","kind":"causal"},{"label":"SMAD4","kind":"causal"},{"label":"STK11","kind":"causal"},{"label":"ACVR1B","kind":"causal"},{"label":"KRAS","kind":"causal"},{"label":"BRCA2","kind":"correlated"},{"label":"PALB2","kind":"correlated"},{"label":"PALLD","kind":"correlated"},{"label":"BRCA1","kind":"correlated"},{"label":"RABL3","kind":"correlated"},{"label":"CDKN2A","kind":"correlated"}],"visits":4,"openQuestions":["Does TROP2 protein rise on treatment in paired pre/progression biopsies from daraxonrasib- or KRAS-G12D-inhibitor-treated PDAC patients, and does TRIM22/IRF1 expression mark the patients who escape by cell-state rather than by RAS mutation?","In a contamination-controlled quantitative assay (total-cdd qPCR with blanks, culture, intratumoral LC-MS gemcitabine:dFdU), does any subset of human PDAC resections carry functionally deaminating bacteria at all, given the negative 16S bio","Is adaptive RTK bypass of pan-RAS(ON) genuinely absent, or merely attenuated, in mesenchymal FGFR1-high versus epithelial EGFR/ERBB3-high PDAC, and does differentiation state predict daraxonrasib depth of response?","Does autophagy inhibition plus RAS-pathway blockade produce differential benefit in KRAS G12R versus G12D PDAC models, and does restored surface MHC-I translate into anti-PD-1 sensitivity?","Can the residual case for allele-selective G12D degradation be settled by a head-to-head window comparison (crypt proliferation, skin/GI toxicity, chemo- and ADC-combinability) against pan-RAS at equivalent pERK suppression?"],"leads":[{"id":"L1","title":"cdd_L+ intratumoral Enterobacter as an antibiotic-reversible driver of gemcitabine inactivation","mechanism":"Bacterial cytidine deaminase (CDD_L and, contrary to the original claim, CDD_S) deaminates gemcitabine to inactive dFdU in situ; cdd ablation or GSH-cleavable tobramycin-gemcitabine conjugates restore sensitivity in models (PMID:42099454, PMID:42302584, PMID:42345004). NEW human data undercut the premise: 16S sequencing of 26 frozen PDAC resections plus 5 FFPE cases found bacterial DNA at negative-control/paraffin-blank levels in tumour and adjacent normal, with no separation between long- and short-term survivors after neoadjuvant gemcitabine (PMID:39795998). [INFERRED] intratumoral carriage is either rare, focal, or below 16S detection; the remaining supporting literature is review-level (","approach":"Abandon 16S as the prevalence assay. Required next step: contamination-controlled absolute quantification - total cdd (both isoforms) qPCR with extraction/paraffin blanks, anaerobic+aerobic culture, and functional ex vivo gemcitabine-deamination plus intratumoral LC-MS gemcitabine:dFdU ratio on banked neoadjuvant-treated resections with paired oral swabs, nested into NCT07226154. Pre-specify that a null result retires the lead. Only if a cdd-high functional subset exists do interventions (tumour-restricted GSH-cleavable antibiotic conjugate, tetrahyduridine-class deaminase inhibition) remain worth testing; periodontal-pathogen carriage (Aggregatibacter, P. gingivalis) is the most plausible e","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42099454","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07226154","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42302584","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41963781","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41758194","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42345004","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42178725","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40723890","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41658610","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41300985","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"39795998","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"41422344","verified":true,"isNew":true,"addedVisit":4}],"corrobVisits":4,"createdVisit":1,"createdCycle":2,"lastVisit":4,"lastNote":"Demoted from CANDIDATE: the first human resection cohort testing this hypothesis found low bacterial biomass indistinguishable from negative controls and no survival separation after neoadjuvant gemcitabine (PMID:39795998). Mechanism remains real in vitro; human relevance now unsupported.","history":[{"visit":4,"cycle":139,"status":"WEAKENED","note":"Demoted from CANDIDATE: the first human resection cohort testing this hypothesis found low bacterial biomass indistinguishable from negative controls and no survival separation after neoadjuvant gemcitabine (PMID:39795998). Mechanism remains real in vitro; human relevance now unsupported."},{"visit":3,"cycle":61,"status":"STRENGTHENED","note":"Third independent lab confirms direct CDD-mediated resistance and extends it to oral taxa, but contradicts CDD_S inertness — biomarker rewritten from cdd_L genotype to total cdd + functional deamination. DOSSIER deliberately withheld: still zero human carriage/response data."},{"visit":2,"cycle":6,"status":"STRENGTHENED","note":"Promoted: independent second lab/model reproduces the mechanism and supplies a delivery fix (PMID:42302584); reviews generalise the axis; PMID:42178725 added as an explicit brake on extrapolating antibiotic-potentiation effect sizes from SPF mice."},{"visit":1,"cycle":2,"status":"NEW","note":"New this visit from PMID:42099454; chosen as the lead lead because it couples a defined enzyme, a full genetic rescue, an in vivo dose-sparing effect, and only approved drugs."}]},{"id":"L2","title":"KRAS G12D targeted degradation (ARV-806) in PDAC","mechanism":"G12D lacks a covalent handle; event-driven degradation removes the protein pool (PMID:41423807, PMID:41598808) and should retain activity against KRAS-overabundance escape. NEW evidence narrows the niche: adaptive RAS-MAPK reactivation after mutant-selective G12D blockade is driven by EGFR/ERBB3 in epithelial-differentiated PDAC and by FGFR1 in mesenchymal PDAC, with the corresponding lineage markers correlated in TCGA (PMID:41801133), on top of PI3K-dependent GAB1 membrane recruitment nucleating EGFR/SHP2/SOS1-dependent WT-RAS complexes (PMID:42095550). [INFERRED] a G12D-selective agent therefore needs a differentiation-state-matched RTK/PI3K co-drug, whereas pan-RAS(ON) engagement pre-empt","approach":"Follow NCT07023731 for depth/duration of pERK suppression and mutant selectivity, benchmarked against daraxonrasib (PMID:42223072). Preclinically: ARV-806 plus PI3Kalpha inhibitor in epithelial-differentiated models versus ARV-806 plus FGFR inhibitor in mesenchymal models, stratified by EGFR/ERBB3 vs FGFR1/mesenchymal signature, with pERK, pAKT, membrane GAB1 and RAS-complex proximity readouts. Key differentiating experiment: crypt proliferation index and skin toxicity of ARV-806 combinations versus daraxonrasib at equi-pERK-suppression, to test whether the spared WT window buys chemo- or ADC-combinability that pan-RAS cannot. Resistance: KRAS amplification, CRBN/VHL loss, TRIM22/NF-kB-EMT s","level":"CANDIDATE","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT07023731","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41423807","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41598808","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41924551","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42095550","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42571850","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41801133","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42008116","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42223072","verified":true,"isNew":false,"addedVisit":4}],"corrobVisits":4,"createdVisit":1,"createdCycle":2,"lastVisit":4,"lastNote":"Weakened: NEW evidence (PMID:41801133) shows the bypass problem for mutant-selective agents is dual and lineage-dependent (EGFR and FGFR), requiring a differentiation-matched co-drug; the lead now survives only on the window/combinability argument, which must be measured head-to-head.","history":[{"visit":4,"cycle":139,"status":"WEAKENED","note":"Weakened: NEW evidence (PMID:41801133) shows the bypass problem for mutant-selective agents is dual and lineage-dependent (EGFR and FGFR), requiring a differentiation-matched co-drug; the lead now survives only on the window/combinability argument, which must be measured head-to-head."},{"visit":3,"cycle":61,"status":"STRENGTHENED","note":"Promoted on NEW primary mechanistic evidence (PMID:42095550) that closes open question 4 in favour of PI3K, but repositioned: with pan-RAS now phase-3 validated, allele-selective degradation must justify itself on window/sequencing, not efficacy alone."},{"visit":2,"cycle":6,"status":"STRENGTHENED","note":"Review-only corroboration, so no promotion; substantive change is elevating PI3K/AKT as a co-target for G12D specifically."},{"visit":1,"cycle":2,"status":"NEW","note":"New; trial-anchored only, no efficacy data yet in pack, so confidence capped."}]},{"id":"L3","title":"Vertical MAPK+CDK4/6 blockade (ulixertinib + palbociclib) for KRAS-mutant/CDKN2A-deleted PDAC","mechanism":"KRAS and CDKN2A co-occur in the KG anchor; CDKN2A loss [SOMATIC] is undruggable directly but releases CDK4/6-cyclin D, and ERK-driven cyclin D induction is the principal route of adaptive resistance to either agent alone. [INFERRED] Simultaneous ERK1/2 catalytic inhibition plus CDK4/6 inhibition converts a tumour-suppressor loss into a synthetic-lethal dependency. Normal tissue: ERK1/2 is essential in gut and skin epithelium and CDK4/6 in marrow, predicting overlapping mucosal and haematologic toxicity as the window-limiting problem.","approach":"Track NCT03454035 for tolerated combination dose and any RB1-intact/CDKN2A-null enrichment signal; require paired-biopsy pRB and cyclin D1 pharmacodynamics. Resistance routes: RB1 loss, CCNE1/CDK2 activation, MYC amplification, and ERK-independent PI3K/AKT flux.","level":"LEAD","confidence":0.35,"citations":[{"kind":"NCT","id":"NCT03454035","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":2,"lastVisit":1,"lastNote":"New; phase 1 only, biomarker selection not stated in the record, so this is a hypothesis to be tested rather than an emerging result.","history":[{"visit":1,"cycle":2,"status":"NEW","note":"New; phase 1 only, biomarker selection not stated in the record, so this is a hypothesis to be tested rather than an emerging result."}]},{"id":"L4","title":"PARP1-selective inhibition and combination in germline BRCA1/2- and PALB2-associated PDAC","mechanism":"BRCA2, BRCA1 and PALB2 appear as correlated genes but in PDAC are predominantly [GERMLINE] predisposition alleles with somatic second-hit LOH driving HR deficiency in the tumour; this is the BRCA/PARP synthetic-lethal paradigm [KNOWN]. First-generation PARP inhibitors trap both PARP1 and PARP2, and PARP2 inhibition drives the marrow toxicity that blocks combination with gemcitabine or platinum; PARP1-selective trapping (AZD5305) is the mechanistic fix. Normal-tissue role: PARP1 base-excision repair is dispensable in HR-proficient tissue, PARP2 is required for erythropoiesis - that difference is the window.","approach":"Read NCT04550494 (talazoparib in DDR-variant tumours) for PDAC-specific response in BRCA2/PALB2 versus broader DDR variants, and NCT04644068 for AZD5305 combinability with platinum/taxane and ADCs. Then test PARP1-selective agent plus platinum maintenance in germline-BRCA/PALB2 PDAC. Assays: germline+somatic panel with LOH/HRD score, RAD51 foci as functional HRD readout. Resistance: BRCA reversion mutations, 53BP1/SHLD loss, PARP1 mutation abolishing trapping, ABCB1 upregulation.","level":"LEAD","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT04550494","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04644068","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":2,"lastVisit":1,"lastNote":"New; explicitly separates germline predisposition from somatic HRD phenotype and names PARP1-selectivity as the testable advance.","history":[{"visit":1,"cycle":2,"status":"NEW","note":"New; explicitly separates germline predisposition from somatic HRD phenotype and names PARP1-selectivity as the testable advance."}]},{"id":"L5","title":"Lactate efflux blockade (syrosingopine/MCT4) plus immunogenic cell death to sensitise PDAC to PD-1 blockade","mechanism":"PDAC accumulates lactate, which suppresses DC maturation, expands Tregs/MDSCs and polarises macrophages to M2, forming a core barrier to checkpoint blockade (PMID:42603919). Co-delivery of the MCT4 inhibitor syrosingopine with the pyroptosis/STING inducer Polyphyllin VI lowered intratumoral lactate, matured DCs, raised CD8+ and NK infiltration, repolarised macrophages to M1 and sensitised models to PD-1 blockade (PMID:42335581). Normal tissue: MCT4 is expressed in glycolytic skeletal muscle and white blood cells, so systemic MCT4 blockade risks exercise intolerance and lymphocyte metabolic stress - the argument for tumour-directed delivery or intermittent dosing.","approach":"Repurposing-first: syrosingopine is an approved antihypertensive [KNOWN], and [KNOWN] it is synthetically lethal with metformin via NAD+/lactate stress - test syrosingopine +/- metformin plus anti-PD-1 in KPC orthotopic and autochthonous models with intratumoral lactate (hyperpolarised 13C or microdialysis) as pharmacodynamic endpoint before invoking nanoformulation. Resistance: compensatory MCT1/LDHB flux, glutamine or lipid substrate switching (PMID:42364496), stromal CAF-supplied nutrients.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42335581","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42603919","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42364496","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":2,"lastVisit":1,"lastNote":"New; evidence is preclinical and confounded by the nanocarrier, so the lead is deliberately reframed around the free approved drug to make it falsifiable.","history":[{"visit":1,"cycle":2,"status":"NEW","note":"New; evidence is preclinical and confounded by the nanocarrier, so the lead is deliberately reframed around the free approved drug to make it falsifiable."}]},{"id":"L6","title":"Pan-RAS(ON) tri-complex inhibition as the wild-type-bypass-proof alternative to allele-selective G12D therapy","mechanism":"Daraxonrasib is an oral molecular-glue tri-complex inhibitor of GTP-bound mutant and wild-type RAS; randomised phase 3 RASolute-302 gave median OS 13.2 vs 6.6 months versus investigator's-choice chemotherapy in previously treated mPDAC (PMID:42223072, PMID:42571010) with manageable epithelial toxicity (PMID:42557936, PMID:42433811). NEW mechanistic corroboration of the core rationale: adaptive RAS-MAPK reactivation after mutant-selective KRAS-G12D blockade is lineage-partitioned - EGFR/ERBB3-driven in epithelial-differentiated PDAC, FGFR1-driven in mesenchymal models, mirrored by TCGA expression correlations - and a RAS(ON) multi-selective inhibitor was assessed in the same system (PMID:4180","approach":"Treat daraxonrasib as comparator/backbone in every future PDAC RAS design. (i) Mine RASolute-302 correlatives for on-treatment ctDNA escape spectrum and G12 vs non-G12 subgroup effect; (ii) test first-line and gemcitabine/nab-paclitaxel combination sequencing under CYP3A4/ABCB1/OATP-dependent PK (PMID:42107507); (iii) paired-biopsy CD8/Treg/myeloid immunophenotyping plus surface MHC-I to test whether pan-RAS converts PD-1 refractoriness (PMID:42226008); (iv) crypt proliferation index and skin/GI grading as window readouts; (v) prospectively genotype epithelial vs mesenchymal differentiation and EGFR/FGFR1 expression to test whether pan-RAS truly neutralises both bypasses (PMID:41801133). Res","level":"DOSSIER","confidence":0.8,"citations":[{"kind":"PMID","id":"41924551","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41423807","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41598808","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42223072","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42571010","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42557936","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42433811","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42107507","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41801133","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42279426","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42226008","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42095550","verified":true,"isNew":false,"addedVisit":4}],"corrobVisits":3,"createdVisit":2,"createdCycle":6,"lastVisit":4,"lastNote":"Promoted to DOSSIER on visit 4: NEW independent mechanistic evidence (PMID:41801133, PMID:42279426) that the lineage-dependent EGFR/FGFR bypass which defeats allele-selective agents is the specific liability pan-RAS(ON) engagement pre-empts, layered on phase 3 OS data from visit 3. It has survived the visit-2 wild-type-window objection and the visit-4 cell-state-escape objection (which limits but ","history":[{"visit":4,"cycle":139,"status":"STRENGTHENED","note":"Promoted to DOSSIER on visit 4: NEW independent mechanistic evidence (PMID:41801133, PMID:42279426) that the lineage-dependent EGFR/FGFR bypass which defeats allele-selective agents is the specific liability pan-RAS(ON) engagement pre-empts, layered on phase 3 OS data from visit 3. It has survived the visit-2 wild-type-window objection and the visit-4 cell-state-escape objection (which limits but "},{"visit":3,"cycle":61,"status":"STRENGTHENED","note":"Promoted on NEW phase 3 primary data (PMID:42223072) plus three independent NEW commentaries; the visit-2 therapeutic-window objection to wild-type RAS engagement is answered empirically. Head-to-head versus mutant-selective agents still untested."},{"visit":2,"cycle":6,"status":"NEW","note":"New this visit; split off from L2 because it makes the opposite therapeutic-window bet and needs its own falsification path. Review-level evidence only — no primary efficacy data in pack."}]},{"id":"L7","title":"LIF neutralisation (AZD0171) plus PD-L1 blockade on the gemcitabine/nab-paclitaxel backbone","mechanism":"[KNOWN] LIF is a stromal/CAF- and tumour-derived cytokine that signals through LIFR-JAK-STAT3 in PDAC, supporting an immunosuppressive, chemoprotective desmoplastic niche; blocking it is intended to lower STAT3 tone and permit chemo-immunotherapy synergy. Trial-anchored only: AZD0171 + durvalumab + gemcitabine/nab-paclitaxel (NCT04999969). Normal tissue: LIF has roles in trophoblast implantation, neural and haematopoietic support, predicting fertility/neurologic caution and marrow interaction rather than acute organ toxicity.","approach":"Read NCT04999969 for PDAC-specific response, and require pSTAT3 by paired biopsy plus plasma LIF as pharmacodynamic proof of target engagement. [SPECULATIVE] Combine with L1: if intratumoral bacteria are cleared and gemcitabine exposure restored, LIF blockade may add stromal permissiveness rather than duplicate it — test in bacteria-colonised orthotopic models. Resistance: IL-6/OSM redundancy through the same gp130-STAT3 node, CAF heterogeneity, JAK-independent STAT3 activation.","level":"LEAD","confidence":0.3,"citations":[{"kind":"NCT","id":"NCT04999969","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":6,"lastVisit":2,"lastNote":"New from the trial list; only combination in the pack pairing stromal signalling blockade with the standard PDAC backbone. No efficacy data, so confidence capped.","history":[{"visit":2,"cycle":6,"status":"NEW","note":"New from the trial list; only combination in the pack pairing stromal signalling blockade with the standard PDAC backbone. No efficacy data, so confidence capped."}]},{"id":"L8","title":"Post-daraxonrasib resistance: sequencing RAS degraders, RAS-cleaving biologics and prenylation-bypass co-inhibition after pan-RAS failure","mechanism":"NEW primary evidence gives non-genetic escape a named axis: prolonged KRAS-MAPK inhibition relieves ERK-mediated transcriptional repression, inducing IRF1/IRF9-driven TRIM22, an IFN-inducible E3 ligase that degrades IkBa, producing sustained NF-kB signalling, EMT and a basal-like state with marked upregulation of the NF-kB target TROP2 (TACSTD2); sacituzumab govitecan combined with KRAS or ERK inhibitors suppressed PDAC xenograft growth (PMID:42008116). This complements genetic escape routes - ternary-complex-disrupting mutations and KRAS overabundance (PMID:42557936), against which occupancy-based glues fail but degraders should not - and PI3K/GAB1-WT-RAS reactivation (PMID:42095550) plus l","approach":"Post-pan-RAS resistance registry: mandatory progression biopsy plus ctDNA from daraxonrasib-treated PDAC, classifying escape as (a) ternary-complex mutation, (b) KRAS overabundance/amplification, (c) PI3K-GAB1 or EGFR/FGFR RTK reactivation, (d) IFN-TRIM22-NF-kB/EMT cell state. Add TROP2 IHC/H-score and TRIM22, IRF1, IRF9 transcript readouts to every paired biopsy - the immediate testable prediction is that TROP2 rises on treatment and marks route (d). Assign: (a)/(b) -> RAS degrader or RAS-cleaving biologic; (c) -> PI3K or FGFR add-back matched to differentiation state; (d) -> sacituzumab govitecan concurrent with continued RAS inhibition (concurrent, not sequential, per PMID:42008116). Deri","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"PMID","id":"42557936","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42571010","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42571850","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42107507","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42095550","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42008116","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"41801133","verified":true,"isNew":true,"addedVisit":4}],"corrobVisits":2,"createdVisit":3,"createdCycle":61,"lastVisit":4,"lastNote":"Promoted to CANDIDATE on NEW primary mechanistic and in vivo evidence (PMID:42008116) that converts vague 'cell-state escape' into a specific IFN-TRIM22-NF-kB-TROP2 axis with an approved ADC as the matched intervention.","history":[{"visit":4,"cycle":139,"status":"STRENGTHENED","note":"Promoted to CANDIDATE on NEW primary mechanistic and in vivo evidence (PMID:42008116) that converts vague 'cell-state escape' into a specific IFN-TRIM22-NF-kB-TROP2 axis with an approved ADC as the matched intervention."},{"visit":3,"cycle":61,"status":"NEW","note":"Created because phase 3 success (PMID:42223072) makes acquired pan-RAS resistance the programme's new frontier; evidence is review/abstract-level for the specific agents, hence LEAD only."}]},{"id":"L9","title":"Autophagy blockade as dual-purpose therapy for KRAS G12R PDAC and for KRAS-enforced MHC-I loss","mechanism":"KRAS G12R (15-20% of PDAC) places a bulky positively charged arginine into the switch-II pocket, sterically precluding covalent and competitive pocket-directed engagement, and rewires signalling with impaired PI3Kalpha and MEK coupling but amplified autophagy-dependent survival (PMID:42226005). Independently, oncogenic KRAS enforces immune exclusion partly through autophagy-mediated degradation of MHC-I, and autophagy inhibition restores surface MHC-I and antigen-dependent CD8+ T-cell killing (PMID:42226008). [INFERRED] one intervention therefore addresses both the G12R-specific survival dependency and the antigen-presentation defect, and it is orthogonal to pocket occupancy - so it should c","approach":"Repurposing-first: hydroxychloroquine (approved) plus daraxonrasib, or plus ERK inhibition, in G12R-mutant versus G12D-mutant PDAC organoids, PDX and autochthonous models, with autophagic flux (LC3-II/p62), surface MHC-I flow cytometry, and CD8 infiltration as co-primary pharmacodynamics; test whether MHC-I restoration confers anti-PD-1 sensitivity in otherwise refractory models. Stratification hypothesis to test clinically: G12R tumours derive disproportionate benefit from autophagy inhibition, G12D from PI3K/RTK co-targeting. Assays: allele-resolved genotyping, mesenchymal/epithelial signature, spatial CD8-epithelium proximity (PMID:42226008). Resistance: lysosomal biogenesis via TFEB, mac","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42226005","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42226008","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42223072","verified":true,"isNew":false,"addedVisit":4},{"kind":"PMID","id":"42008116","verified":true,"isNew":true,"addedVisit":4}],"corrobVisits":1,"createdVisit":4,"createdCycle":139,"lastVisit":4,"lastNote":"New this visit: two NEW reviews converge on autophagy as both the G12R-specific dependency created by an undruggable pocket and the mechanism of KRAS-driven MHC-I loss, making an approved-drug combination testable in the pan-RAS era. Review-level evidence only, hence LEAD.","history":[{"visit":4,"cycle":139,"status":"NEW","note":"New this visit: two NEW reviews converge on autophagy as both the G12R-specific dependency created by an undruggable pocket and the mechanism of KRAS-driven MHC-I loss, making an approved-drug combination testable in the pan-RAS era. Review-level evidence only, hence LEAD."}]}],"retired":[],"nextQueries":["(\"pancreatic ductal adenocarcinoma\" AND (TROP2 OR TACSTD2 OR \"sacituzumab govitecan\" OR datopotamab) AND (KRAS OR \"RAS inhibitor\" OR resistance)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"pancreatic\" AND (\"KRAS G12R\" OR autophagy OR hydroxychloroquine OR PPT1 OR ULK1) AND (\"MHC-I\" OR \"antigen presentation\" OR immunotherapy OR trial)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(pancrea* AND (daraxonrasib OR \"RMC-6236\" OR \"pan-RAS\") AND (FGFR OR EGFR OR mesenchymal OR \"cell state\" OR ctDNA OR \"acquired resistance\")) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]"],"updatedAt":"2026-08-19T22:09:19.355Z"},{"key":"cholangiocarcinoma","name":"cholangiocarcinoma","mondo":{"id":"MONDO:0019087","name":"cholangiocarcinoma"},"genes":[{"label":"BRCA2","kind":"correlated"},{"label":"PTPN3","kind":"correlated"},{"label":"ROS1","kind":"correlated"},{"label":"BRCA1","kind":"correlated"}],"visits":4,"openQuestions":["What is the actual co-occurrence of MTAP IHC loss with FGFR2 fusion status in one CCA cohort — does the large-duct skew of MTAP loss mean PRMT5i eligibility is depleted, not enriched, among FGFRi-refractory fusion tumours?","Does non-deletional MTAP protein loss (IHC-negative, 9p21-intact by NGS) confer the same MTA accumulation and PRMT5i sensitivity as homozygous deletion?","Does TP53/RAS-pathway co-alteration outperform CDKN2A as the predictive marker of FGFR inhibitor failure when both are tested in the same cohort?","Is the DNMTi+PARPi effect in CCA HR-dependent (RAD51-foci loss) or senescence/SASP- and immune-dependent, and does priming-then-PARPi beat concurrent dosing?","Is MTAP-null CCA immunologically cold, and does PRMT5 inhibition restore antigen presentation or T-cell infiltration in immunocompetent MTAP-null models?","With CDKN2A-null FGFR2-fusion tumours now lacking an MTAP-based rescue, is there any published FGFRi + CDK4/6i biliary data or preclinical support at all?"],"leads":[{"id":"L1","title":"Covalent pan-FGFR inhibition (futibatinib) and combination FGFR/VEGF/PD-L1 blockade in FGFR2-fusion cholangiocarcinoma","mechanism":"FGFR2 fusions drive ligand-independent RAS-MAPK/PI3K signalling; futibatinib's covalent binding covers much of the kinase-domain resistance spectrum (PMID:41869869). Resistance is both primary/co-alteration-driven (44.4% concomitant GAs; CDKN2A mutation halved pemigatinib PFS 4.79 vs 8.66 mo — PMID:42494243) and acquired via secondary kinase-domain mutations plus bypass signalling, with ctDNA emerging as the non-invasive monitoring tool (PMID:41682001). Prospective profiling of 1254 BTCs nominates TP53/RAS-pathway rather than CDKN2A as the adverse co-alteration and documents driver retention at progression (PMID:42360806).","approach":"Unchanged: baseline co-alteration NGS (TP53, RAS-pathway, CDKN2A/B, MTAP, PTEN, BAP1) as a stratification factor in NCT06439485 and futibatinib cohorts; report FGFRi PFS by TP53/RAS versus CDKN2A status in the same cohort to adjudicate the two competing markers. FGFRi+CDK4/6i in CDKN2A/B-null, FGFRi+PI3K/AKTi in PTEN-null; MTAP IHC now added as a co-test to define PRMT5i eligibility within this population. Paired ctDNA at progression to separate kinase-domain alleles from MET/EGFR/PIK3CA bypass. Report Eastern versus Western enrolment fractions.","level":"CANDIDATE","confidence":0.75,"citations":[{"kind":"PMID","id":"41869869","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42146765","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06439485","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42494243","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42330567","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42491302","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42360806","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41912087","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41682001","verified":true,"isNew":true,"addedVisit":4}],"corrobVisits":4,"createdVisit":1,"createdCycle":3,"lastVisit":4,"lastNote":"P10 is a narrative review that restates prevalence and resistance biology without new data and does not adjudicate CDKN2A vs TP53/RAS, so no promotion. Marked down slightly because the MTAP-based rescue path I attached to CDKN2A-null fusions now looks anatomically mismatched (P8), leaving CDKN2A-null fusion tumours still without a druggable handle.","history":[{"visit":4,"cycle":140,"status":"WEAKENED","note":"P10 is a narrative review that restates prevalence and resistance biology without new data and does not adjudicate CDKN2A vs TP53/RAS, so no promotion. Marked down slightly because the MTAP-based rescue path I attached to CDKN2A-null fusions now looks anatomically mismatched (P8), leaving CDKN2A-null fusion tumours still without a druggable handle."},{"visit":3,"cycle":62,"status":"STRENGTHENED","note":"Strengthened by NEW P8: independent prospective confirmation that co-alterations govern FGFR2-driven outcomes, plus direct evidence of oncogenic-driver retention at progression. But P8 nominates TP53/RAS rather than CDKN2A, so the specific CDKN2A-predictive claim is not yet independently replicated; and a targeted search found zero published FGFRi+CDK4/6i CCA data, so open question 1 is still enti"},{"visit":2,"cycle":7,"status":"STRENGTHENED","note":"Two NEW independent cohorts (P2 real-world PEMIREAL-PEMIBIL; P7 agnostic single-centre) add a co-alteration resistance axis and simultaneously weaken the sequential-FGFRi salvage assumption. Lead pivots from 'covalent inhibitor solves resistance' to 'co-alteration-directed combination'."},{"visit":1,"cycle":3,"status":"NEW","note":"New lead created this visit from P10 (futibatinib retains activity against FGFR2 resistance mutations), P9 (FGFR2 fusion as validated actionable class in BTC) and T8 (active combination trial)."}]},{"id":"L2","title":"IDH1/2-mutant BRCAness: PARP inhibition, sequenced rather than combined with IDH inhibitors","mechanism":"Mutant IDH1/2 2-HG production impairs homologous recombination, creating a PARPi-sensitive state [KNOWN]. BilT-02 tested rucaparib + nivolumab maintenance after 4-6 months of first-line platinum in advanced BTC and missed its primary endpoint (4-month PFS 54.8%, 95% CI 36.0-72.7, vs 63% null; 2/31 PR), so the unselected chemo-maintenance strategy is falsified (PMID:42489677). The same trial reported 4-month PFS of 83.3% in DDR-mutant (BRCA2 n=3, ATM n=2, FANCA n=1; somatic/germline status not stated in abstract) and 100% in IDH1-mutant (n=3) patients — directionally supportive but n=9 and non-randomised.","approach":"Restrict to biomarker-selected monotherapy: olaparib in IDH1/IDH2-mutant CCA (NCT03212274) with functional HRD readout (RAD51 foci, HR scar signature) on paired biopsies; require prospective HRD confirmation before any further PARPi/PD-1 combination in BTC. Test sequential ivosidenib-then-olaparib versus concurrent dosing preclinically, since 2-HG depletion should restore HR and antagonise concurrent PARPi [INFERRED]. Tag BRCA1/2 events [GERMLINE] vs [SOMATIC] explicitly. Expected resistance: HR restoration, 53BP1 loss, ABCB1 upregulation. Anaemia/neutropenia (12.9%/9.7% grade >=3) define the haematologic window.","level":"LEAD","confidence":0.48,"citations":[{"kind":"NCT","id":"NCT03212274","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42146765","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42489677","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":3,"lastVisit":2,"lastNote":"NEW negative phase 2 (BilT-02) retires unselected PARPi + PD-1 maintenance in BTC — logged so the desk never re-proposes it. Only the biomarker-restricted core survives, on very small subgroup numbers.","history":[{"visit":2,"cycle":7,"status":"WEAKENED","note":"NEW negative phase 2 (BilT-02) retires unselected PARPi + PD-1 maintenance in BTC — logged so the desk never re-proposes it. Only the biomarker-restricted core survives, on very small subgroup numbers."},{"visit":1,"cycle":3,"status":"NEW","note":"New lead; T4 supplies a CCA-inclusive PARP trial and P9 confirms IDH1/2 as a defined actionable subset. KG BRCA1/BRCA2 correlated anchors converge on the same synthetic-lethal axis."}]},{"id":"L3","title":"CD73/adenosine blockade added to first-line chemo-immunotherapy in biliary tract cancer","mechanism":"Gemcitabine/cisplatin releases extracellular ATP; CD73 (NT5E) hydrolyses AMP to adenosine, and A2A receptor signalling on CD8 T and NK cells raises cAMP and suppresses effector function, plausibly capping the modest absolute benefit of PD-1/PD-L1 blockade on chemotherapy backbones in BTC [KNOWN]. Quemliclustat (CD73) plus zimberelimab (PD-1) is designed to remove this brake.","approach":"Follow NCT06048133 (QUIC) for response depth and CD73/adenosine-signature biomarkers; require baseline NT5E IHC, intratumoural adenosine-pathway transcriptional score, and on-treatment CD8 infiltration as go/no-go readouts. Normal-tissue caveat: CD73 is broadly expressed on endothelium and lymphocytes, so window depends on tumour-restricted flux rather than absolute expression.","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT06048133","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":3,"lastVisit":1,"lastNote":"New lead from T6; single trial citation only, so held at low confidence pending literature corroboration of CD73 as a BTC-specific immune brake.","history":[{"visit":1,"cycle":3,"status":"NEW","note":"New lead from T6; single trial citation only, so held at low confidence pending literature corroboration of CD73 as a BTC-specific immune brake."}]},{"id":"L4","title":"KRAS G12D degradation (ARV-806) in the KRAS-mutant, predominantly extrahepatic/gallbladder cholangiocarcinoma subset","mechanism":"KRAS alterations occur in 17% of 1254 prospectively profiled BTCs (PMID:42360806), with prevalence varying by anatomic subtype and geography (PMID:41912087). Allele-selective degradation removes KRAS G12D protein rather than occupying switch-II, which should blunt RTK-driven RAS reactivation and nucleotide-cycling escape [INFERRED]; SHP2 is the upstream RTK-to-RAS-GTP loading node and a resistance conduit with additional GI-TME effects (PMID:42310679).","approach":"Obtain CCA/GBC-specific enrolment and response data from NCT07023731. Design leverage is now concrete: ABC-01/-02/-03 individual-level post-hoc data give benchmark CisGem survival for 117 eCCA (68 pCCA, 49 dCCA) and 112 GBC (PMID:41887529), supplying the external comparator any single-arm eCCA/GBC expansion needs given that BTC targeted therapy has improved PFS without OS. Pre-plan degrader + allosteric SHP2i and degrader + EGFR/MET arms with MAPK-reactivation ctDNA surveillance and paired pERK/DUSP6 biopsies. Window: KRAS is required in normal epithelium, so allele selectivity is the argument; SHP2i adds oedema/thrombocytopenia.","level":"LEAD","confidence":0.46,"citations":[{"kind":"NCT","id":"NCT07023731","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42146765","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42360806","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42310679","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41912087","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41887529","verified":true,"isNew":true,"addedVisit":4}],"corrobVisits":3,"createdVisit":1,"createdCycle":3,"lastVisit":4,"lastNote":"NEW benchmark survival data for advanced eCCA and GBC on first-line CisGem strengthens the trial-design half of this lead only; target validation in biliary tissue is still absent, so confidence moves marginally. Kill criterion unchanged: no biliary signal in the ARV-806 phase 1 retires it.","history":[{"visit":4,"cycle":140,"status":"STRENGTHENED","note":"NEW benchmark survival data for advanced eCCA and GBC on first-line CisGem strengthens the trial-design half of this lead only; target validation in biliary tissue is still absent, so confidence moves marginally. Kill criterion unchanged: no biliary signal in the ARV-806 phase 1 retires it."},{"visit":3,"cycle":62,"status":"STRENGTHENED","note":"Prevalence now anchored in a NEW 1254-patient prospective cohort (17% KRAS) and combination logic supported by a NEW SHP2/GI-TME review. Still zero CCA-specific ARV-806 efficacy data — remains a placeholder to be killed if the phase 1 shows no biliary signal."},{"visit":1,"cycle":3,"status":"NEW","note":"New lead; pan-tumour G12D trial (T1) plus P9's precision-oncology framing for BTC. No CCA-specific efficacy data yet — explicitly a placeholder to be killed if the phase 1 shows no biliary signal."}]},{"id":"L5","title":"Epigenetically induced BRCAness: azacitidine (DNMT3B axis) plus PARP inhibitor in biliary tract cancer","mechanism":"Aberrant DNA hypermethylation is a core CCA epigenetic lesion, but DNMTi monotherapy (decitabine, azacitidine) is near-inert against CCA proliferation; a combinatorial drug screen identified PARP inhibitors as the synergy partner, with efficacy across four new patient-derived CCA lines, organoids, cell-line xenografts, PDX and hydrodynamic-tail-vein autochthonous mouse CCA, mechanistically via synergistic DNA damage, senescence induction, activation of inflammatory signalling and suppression of cell-cycle pathways (PMID:40520005). This is mechanistically distinct from the earlier azacitidine/DNMT3B-OGFR HR-impairment account that sensitised TFK-1 and RBE to niraparib (PMID:41463187) — two in","approach":"Resolve mechanism before designing schedule: paired RAD51-foci/HR gene-conversion assays versus senescence (SA-beta-gal, p21, SASP cytokine) and IFN/STING transcriptional readouts in the same CCA organoid panel under priming-then-PARPi versus concurrent dosing. Test immune dependence by repeating the autochthonous/syngeneic model in immunocompetent versus T-cell-depleted hosts, since a senescence/SASP mechanism predicts loss of efficacy without immunity [SPECULATIVE]. CRISPR (not siRNA) validation of DNMT3B and OGFR. Ask whether efficacy tracks molecular cluster or MTAP/CDKN2A status. Window: both classes are myelosuppressive, so low-dose intermittent hypomethylating priming with sequential ","level":"CANDIDATE","confidence":0.58,"citations":[{"kind":"PMID","id":"41463187","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40520005","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41762718","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41335282","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41673722","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":7,"lastVisit":3,"lastNote":"Promoted on NEW independent corroboration (P2): different group, four fresh patient-derived lines, organoids, PDX and an autochthonous model — far beyond the two-cell-line in vitro origin. Caveat recorded: P2's mechanism is senescence/inflammatory rather than HR loss, so the 'induced BRCAness' framing is now only one of two candidate mechanisms.","history":[{"visit":3,"cycle":62,"status":"STRENGTHENED","note":"Promoted on NEW independent corroboration (P2): different group, four fresh patient-derived lines, organoids, PDX and an autochthonous model — far beyond the two-cell-line in vitro origin. Caveat recorded: P2's mechanism is senescence/inflammatory rather than HR loss, so the 'induced BRCAness' framing is now only one of two candidate mechanisms."},{"visit":2,"cycle":7,"status":"NEW","note":"New lead from P4 (NEW this visit); provides an orthogonal, repurposing-first route to the same synthetic lethality that BilT-02 failed to demonstrate in unselected patients. In vitro only, two cell lines — deliberately held at low confidence."}]},{"id":"L6","title":"TNK1 as a cluster-directed kinase target in cholangiocarcinoma (TP-5801)","mechanism":"Unbiased multiomic profiling (WES, mRNA-seq, proteome/phosphoproteome) across all anatomic CCA subtypes defines three clusters — immunomodulatory, metabolic, gene-regulation/cell-fate — that are independent of anatomic site yet correlate with post-resection overall survival; kinase-enrichment analysis of phosphoproteomic activity nominated TNK1, and the selective TNK1 inhibitor TP-5801 showed in vivo activity in cluster-matched PDX models (PMID:41020779). TNK1 is a non-receptor tyrosine kinase acting on inflammatory/STAT and stress signalling [KNOWN]; this is a phosphoproteomic dependency invisible to DNA-based NGS, which matters because most CCA lacks a druggable mutation (PMID:42543673).","approach":"Independently reproduce the cluster assignment in an external CCA cohort and confirm TNK1 phosphosite activity by targeted MS; CRISPR/degrader knockout of TNK1 in cluster-matched versus non-matched CCA organoids to establish dependency rather than correlation; define a clinically deployable RNA-based cluster classifier suitable for FFPE before any trial. Normal-tissue role: TNK1 expression is largely haematopoietic/germline-restricted in adult tissue [KNOWN], which if true is a favourable window argument. Expected resistance: parallel SRC-family/JAK activation.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"41020779","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42543673","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":7,"lastVisit":2,"lastNote":"New lead from P1 (NEW this visit). Single group, single inhibitor, PDX-level evidence; the deliverable that would move it is an independent cohort reproducing cluster-to-TNK1-dependency mapping.","history":[{"visit":2,"cycle":7,"status":"NEW","note":"New lead from P1 (NEW this visit). Single group, single inhibitor, PDX-level evidence; the deliverable that would move it is an independent cohort reproducing cluster-to-TNK1-dependency mapping."}]},{"id":"L7","title":"Tinengotinib (Aurora A/B + FGFR1-3 + VEGFR2 + JAK1/2) in FGFR-inhibitor-refractory cholangiocarcinoma","mechanism":"Post-FGFRi CCA escapes through both kinase-domain alleles and non-genetic angiogenic/mitotic rewiring; a multikinase agent that simultaneously covers FGFR1-3, VEGFR2 and Aurora A/B could suppress bypass angiogenesis and force mitotic catastrophe in FGFR-independent clones [INFERRED]. In a 197-patient phase Ib/II across solid tumours, tinengotinib produced clinical benefit in 20.8% overall with CCA ORR 13.0% (n=23), and notably low hyperphosphataemia and ocular toxicity with hypertension as the dominant treatment-related AE; exploratory genomics correlated FGFR alterations with response (PMID:42489683). The modest CCA ORR is consistent with the general poor performance of second FGFRi exposur","approach":"Enrichment is the whole argument: evaluate tinengotinib only in FGFR2-fusion CCA after progression on a reversible or covalent FGFRi, with mandatory ctDNA genotyping to separate kinase-domain-mutant from fusion-retained/bypass-driven progression, and prespecified response analysis by those strata. Compare the tinengotinib toxicity profile (hypertension, low hyperphosphataemia) against selective FGFRi to test whether reduced FGFR1 engagement costs efficacy. Watch Aurora-driven neutropenia. Expected resistance: MET/EGFR bypass, EMT.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42489683","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42330567","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":7,"lastVisit":2,"lastNote":"New lead from P3 (NEW this visit), tempered at creation by P7's data on inferior second FGFRi exposure — the 13% unselected CCA ORR is not yet evidence of post-FGFRi activity in the fusion-defined population.","history":[{"visit":2,"cycle":7,"status":"NEW","note":"New lead from P3 (NEW this visit), tempered at creation by P7's data on inferior second FGFRi exposure — the 13% unselected CCA ORR is not yet evidence of post-FGFRi activity in the fusion-defined population."}]},{"id":"L8","title":"PRMT5 inhibition in MTAP-deleted biliary tract cancer, enriched in the CDKN2A-null FGFRi-refractory subset","mechanism":"MTAP loss (9p21, co-deleted with CDKN2A/B) raises intracellular methylthioadenosine, which partially inhibits PRMT5 and creates collateral-lethal dependence on residual PRMT5 activity [KNOWN]. NEW IHC data quantify the eligible population: MTAP expression loss in 21% small-duct iCCA, 35% large-duct iCCA, 19% extrahepatic CCA, 21% cHCC-CCA, 7% IPNB (invasive only), 0% bile duct adenoma, concordant with p16 loss and detectable in bile duct biopsy specimens (PMID:42242395) — higher than the 12.8% NGS-based deletion frequency in 1254 prospectively profiled BTCs (PMID:42360806), consistent with IHC also capturing hemizygous/epigenetic silencing [INFERRED]. P7 independently frames MTAP loss as def","approach":"Co-stain MTAP IHC with FGFR2 fusion status (FISH/RNA) and copy-number NGS in a single CCA cohort to measure true concordance and settle whether PRMT5i eligibility is enriched or depleted within fusion-positive disease. Use loss of cytoplasmic MTAP staining on core biopsies as the prospective screening assay (validated feasibility per PMID:42242395), with NGS confirmation of 9p21 deletion versus non-deletional loss. Preclinically test MTA-cooperative PRMT5 inhibitors as monotherapy and with pemigatinib/futibatinib in isogenic MTAP-null vs MTAP-restored CCA organoids; PD readouts SDMA on SmD3/MRE11, MDM2/p53 status recorded. Add an immune arm: PRMT5i +/- PD-1 blockade in immunocompetent MTAP-n","level":"CANDIDATE","confidence":0.6,"citations":[{"kind":"PMID","id":"42360806","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42494243","verified":true,"isNew":false,"addedVisit":3},{"kind":"PMID","id":"42242395","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42352533","verified":true,"isNew":true,"addedVisit":4}],"corrobVisits":2,"createdVisit":3,"createdCycle":62,"lastVisit":4,"lastNote":"Promoted: NEW independent IHC series across 287 hepatobiliary tumours quantifies the MTAP-null subset and proves biopsy/FFPE deployability, plus a NEW independent review naming MTAP loss as an immunophenotype-defining lesion. Same evidence weakens the assumed L1 linkage, since MTAP loss skews to large-duct iCCA while FGFR2 fusions skew small-duct.","history":[{"visit":4,"cycle":140,"status":"STRENGTHENED","note":"Promoted: NEW independent IHC series across 287 hepatobiliary tumours quantifies the MTAP-null subset and proves biopsy/FFPE deployability, plus a NEW independent review naming MTAP loss as an immunophenotype-defining lesion. Same evidence weakens the assumed L1 linkage, since MTAP loss skews to large-duct iCCA while FGFR2 fusions skew small-duct."},{"visit":3,"cycle":62,"status":"NEW","note":"New this visit from P8's prevalence data. Chosen deliberately because it converts the CDKN2A-loss problem flagged in L1 from an undruggable deletion into a synthetic-lethal target; no CCA-specific PRMT5i data exists yet, so it stays a LEAD."}]}],"retired":[],"nextQueries":["(cholangiocarcinoma OR \"biliary tract cancer\" OR \"intrahepatic cholangiocarcinoma\") AND (MTAP AND (FGFR2 OR \"large duct\" OR \"small duct\")) AND SRC:MED","(cholangiocarcinoma OR \"biliary tract cancer\") AND (\"CDK4/6\" OR palbociclib OR abemaciclib OR ribociclib) AND (FGFR OR CDKN2A) AND SRC:MED","(cholangiocarcinoma OR \"biliary tract cancer\") AND (azacitidine OR decitabine OR \"hypomethylating\") AND (PARP OR olaparib OR niraparib OR senescence) AND SRC:MED"],"updatedAt":"2026-08-19T22:12:46.433Z"},{"key":"small cell lung cancer","name":"small cell lung cancer","mondo":{"id":"MONDO:0008433","name":"small cell lung carcinoma"},"genes":[{"label":"RB1","kind":"causal"},{"label":"TP53","kind":"correlated"},{"label":"TP73","kind":"correlated"}],"visits":4,"openQuestions":["Is there any citable SCLC-specific synthetic-lethal dataset - SLFN11-stratified PARP/temozolomide, ATR (berzosertib), CHK1, WEE1 or Aurora - in RB1/TP53-null disease? (fourth attempt, now with single-anchor queries)","In relapsed SCLC lesions, do DLL3+ and YAP1+/B7-H3+ compartments coexist spatially (mandating concurrent engager + B7-H3 ADC or a bystander payload) or replace each other temporally (permitting sequencing)?","What are DLL3, SEZ6 and B7-H3 internalization kinetics in NE versus YAP1+ persister states - is impaired endocytosis a real SCLC persister feature favouring extracellular-release ADC design?","What is the CD58 expression status of SCLC and of the YAP1-emergent state, and is CD58 loss an independent DLL3-engager resistance route?","Are there ifinatamab deruxtecan or SEZ6-ADC efficacy data in DLL3-engager-pretreated patients, and is antigen profiling used for selection?","Does the NCT07203053 PS 2 read-out separate toxicity-driven discontinuation from efficacy loss - is the engager ceiling in unfit patients T-cell-fitness-limited or tumour-biology-limited?"],"leads":[{"id":"L1","title":"DLL3xCD3 T-cell engagers as lineage-restricted therapy in neuroendocrine SCLC","mechanism":"ASCL1/NEUROD1-driven NE SCLC aberrantly surfaces DLL3, permitting MHC-independent cytolysis agnostic to the RB1/TP53-null genotype [KNOWN/INFERRED]. Escape is lineage-state drift to a YAP1+/LCNEC-like persister with coordinate DLL3/SEZ6 loss (PMID:42019833), now independently framed as non-genetic, epigenetically driven antigen escape analogous to lineage switching in haematologic malignancies (PMID:42147254). Clinical ceiling is set by an immune-excluded 'cold' microenvironment: 60-70% first-line ORR but only 10-20% durable response, with tarlatamab and lurbinectedin the only later-line standards (PMID:42306740).","approach":"Follow NCT07203053 (PS 2) and NCT07472517 (obrixtamig + atezolizumab/carbo/etoposide, first line). Mandate paired pre/post biopsies plus CTC/ctDNA quantifying DLL3, SEZ6, B7-H3, TROP2, YAP1 at progression; DLL3 loss as primary correlative endpoint; separate toxicity-driven from efficacy-driven failure in PS 2; benchmark against the 10-20% durable-response ceiling rather than ORR.","level":"CANDIDATE","confidence":0.66,"citations":[{"kind":"NCT","id":"NCT07203053","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07472517","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42271190","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42019833","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42147254","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42306740","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":4,"lastVisit":3,"lastNote":"Third evidence-bearing visit and two new independent citations, but DOSSIER promotion deliberately withheld: both are reviews and the programme still holds no patient-level efficacy or antigen-kinetics data for any DLL3 engager. PMID:42306740 sharpens the bar (durable response 10-20%).","history":[{"visit":3,"cycle":63,"status":"STRENGTHENED","note":"Third evidence-bearing visit and two new independent citations, but DOSSIER promotion deliberately withheld: both are reviews and the programme still holds no patient-level efficacy or antigen-kinetics data for any DLL3 engager. PMID:42306740 sharpens the bar (durable response 10-20%)."},{"visit":2,"cycle":8,"status":"STRENGTHENED","note":"Promoted: second evidence-bearing visit with new independent literature. PMID:42271190 records tarlatamab as the only classical CD3 engager approved in solid tumours (external modality validation beyond the two sponsor trials); PMID:42019833 supplies the antigen-loss resistance model. Confidence up only 0.02 because the same paper that validates the axis predicts its escape route; still zero effic"},{"visit":1,"cycle":4,"status":"NEW","note":"New this visit. Two sponsors, two disease settings (first-line randomised phase 3 and pretreated PS 2 phase 2) give independent structural support; still no efficacy data in the pack, and antigen-loss/plasticity resistance is unmeasured."}]},{"id":"L2","title":"UGT1A1 genotype-directed belinostat with cisplatin/etoposide in RB1/TP53-null tumours","mechanism":"RB1/TP53-null SCLC lacks G1 checkpoint control and is chromatin-regulator dependent; HDAC inhibition may amplify topoisomerase-II/platinum DNA damage [INFERRED]. Belinostat is glucuronidated by UGT1A1, so germline UGT1A1 [GERMLINE] genotype predicts exposure and toxicity - the historical barrier to HDAC-plus-chemotherapy combinations is index, not target.","approach":"Follow NCT06406465 (genotype-directed belinostat PK/toxicity with cisplatin/etoposide) for a tolerable dose band; only then ask whether SCLC-specific efficacy exists. Expected liabilities: myelosuppression on an already myelotoxic backbone, QT prolongation, and lack of a predictive tumour biomarker.","level":"LEAD","confidence":0.25,"citations":[{"kind":"NCT","id":"NCT06406465","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":4,"lastVisit":1,"lastNote":"New but deliberately low confidence: the trial is a pharmacogenomic dosing study across solid tumours, not an SCLC efficacy signal, and the abstract provides no SCLC-specific rationale.","history":[{"visit":1,"cycle":4,"status":"NEW","note":"New but deliberately low confidence: the trial is a pharmacogenomic dosing study across solid tumours, not an SCLC efficacy signal, and the abstract provides no SCLC-specific rationale."}]},{"id":"L3","title":"Sequenced B7-H3 / TROP2 ADC coverage of the YAP1-emergent post-engager escape state","mechanism":"Relapsed SCLC harbours a YAP1+ drug-tolerant persister population lacking DLL3/SEZ6 but enriched for B7-H3 and TROP2 (PMID:42019833); antigen switching is the escape currency and the escape state carries its own surfaceome. Plasticity-driven antigen escape is now generalised across SCLC therapy (PMID:42147254). B7-H3 (CD276) protein is minimally expressed on normal adult tissue; TROP2 is broadly epithelial so its window is payload-driven and narrower [KNOWN]. Ifinatamab deruxtecan is in the predicted 2026 regulatory-review cohort (PMID:41560619), making the B7-H3 arm near-registrational rather than conceptual; ADC efficacy determinants (epitope, linker, payload potency, DAR, bystander effect","approach":"Pre-specify crossover or concurrent addition of a B7-H3 ADC at engager progression, selected by post-progression biopsy/CTC antigen profile rather than baseline subtype. Assays: multiplex IF for DLL3/SEZ6/B7-H3/TROP2/YAP1 on paired lesions; CTC surfaceome as non-invasive surrogate. Watch overlapping myelosuppression and ILD on chemo-exposed marrow; the key unresolved design question is spatial coexistence (concurrent) versus temporal replacement (sequential).","level":"CANDIDATE","confidence":0.62,"citations":[{"kind":"PMID","id":"42019833","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41411619","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41824576","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41220942","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41560619","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42070121","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42147254","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":8,"lastVisit":3,"lastNote":"Promoted: second evidence-bearing visit with new independent literature. I-DXd's late-stage/regulatory-review status (PMID:41560619) makes the covering agent real and near-term; PMID:42070121 supplies the design grammar for choosing payload/linker.","history":[{"visit":3,"cycle":63,"status":"STRENGTHENED","note":"Promoted: second evidence-bearing visit with new independent literature. I-DXd's late-stage/regulatory-review status (PMID:41560619) makes the covering agent real and near-term; PMID:42070121 supplies the design grammar for choosing payload/linker."},{"visit":2,"cycle":8,"status":"NEW","note":"New this visit, directly from the one primary research article in the pack. Answers open question 3 by deriving the covering antigens from the escape state itself rather than from baseline subtype surveys. No clinical data yet in this programme's citable set."}]},{"id":"L4","title":"CD2-based tumour-dependent costimulation to widen the DLL3 engager dose window in unfit SCLC","mechanism":"CD3 engagers are capped by cytokine toxicity and absent costimulation; a non-blocking CD2-agonist bispecific restores cytotoxicity of a sub-efficacious engager dose, compensates for tumour CD58 loss and recruits CD28-negative CD8 T cells prevalent in elderly patients (PMID:42271190). Relevant to the cold, immune-excluded SCLC microenvironment described in PMID:42306740. Format feasibility is no longer the obstacle: 501 multispecifics across 112 clinical-stage formats are catalogued (PMID:41542910). CD2/CD58 is a normal T-cell adhesion axis, so tumour-dependency of agonism is the entire window.","approach":"Build a DLL3xCD3 engager plus DLL3- or SEZ6-anchored CD2-costimulatory bispecific pair in SCLC PDX/humanised models; measure CD58 status of SCLC lines and relapsed biopsies and CD28-negativity of patient T cells as predictive covariates. Test against the NCT07203053 PS 2 read-out: if PS 2 failure is fitness/costimulation-limited rather than antigen-limited, low-dose engager plus costimulation is the fix. 4-1BB (PMID:41645963) is the alternative axis with worse hepatotoxicity legacy; CD28 formats carry the TGN1412 legacy [KNOWN].","level":"LEAD","confidence":0.37,"citations":[{"kind":"PMID","id":"42271190","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41645963","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41700001","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT07203053","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41542910","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42306740","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":8,"lastVisit":3,"lastNote":"Modest strengthening only: PMID:41542910 establishes engineering feasibility of the format class and PMID:42306740 supports the cold-TME rationale, but no DLL3-CD2 construct and no SCLC CD58 data exist in the citable set.","history":[{"visit":3,"cycle":63,"status":"STRENGTHENED","note":"Modest strengthening only: PMID:41542910 establishes engineering feasibility of the format class and PMID:42306740 supports the cold-TME rationale, but no DLL3-CD2 construct and no SCLC CD58 data exist in the citable set."},{"visit":2,"cycle":8,"status":"NEW","note":"New. Speculative extrapolation from a HER2xCD2 / EpCAMxCD3 proof-of-concept in xenografts to SCLC - no DLL3-specific CD2 construct exists in the citable set. Kept at 0.35 for that reason, but it is the only pack-supported route to the PS 2 / cytokine-ceiling problem."}]},{"id":"L6","title":"Bystander-capable / non-internalizing ADC payload design to kill antigen-negative SCLC persister compartments","mechanism":"PMID:41866709 identifies antigen loss, intratumoural heterogeneity and impaired endocytosis as the mechanisms defeating conventional internalizing ADCs, and proposes non-internalizing constructs with tumour-microenvironment- or trigger-activated linkers that release diffusible payload extracellularly, killing antigen-negative neighbours by bystander effect; PMID:42070121 lists bystander capacity as a tunable design axis. In SCLC the escape state is a DLL3-/SEZ6- YAP1+ persister interspersed with antigen-positive cells (PMID:42019833, PMID:42147254), so a payload that diffuses 2-3 cell diameters converts intratumoural antigen heterogeneity from a resistance mechanism into a coverage problem [","approach":"Preclinical: in mosaic SCLC models mixing DLL3+ and isogenic DLL3-knockout/YAP1+ persister cells, compare a non-cleavable internalizing DLL3 or SEZ6 ADC against a cleavable/extracellular-release construct; read out killing of the antigen-negative fraction, not bulk shrinkage. Measure DLL3 and B7-H3 internalization rate in NE versus YAP1+ states (impaired endocytosis is a predicted persister feature). Notebook constraint: rovalpituzumab tesirine already failed on the DLL3-ADC axis [KNOWN], so re-entry must be payload/linker-differentiated, and off-tumour payload release plus ILD/ocular toxicity are the anticipated liabilities.","level":"LEAD","confidence":0.32,"citations":[{"kind":"PMID","id":"41866709","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42070121","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42019833","verified":true,"isNew":false,"addedVisit":3},{"kind":"PMID","id":"42147254","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":63,"lastVisit":3,"lastNote":"New this visit from ADC-engineering reviews; no SCLC-specific experiment exists in the citable set, hence low confidence. It is the only route in the pack that addresses antigen-negative cells without needing a second target.","history":[{"visit":3,"cycle":63,"status":"NEW","note":"New this visit from ADC-engineering reviews; no SCLC-specific experiment exists in the citable set, hence low confidence. It is the only route in the pack that addresses antigen-negative cells without needing a second target."}]},{"id":"L7","title":"SLFN11-stratified, HR-independent PARP re-entry in RB1/TP53-null SCLC via dual-target inhibitors or PARP1-selective degraders","mechanism":"RB1/TP53-null SCLC [RB1 GERMLINE-likely per KG anchor; TP53 SOMATIC] is checkpoint-free and replication-stress-high but not homologous-recombination-deficient, which is exactly the limitation PMID:41395847 identifies as capping PARP-inhibitor utility (HR-deficiency dependence plus haematological toxicity). A dual-target PARP entity that co-engages a synergistic replication-stress node in one molecule avoids the additive marrow toxicity of multi-drug regimens (PMID:41395847), and PARP-selective PROTAC degradation (PMID:41885448) is an orthogonal route to widen the window against an already myelotoxic platinum/etoposide backbone. Predicted stratifier is SLFN11 [SOMATIC] expression [KNOWN]; pre","approach":"Purely pharmacological at this stage: no SCLC data exist in the citable set. Next step is retrieval, not experiment - find SLFN11-stratified PARP or ATR data in SCLC. Preclinically, benchmark a dual-target PARP agent and a PARP1-selective degrader against a classical PARPi in SLFN11-high versus SLFN11-null isogenic SCLC lines, with marrow-toxicity surrogates and explicit non-overlap with etoposide scheduling. Retirement rule: if visit 6 still yields no SCLC- or SLFN11-anchored data, retire.","level":"LEAD","confidence":0.18,"citations":[{"kind":"PMID","id":"41395847","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"41885448","verified":true,"isNew":true,"addedVisit":4}],"corrobVisits":1,"createdVisit":4,"createdCycle":141,"lastVisit":4,"lastNote":"New but deliberately near-floor confidence: created only to convert three visits of failed synthetic-lethality retrieval into a tracked, falsifiable object and to record the negative constraint that unstratified PARP inhibition in HR-proficient RB1/TP53-null SCLC has no citable rationale. Both citations are medicinal-chemistry reviews with no SCLC content.","history":[{"visit":4,"cycle":141,"status":"NEW","note":"New but deliberately near-floor confidence: created only to convert three visits of failed synthetic-lethality retrieval into a tracked, falsifiable object and to record the negative constraint that unstratified PARP inhibition in HR-proficient RB1/TP53-null SCLC has no citable rationale. Both citations are medicinal-chemistry reviews with no SCLC content."}]}],"retired":[{"title":"Epigenetic blockade of subtype plasticity to prevent, not chase, antigen loss","note":"Retired on the pre-registered condition set at visit 3: three consecutive visits, no SCLC experiment showing pharmacological prevention or reversal of subtype switching. PMID:41869709 again only lists epigenetic reprogramming and subtype transition among cisplatin-resistance mechanisms. Notebook constraint recorded so the desk does not re-propose LSD1/EZH2-plus-engager as if it were supported.","cycle":141,"ts":"2026-08-19T22:16:03.715Z"}],"nextQueries":["SLFN11 AND (\"small cell lung\" OR SCLC) AND (talazoparib OR temozolomide OR olaparib OR berzosertib OR ATR) AND SRC:MED","(tarlatamab OR \"DLL3 bispecific\" OR obrixtamig) AND (biopsy OR ctDNA OR \"antigen loss\" OR relapse OR resistance) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","(ifinatamab OR \"B7-H3\" OR SEZ6) AND \"small cell lung\" AND (heterogeneity OR internalization OR bystander OR multiplex) AND SRC:MED"],"updatedAt":"2026-08-19T22:16:03.715Z"},{"key":"esophageal cancer","name":"esophageal cancer","mondo":{"id":"MONDO:0007576","name":"esophageal cancer"},"genes":[{"label":"DCC","kind":"causal"},{"label":"RNF6","kind":"causal"},{"label":"TGFBR2","kind":"causal"},{"label":"LZTS1","kind":"causal"},{"label":"WWOX","kind":"causal"},{"label":"DLEC1","kind":"correlated"},{"label":"ERBB2","kind":"correlated"}],"visits":3,"openQuestions":["What fraction of the PMID:42153907 UASCC cohort is esophageal, and does ETS1-high status independently predict PD-1 failure in ESCC-only cohorts?","Do ETS1-high/STAT1-PD-L1-high and KLF4-low/HLA-ABC-low cold phenotypes co-segregate or define mutually exclusive ESCC strata on the same tissue cores?","Is HSP90i benefit in ETS1-high ESCC ETS1-dependent and CD8-dependent, and can intermittent dosing separate efficacy from known ocular/hepatic toxicity?","Which agent induced KLF4 in PMID:42493491, and is the MHC-I/CD8 rescue abolished in KLF4-null and B2M-null isogenics?","Is there any esophageal-specific PGE2/EP4 or cDC1 primary dataset, and does dual EP2/EP4 antagonism outperform COX-2 inhibition in 4NQO-driven ESCC?","Is there any esophageal-specific SHP2/PTPN11 dependency genotype (ERBB2/EGFR amplification, NF1 loss) with synergy over additivity when combined with anti-ERBB2?"],"leads":[{"id":"L1","title":"KLF4 re-induction to reopen MHC-I chromatin and rescue PD-1 blockade in esophageal cancer","mechanism":"Unchanged: KLF4 loss closes chromatin at MHC-I loci, lowering surface HLA-ABC and producing CD8-poor, anti-PD-1-resistant niches; KLF4 induction restores antigen presentation and anti-PD-1 efficacy in allografts (PMID:42493491), with antigen-presentation impairment listed among core ESCC ICB-resistance mechanisms (PMID:40837744) and KLF4 confirmed as an epigenetically silenced tumour suppressor (PMID:42598083).","approach":"Unchanged, but now with an added discriminator: co-stain HLA-ABC/B2M/KLF4 with ETS1 (see new lead) to establish whether MHC-I-low and ETS1-high cold tumours are the same or different patients before designing any add-on arm to PD-1 backbones (NCT06780111, NCT06203600). Still requires KLF4-null and B2M-null isogenics plus anti-CD8 depletion.","level":"CANDIDATE","confidence":0.54,"citations":[{"kind":"PMID","id":"42493491","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06780111","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06203600","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40837744","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42598083","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":9,"lastVisit":3,"lastNote":"Second consecutive visit in which a query written explicitly for ESCC + HLA class I/B2M + PD-1 biomarker returned no primary esophageal data; the core chromatin mechanism stays single-source and clinically unvalidated. Recorded as a negative and confidence trimmed; no promotion.","history":[{"visit":3,"cycle":142,"status":"WEAKENED","note":"Second consecutive visit in which a query written explicitly for ESCC + HLA class I/B2M + PD-1 biomarker returned no primary esophageal data; the core chromatin mechanism stays single-source and clinically unvalidated. Recorded as a negative and confidence trimmed; no promotion."},{"visit":2,"cycle":64,"status":"STRENGTHENED","note":"Second evidence-bearing visit: P4 independently establishes antigen-presentation loss as an ESCC ICB-resistance mechanism tied to negative clinical tails, P9 corroborates KLF4 as an epigenetically silenced tumour suppressor and maps available KLF-targeting modalities. Caveat carried forward: the specific KLF4->MHC-I chromatin mechanism remains single-source, and both new citations are reviews, not"},{"visit":1,"cycle":9,"status":"NEW","note":"New this visit from P9, the only fresh paper offering a mechanistically complete, genetically and pharmacologically supported route to reversing primary PD-1 resistance in esophageal cancer; MHC-I restoration is a defect-correction strategy, so the therapeutic window argument is favourable (KLF4 is a normal squamous differentiation factor). Key uncertainty: the inducer's identity and selectivity a"}]},{"id":"L2","title":"Allosteric SHP2 inhibition as the drug-tractable node downstream of ERBB2/EGFR in ESCC","mechanism":"SHP2/PTPN11 couples RTKs to RAS-ERK and, per PMID:38741380, PTPs act as convergent hubs that let tumours survive both targeted and checkpoint therapy, motivating PTP inhibitors as sensitisers rather than monotherapy. BGC1201 (SHP2-WT IC50 2.47 nM) suppressed p-ERK and inhibited KYSE-520 ESCC xenograft growth while sparing HUVEC (PMID:42388521); ERBB2 is the only [SOMATIC] actionable KG anchor (PMID:42425097). PMID:40598214 documents nuclear PTPN11 translocation as a non-canonical function, meaning p-ERK alone is an incomplete pharmacodynamic readout.","approach":"Vertical combination testing only: SHP2i plus anti-ERBB2/anti-EGFR in RTK-amplified ESCC/EAC lines and PDX, stratified by ERBB2/EGFR copy number, PIK3CA and KEAP1/NFE2L2 status; add a checkpoint-combination arm given the PTP/immune-suppression framing in PMID:38741380. Pharmacodynamics should include nuclear vs cytoplasmic PTPN11 localisation, not just p-ERK. [INFERRED] resistance routes: RAS-GTP reloading, MEK/ERK reactivation, PTPN11 allosteric-pocket mutations, FGFR/MET bypass. On-target toxicity watch: cytokine signalling and haematopoiesis require SHP2 [KNOWN].","level":"LEAD","confidence":0.38,"citations":[{"kind":"PMID","id":"42388521","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42425097","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"38741380","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40598214","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":9,"lastVisit":2,"lastNote":"Combination rationale strengthened by P1, but a query written explicitly for ESCC + SHP2/PTPN11/ERBB2-amplification returned no esophageal-specific primary literature this visit — recorded as a negative so the desk stops expecting disease-specific dependency data to appear passively. Stays at LEAD; esophageal SHP2 dependency still rests on one xenograft.","history":[{"visit":2,"cycle":64,"status":"STRENGTHENED","note":"Combination rationale strengthened by P1, but a query written explicitly for ESCC + SHP2/PTPN11/ERBB2-amplification returned no esophageal-specific primary literature this visit — recorded as a negative so the desk stops expecting disease-specific dependency data to appear passively. Stays at LEAD; esophageal SHP2 dependency still rests on one xenograft."},{"visit":1,"cycle":9,"status":"NEW","note":"New this visit. Evidence is thin: single ESCC xenograft, single agent, no combination or resistance data, and antiproliferative IC50 range spans 0.02-8.66 uM across a mixed panel, so esophageal-specific dependency is unproven. Retained because it is the only fresh chemically tractable link to the ERBB2 anchor."}]},{"id":"L3","title":"Decolonisation-gated ferroptosis sensitisation: intratumour Lactobacillus D-lactate/STAT3-K631 lactylation as a resistance switch","mechanism":"Unchanged: tumour-resident L. reuteri D-lactate drives STAT3 K631 lactylation, dimerisation and nuclear translocation, upregulating GPX4/FTH1 and blunting ferroptosis; ldhD deletion and STAT3-K631R abolish it (PMID:42281240), within a broader antioxidant-reprogramming context (PMID:42275298). Generic support added that intratumour and gut microbiota modulate drug and immunotherapy response partly through antigen presentation and myeloid polarisation (PMID:41963781, PMID:42207498).","approach":"Unchanged: stratify ESCC by intratumour Lactobacillus load and test GPX4i/cyst(e)ine-deprivation sensitivity with and without targeted decolonisation or ldhD blockade; validate K631-lactylation as a PD biomarker. Added: test whether Lactobacillus-high ESCC also differs in HLA-ABC/CD8 to see if the axis touches immunotherapy at all, using organoid-microbe co-culture as the platform.","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"42281240","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42275298","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41963781","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42207498","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":9,"lastVisit":3,"lastNote":"Open question 6 answered only at review level and only for microbiota in general; nothing links the D-lactate/STAT3-K631 axis specifically to ICB. Minimal increment — the ferroptosis arm remains the testable part.","history":[{"visit":3,"cycle":142,"status":"STRENGTHENED","note":"Open question 6 answered only at review level and only for microbiota in general; nothing links the D-lactate/STAT3-K631 axis specifically to ICB. Minimal increment — the ferroptosis arm remains the testable part."},{"visit":1,"cycle":9,"status":"NEW","note":"New this visit. Attractive because the causal chain is genetically dissected at both bacterial (ldhD) and host (K631R) ends in patient-derived cohorts (102 blocks, 27 patients), but no therapeutic agent exists yet and xenografts in nude mice cannot address immune contributions."}]},{"id":"L4","title":"B7-H3-directed ADC plus PD-1 blockade in esophageal cancer","mechanism":"Unchanged: I-DXd topoisomerase-I payload delivery to CD276/B7-H3-expressing tumour cells with pembrolizumab, DNA-damage-driven immunogenic cell death as the [INFERRED] synergy rationale (NCT06780111, PMID:42425097).","approach":"Downgraded to pure trial-tracking of KEYMAKER-U06 substudy 06E. Retire at next visit unless esophageal CD276 prevalence/intensity data or a 06E biomarker readout appears.","level":"LEAD","confidence":0.22,"citations":[{"kind":"NCT","id":"NCT06780111","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42425097","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":9,"lastVisit":3,"lastNote":"Third visit with no B7-H3 expression or efficacy data in esophageal cancer despite targeted searching; flagged for retirement to stop it consuming programme attention.","history":[{"visit":3,"cycle":142,"status":"WEAKENED","note":"Third visit with no B7-H3 expression or efficacy data in esophageal cancer despite targeted searching; flagged for retirement to stop it consuming programme attention."},{"visit":1,"cycle":9,"status":"NEW","note":"New this visit, trial-derived only; no esophageal efficacy or biomarker data in the pack, so this is a placeholder to be tested or retired when readouts or B7-H3 expression papers appear. NCT07023731 (ARV-806, KRAS G12D degrader) and the CRBN-ligand review PMID:42418534 were considered and not promoted to a lead: KRAS G12D is rare in esophageal cancer [KNOWN] and no esophageal data exist. TFPI2 (P"}]},{"id":"L5","title":"Dual restoration of direct and cross-presentation: PGE2/VEGF blockade layered onto MHC-I re-induction plus PD-1 in antigen-presentation-low ESCC","mechanism":"Two separable evasion routes — tumour MHC-I loss and PGE2/VEGF/IL-6/IL-10-mediated suppression of DC cross-presentation (PMID:41758201), both implicated in ESCC ICB resistance (PMID:40837744). New specificity: dual EP2+EP4 antagonism reverses immunosuppression better than single-receptor blockade, EP4 antagonist plus anti-PD-1/anti-CTLA-4 increases T-cell infiltration and cytotoxicity, and PTGES1 inhibition or 15-PGDH augmentation are alternative nodes for lowering intratumour PGE2 (PMID:40712694); DC heterogeneity, TME crosstalk and metabolic reprogramming define the cross-presentation defect to be corrected (PMID:41430039).","approach":"Prefer dual EP2/EP4 antagonism or PTGES1 inhibition over non-selective COX-2 inhibition in immunocompetent 4NQO/syngeneic ESCC models, each with and without anti-PD-1 and with an MHC-I-restoring agent from L1; primary readouts cDC1 abundance, ex vivo cross-presenting capacity, CD8 clonal expansion. Human anchor unchanged: PTGS2/PTGES/15-PGDH, VEGFA and cDC1 signatures scored against HLA-ABC/B2M IHC, now with ETS1 added to the panel.","level":"LEAD","confidence":0.34,"citations":[{"kind":"PMID","id":"41758201","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40837744","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42493491","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"40712694","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41430039","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":64,"lastVisit":3,"lastNote":"Mechanistic specificity improved (EP2+EP4 dual blockade, PTGES1, 15-PGDH), but both supporting papers are non-esophageal reviews and the esophagus-directed PGE2/cDC1 query returned no primary ESCC data — explicit cross-disease borrowing, so only a small confidence increment.","history":[{"visit":3,"cycle":142,"status":"STRENGTHENED","note":"Mechanistic specificity improved (EP2+EP4 dual blockade, PTGES1, 15-PGDH), but both supporting papers are non-esophageal reviews and the esophagus-directed PGE2/cDC1 query returned no primary ESCC data — explicit cross-disease borrowing, so only a small confidence increment."},{"visit":2,"cycle":64,"status":"NEW","note":"New this visit from P7, which supplies a mechanistic constraint on L1 rather than support: restoring tumour MHC-I cannot rescue priming if DC cross-presentation is suppressed. Currently a rationale-level lead with no esophageal-specific PGE2/cDC1 data in the pack."}]},{"id":"L6","title":"ETS1-high hybrid-EMT immune-cold ESCC: HSP90 inhibition as biomarker-selected ICB sensitiser","mechanism":"Single-cell dissection of upper aerodigestive squamous carcinoma identifies ETS1 as master regulator of a hybrid-EMT intratumoural heterogeneity programme that both activates prometastatic genes and builds an immune-cold TME by transcriptionally activating STAT1 and CD274/PD-L1 while excluding T lymphocytes; ETS1-high tumours show poor survival and ICB resistance across cohorts, and are selectively vulnerable to HSP90 inhibitors (alvespimycin) which suppress ETS1 via disruption of HIF-1alpha-mediated transcription (PMID:42153907). [INFERRED] this is an IFN-mimicry/adaptive-resistance state mechanistically distinct from the antigen-presentation-loss state of L1/L5, implying two separable immu","approach":"Confirm the ESCC (vs head and neck) fraction of PMID:42153907 and score ETS1 protein against HLA-ABC/B2M, KLF4 and PD-L1 CPS on the same ESCC/EAC cores to test co-segregation vs mutual exclusivity of the two cold phenotypes. In ETS1-high ESCC lines/PDX and syngeneic allografts test HSP90i (alvespimycin, ganetespib [KNOWN]) alone and with anti-PD-1; pharmacodynamics = ETS1 and hEMT signature loss, HIF-1alpha target suppression, CD8 infiltration and clonal expansion, not tumour size alone. Mandatory controls: ETS1 knockdown/rescue to prove HSP90i benefit is ETS1-dependent, and anti-CD8 depletion to prove immune dependence. [INFERRED] resistance routes: HSF1-driven heat-shock response, ETS fami","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"42153907","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT06780111","verified":true,"isNew":false,"addedVisit":3},{"kind":"NCT","id":"NCT06203600","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":142,"lastVisit":3,"lastNote":"New from the only primary paper in this visit's pack; supplies a second, mechanistically distinct ICB-resistance axis in squamous esophagus and a repurposable (if toxicity-limited) drug class. Caveat: UASCC cohort composition not resolvable from the abstract.","history":[{"visit":3,"cycle":142,"status":"NEW","note":"New from the only primary paper in this visit's pack; supplies a second, mechanistically distinct ICB-resistance axis in squamous esophagus and a repurposable (if toxicity-limited) drug class. Caveat: UASCC cohort composition not resolvable from the abstract."}]}],"retired":[],"nextQueries":["(ETS1 AND (\"esophageal squamous cell carcinoma\" OR \"upper aerodigestive\") AND (\"immune evasion\" OR EMT OR \"HSP90\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","((\"HSP90 inhibitor\" OR alvespimycin OR ganetespib OR onalespib) AND (esophageal OR \"squamous cell carcinoma\") AND (\"PD-1\" OR \"immune checkpoint\" OR xenograft)) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","((\"EP4 antagonist\" OR PTGES1 OR \"15-PGDH\" OR grapiprant) AND (esophageal OR \"squamous cell carcinoma\") AND (immunotherapy OR \"CD8\" OR dendritic)) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"updatedAt":"2026-08-19T22:19:33.068Z"},{"key":"gastric cancer","name":"gastric cancer","mondo":{"id":"MONDO:0001056","name":"gastric cancer"},"genes":[{"label":"KLF6","kind":"causal"},{"label":"KRAS","kind":"causal"},{"label":"MUTYH","kind":"causal"},{"label":"PIK3CA","kind":"causal"},{"label":"APC","kind":"causal"},{"label":"ERBB2","kind":"causal"},{"label":"FGFR2","kind":"causal"},{"label":"IRF1","kind":"causal"},{"label":"CDH1","kind":"causal"},{"label":"CASP10","kind":"causal"},{"label":"IL1B","kind":"correlated"},{"label":"IL1RN","kind":"correlated"}],"visits":3,"openQuestions":["Do RPRD1B-high gastric lines/PDX show ITGA5-FAK activation (pFAK, ITGA5 IHC) and does defactinib sensitise them to fluoropyrimidine, or is the TOPBP1/ATR effector gastric-specific?","Is there ANY primary gastric perturbation experiment (in vivo) of CPT1A, CD36 or FASN inhibition combined with PD-1 blockade, and does the benefit require myeloid rather than tumour-cell FAO?","Which single m6A regulator is rate-limiting in MSS gastric models, and does METTL3 catalytic inhibition (STM2457-class) synergise with platinum/fluoropyrimidine or PD-1 in gastric preclinical data?","In gastric cohorts of NCT04550494 and NCT04644068, do ATM protein-null (IHC) and CDK12-altered tumours respond while MUTYH carriers (pre-registered null) do not?","What is the prevalence and co-mutation structure (PIK3CA, ERBB2, CDH1/CTNNA1) of KRAS G12D in gastric adenocarcinoma, and do G12D gastric PDX exist for ARV-806-class degrader testing (NCT07023731)?","Does SIRT1 loss along the H. pylori cascade intersect the m6A programme (H. pylori-induced METTL3), giving a single chemoprevention node in intestinal metaplasia?"],"leads":[{"id":"L1","title":"RPRD1B(CREPT)-TOPBP1 axis as the druggable node of 5-FU resistance in gastric cancer","mechanism":"RPRD1B/CREPT recruits RNA Pol II to the TOPBP1 promoter, amplifying ATR-dependent DDR and 5-FU resistance (PMID:42542502). The paralogue RPRD1A drives lenvatinib resistance in HCC by competing with RPAP2 for RNA Pol II and derepressing ITGA5 -> FAK (PMID:42171939), establishing the class mechanism but a different effector; whether gastric RPRD1B-high tumours run TOPBP1/ATR, ITGA5/FAK, or both is unresolved [INFERRED].","approach":"Arm (i) RPRD1B knockdown/degradation plus fluoropyrimidine; arm (ii) ATR inhibition (tuvusertib-class, low-DDI per PMID:42142224) or PARP1-selective AZD5305 combinations (NCT04644068), stratified by RPRD1B/TOPBP1 IHC in WES-annotated gastric PDX (PMID:42466845); arm (iii) NEW cheap orthogonal test - ITGA5/FAK immunoblot and pFAK in RPRD1B-high gastric lines, with defactinib (FAK) or volociximab (ITGA5) as repurposing partners if the HCC effector transfers. Watch marrow/crypt overlap toxicity of ATR-TOPBP1 blockade [KNOWN]. Resistance: POLQ/TMEJ, SLFN11 loss, ABCB1, CDK12 bypass.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42542502","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04644068","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42466845","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42142224","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42171939","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":10,"lastVisit":3,"lastNote":"Third consecutive visit with no primary gastric RPRD1B/TOPBP1 corroboration, so confidence 0.45->0.40. Gain is class-level, non-gastric: PMID:42171939 [NEW] shows a paralogue driving TKI resistance via Pol II derepression of ITGA5-FAK, which adds a testable alternative effector and two approved/clinical-stage partner drugs.","history":[{"visit":3,"cycle":143,"status":"WEAKENED","note":"Third consecutive visit with no primary gastric RPRD1B/TOPBP1 corroboration, so confidence 0.45->0.40. Gain is class-level, non-gastric: PMID:42171939 [NEW] shows a paralogue driving TKI resistance via Pol II derepression of ITGA5-FAK, which adds a testable alternative effector and two approved/clinical-stage partner drugs."},{"visit":2,"cycle":65,"status":"WEAKENED","note":"A targeted 2023-2026 gastric RPRD1B/CREPT/TOPBP1/ATRi query returned no primary corroboration this visit; single-paper status persists, so confidence drops 0.50->0.45. Only gain is combination pharmacology feasibility for the ATRi arm (PMID:42142224 [NEW])."},{"visit":1,"cycle":10,"status":"NEW","note":"New this visit from PMID:42542502; only preclinical (abstract-level, no full text), so no promotion. PDX platform PMID:42466845 adopted as the in vivo test bed; CDK12/MSH2 enrichment in fast-growing grafts is an orthogonal DDR hint."}]},{"id":"L2","title":"CAV1-driven fatty-acid beta-oxidation as a metabolic vulnerability in oxaliplatin-resistant gastric cancer","mechanism":"Fatty-acid beta-oxidation sustains survival under platinum stress and is reversible by FAO inhibition across tumour types (PMID:40514365, PMID:42164655, PMID:41640669); gastric lipid programmes (FAO/CD36/FASN/SREBP1) are catalogued in GC-specific reviews (PMID:40901479, PMID:41158287). The originating SNHG15/miR-451a/CAV1 chain (PMID:41972796) remains a single-paper claim and is now treated as a correlate, not the mechanism.","approach":"CPT1A/FAO blockade (etomoxir-class; ranolazine/perhexiline repurposing [SPECULATIVE]) plus oxaliplatin in gastric PDX stratified by baseline palmitate-oxidation flux rather than by CAV1; read out FAO flux, ATP/NADPH, apoptosis. CAV1 IHC and SNHG15 qRT-PCR retained only as exploratory correlates. Intermittent dosing with cardiac monitoring (cardiomyocyte/hepatocyte FAO dependence). Resistance: glycolytic/glutamine switch, lipid-droplet buffering, GPX4-dependent ferroptosis avoidance.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"41972796","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40514365","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40901479","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42164655","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41640669","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":10,"lastVisit":3,"lastNote":"Answers open question 4: after two visits no independent dataset replicates SNHG15-miR-451a-CAV1, so the lead is formally reduced to a CPT1A/FAO-dependency claim with CAV1 as correlate. New FAO syntheses [NEW] support the general claim but add no gastric perturbation data; 0.42->0.40.","history":[{"visit":3,"cycle":143,"status":"WEAKENED","note":"Answers open question 4: after two visits no independent dataset replicates SNHG15-miR-451a-CAV1, so the lead is formally reduced to a CPT1A/FAO-dependency claim with CAV1 as correlate. New FAO syntheses [NEW] support the general claim but add no gastric perturbation data; 0.42->0.40."},{"visit":2,"cycle":65,"status":"STRENGTHENED","note":"Two [NEW] reviews support the FAO-resistance claim generally and in GC lipid biology, but neither replicates the SNHG15-miR-451a-CAV1 chain; support is review-grade so no promotion. Confidence 0.33->0.42 on the FAO-dependency claim only."},{"visit":1,"cycle":10,"status":"NEW","note":"New from PMID:41972796. Single-paper ceRNA mechanism, a genre with reproducibility problems; the actionable claim is the FAO dependency, not the lncRNA itself. Needs independent corroboration before promotion."}]},{"id":"L4","title":"SIRT1 restoration plus H. pylori eradication to reverse precancerous intestinal metaplasia","mechanism":"Clinical mucosal proteomics show progressive SIRT1 loss along the H. pylori-associated cascade; restoring SIRT1 (resveratrol) reactivates autophagy while lactoferrin-driven antimicrobial peptides and fucoidan-enhanced antigen presentation clear H. pylori, jointly reversing intestinal metaplasia in the reported model.","approach":"Chemoprevention arm of the programme: validate SIRT1 loss as a stage biomarker in independent metaplasia cohorts; test SIRT1 agonism (resveratrol/NAD+ precursors) added to standard eradication regimens for histological reversal of IM/OLGIM score, and in IL1B/IL1RN [SOMATIC/correlated] high-inflammation subgroups. Relevant to CDH1 [GERMLINE] carriers only as risk-modification, never as a substitute for surveillance. Expected failure mode: eradication alone plateaus once metaplasia is clonally fixed; SIRT1 agonism could favour survival of already-transformed clones [SPECULATIVE].","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42569414","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":10,"lastVisit":1,"lastNote":"New from PMID:42569414. Nanomedicine formulation is not the transferable asset; the SIRT1-autophagy axis and the biomarker claim are. Preclinical/proteomic only.","history":[{"visit":1,"cycle":10,"status":"NEW","note":"New from PMID:42569414. Nanomedicine formulation is not the transferable asset; the SIRT1-autophagy axis and the biomarker claim are. Preclinical/proteomic only."}]},{"id":"L5","title":"Biomarker question, not yet a lead: PARP inhibitor sensitivity in DNA-repair-altered gastric cancer including MUTYH carriers","mechanism":"ATM loss (germline or somatic) sensitises tumours to both ATR and PARP inhibitors (PMID:42025253), and pan-cancer DDR defects create parallel synthetic-lethal and immune-microenvironment vulnerabilities (PMID:42054804). MUTYH [GERMLINE] is a base-excision repair glycosylase and does not confer HR deficiency, so the BRCA/PARP logic should not be assumed to transfer; CDK12/MSH2 enrichment in fast-growing GC grafts marks the plausible HRD-like/hypermutant stratum.","approach":"Mine gastric cohorts of NCT04550494 (talazoparib in DNA-repair variants) and NCT04644068 (AZD5305 combinations) with pre-specified ATM (biallelic vs monoallelic, protein-null by IHC), CDK12, BRCA1/2 and MSH2 strata, MUTYH mono/biallelic as the pre-registered null; pair with WES-annotated PDX (PMID:42466845). Ceilings to respect: HRD-dependency of efficacy and cumulative haematologic toxicity, the two limits driving interest in dual-target PARP agents (PMID:41395847).","level":"LEAD","confidence":0.3,"citations":[{"kind":"NCT","id":"NCT04550494","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04644068","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42466845","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42025253","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42054804","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41395847","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":10,"lastVisit":2,"lastNote":"Pivoted from an open biomarker question to an ATM-anchored stratification hypothesis on three [NEW] reviews; MUTYH explicitly demoted to negative control so the desk never re-proposes MUTYH-to-PARPi. Evidence remains review-grade and non-gastric-specific, hence no promotion.","history":[{"visit":2,"cycle":65,"status":"STRENGTHENED","note":"Pivoted from an open biomarker question to an ATM-anchored stratification hypothesis on three [NEW] reviews; MUTYH explicitly demoted to negative control so the desk never re-proposes MUTYH-to-PARPi. Evidence remains review-grade and non-gastric-specific, hence no promotion."},{"visit":1,"cycle":10,"status":"NEW","note":"Deliberately entered as a falsifiable stratification question tied to the Monarch MUTYH germline anchor; recorded so the desk does not conflate BER predisposition with HR-deficiency druggability."}]},{"id":"L6","title":"Lipid-metabolic reprogramming of the gastric immune microenvironment to convert MSS/immune-cold GC to ICB-responsive","mechanism":"In GC, FAO, CD36-mediated uptake and FASN/SREBP1 lipogenesis reshape the TIME - TAM polarisation, Treg/MDSC expansion, DC dysfunction, impaired CD8 effector function - contributing to chemo- and ICB resistance (PMID:40901479, PMID:41158287); gastric TME synthesis independently places metabolic reprogramming alongside angiogenesis and fibrosis as a resistance axis (PMID:41630007), and pan-tumour FAO/TME work identifies the same enzymes as targets (PMID:40514365, PMID:41640669). Target compartment is myeloid/T-cell metabolic fitness, distinct from L2.","approach":"CD36 blockade or CPT1A/FASN/SREBP1 inhibition plus PD-1 blockade in MSS, immune-cold gastric models (syngeneic + PDX-humanised); read out intratumoural CD8 lipid peroxidation, CD36+ Treg fraction, TAM CPT1A, TCR clonality; explicitly test whether the effect requires tumour-cell versus myeloid FAO using compartment-restricted Cpt1a deletion. Clinically, nest a correlative lipid-metabolic panel in the taxane+nivolumab MSS-dominated PARAMUNE context (NCT06203600) and monitor NCT07115043 for gastric cohorts. Window: CD36/FAO essential in cardiomyocytes and fasting hepatocytes -> intermittent dosing, cardiac read-outs. Resistance: glutamine/glycolytic compensation in myeloid cells, IL1B/IL1RN [SO","level":"CANDIDATE","confidence":0.45,"citations":[{"kind":"PMID","id":"40901479","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40514365","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT06203600","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT07115043","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41158287","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41630007","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41640669","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":65,"lastVisit":3,"lastNote":"Promoted on independent new gastric-specific corroboration (PMID:41158287 [NEW]) plus gastric TME and FAO-TME syntheses [NEW]. Caveat stated plainly: all support is review-grade; no gastric CD36/CPT1A + PD-1 perturbation experiment exists in any pack so far, which is why confidence stays below 0.5.","history":[{"visit":3,"cycle":143,"status":"STRENGTHENED","note":"Promoted on independent new gastric-specific corroboration (PMID:41158287 [NEW]) plus gastric TME and FAO-TME syntheses [NEW]. Caveat stated plainly: all support is review-grade; no gastric CD36/CPT1A + PD-1 perturbation experiment exists in any pack so far, which is why confidence stays below 0.5."},{"visit":2,"cycle":65,"status":"NEW","note":"New this visit from gastric-specific lipid-immune review [NEW]; enters low because evidence is review-grade with no gastric perturbation data in abstract. Directly addresses open question 4 (MSS/immune-cold GC)."}]},{"id":"L7","title":"KRAS G12D targeted degradation (ARV-806) in KRAS-mutant gastric adenocarcinoma","mechanism":"KRAS is a Monarch causal anchor for gastric cancer; somatic KRAS mutation including G12D occurs in a minority of gastric adenocarcinomas [KNOWN, SOMATIC]. A first-in-class G12D degrader removes the oncoprotein rather than occupying it, which should blunt the nucleotide-cycling/RTK-reactivation escape routes typical of occupancy inhibitors [INFERRED/SPECULATIVE]. Now clinically testable: ARV-806 is in phase 1/2 in KRAS G12D advanced cancers (NCT07023731).","approach":"Seek/assemble a KRAS G12D gastric cohort within or alongside NCT07023731; profile G12D allele fraction, co-occurring PIK3CA and ERBB2 [Monarch anchors] alterations, and CDH1/CTNNA1 diffuse-type context. Preclinically, screen G12D-mutant gastric PDX (PMID:42466845) for degrader monotherapy depth of response and for rational partners (SHP2 or EGFR inhibition, MEK) against expected resistance: wild-type RAS amplification, PI3K-axis bypass, NRAS/BRAF switch, E3-ligase/UPS adaptation to the degrader. Normal tissue: pan-RAS signalling supports gut and skin renewal, so mutant-selective degradation is the entire window argument.","level":"LEAD","confidence":0.28,"citations":[{"kind":"NCT","id":"NCT07023731","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42466845","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":65,"lastVisit":2,"lastNote":"New this visit: first trial-level handle on the KRAS causal anchor for this programme. No gastric-specific efficacy data yet; enters as a stratification/PDX question, not an efficacy claim.","history":[{"visit":2,"cycle":65,"status":"NEW","note":"New this visit: first trial-level handle on the KRAS causal anchor for this programme. No gastric-specific efficacy data yet; enters as a stratification/PDX question, not an efficacy claim."}]},{"id":"L8","title":"m6A regulators (METTL3/FTO/YTHDF axis) as H. pylori-linked drivers of chemo- and immunotherapy resistance in gastric cancer","mechanism":"Gastric-specific synthesis reports that m6A writers, erasers and readers are dysregulated in GC tissue, are induced by H. pylori and transcription factors, correlate with poor prognosis, and mechanistically support stemness, immune evasion and resistance to chemo-, radio- and immunotherapy (PMID:41832397). This places an epitranscriptomic layer upstream of several programme leads and connects to the inflammation-driven precancerous cascade of L4 [INFERRED].","approach":"Define which regulator is rate-limiting in GC subtypes before committing: CRISPR/degron panel of METTL3, METTL14, FTO, ALKBH5, YTHDF1-3 in MSS versus EBV/MSI-H gastric lines; test METTL3 catalytic inhibition (STM2457-class [KNOWN]) plus fluoropyrimidine/platinum and plus PD-1 in immune-cold models, with m6A-seq to confirm on-target loss of methylation on candidate resistance transcripts. Test H. pylori-conditioned induction in gastric organoids to link to L4 chemoprevention. Window argument: m6A machinery is required in normal haematopoiesis and intestinal stem cells [KNOWN], so intermittent dosing and marrow/crypt toxicity read-outs are mandatory; blood-based m6A biomarkers proposed in PMID","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"41832397","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":143,"lastVisit":3,"lastNote":"New this visit from a gastric-specific m6A review [NEW]. Enters low: review-grade, no gastric in vivo inhibitor data in the abstract, and the lead is currently a target-selection question rather than a therapeutic claim.","history":[{"visit":3,"cycle":143,"status":"NEW","note":"New this visit from a gastric-specific m6A review [NEW]. Enters low: review-grade, no gastric in vivo inhibitor data in the abstract, and the lead is currently a target-selection question rather than a therapeutic claim."}]}],"retired":[{"title":"YWHAZ(14-3-3zeta)-G3BP1 stress-granule module sequesters Bax and sets apoptotic resistance in gastric cancer","note":"Pre-committed retirement (open question 6 answered negatively): two evidence-bearing visits, zero gastric primary data, no window argument. Recorded so the desk never re-opens it on review-grade material alone.","cycle":143,"ts":"2026-08-19T22:23:12.844Z"}],"nextQueries":["(\"gastric cancer\" OR \"gastric adenocarcinoma\") AND (CPT1A OR CD36 OR etomoxir OR FASN) AND (\"PD-1\" OR \"anti-PD-1\" OR \"immune checkpoint\") AND (mice OR xenograft OR organoid OR knockout) AND SRC:MED AND PUB_YEAR:[2023 TO ","(\"gastric cancer\" OR \"gastric adenocarcinoma\") AND (METTL3 OR STM2457 OR ALKBH5 OR YTHDF1) AND (chemoresistance OR cisplatin OR 5-fluorouracil OR immunotherapy) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"gastric cancer\" OR \"gastric adenocarcinoma\" OR \"hepatocellular\") AND (RPRD1B OR CREPT OR RPRD1A) AND (ITGA5 OR FAK OR defactinib OR TOPBP1) AND SRC:MED"],"updatedAt":"2026-08-19T22:23:12.844Z"},{"key":"hepatocellular carcinoma","name":"hepatocellular carcinoma","mondo":{"id":"MONDO:0007256","name":"hepatocellular carcinoma"},"genes":[{"label":"APC","kind":"causal"},{"label":"AXIN1","kind":"causal"},{"label":"CASP8","kind":"causal"},{"label":"CTNNB1","kind":"causal"},{"label":"PDGFRL","kind":"causal"},{"label":"MET","kind":"causal"},{"label":"IGF2R","kind":"causal"},{"label":"PIK3CA","kind":"causal"},{"label":"TP53","kind":"causal"},{"label":"DNAJB1","kind":"correlated"},{"label":"TSC2","kind":"correlated"},{"label":"TSC1","kind":"correlated"}],"visits":3,"openQuestions":["Do AXIN1-mutant HCC organoids/lines show selective sensitivity to TEAD palmitoylation-site inhibitors (VT3989/IK-930 class) versus CTNNB1ex3-mutant isogenic controls, and is the effect YAP/TAZ-dependent?","Which readout is right for AXIN1 tumours - increased beta-catenin activity by transcriptomic score (PMID:42156413) or weak/absent activation by IHC and organoid reporter (PMID:41804058, PMID:41550750) - and does that decide whether beta-cat","Does CTNNB1ex3/Wnt-high genotype abolish the complete-VETC predictive effect on atezolizumab-bevacizumab outcome, i.e. is VETC an independent biomarker or a proxy for Wnt-wild-type immune-hot biology?","Is there any direct pharmacology (PKA catalytic-site, Aurora, mTOR, or DNAJB1-PRKACA degrader) with preclinical data in fibrolamellar HCC, given the pack yielded only reviews and case reports?","Is TEAD S-palmitoylation among the ABHD17C substrates in HCC, which would unify L1 and L8 into a single lipidation-dependent resistance node?","In the 2025 French genomic initiative, did any HCC patient receiving an ESCAT III/IV matched therapy derive durable benefit, and which alteration classes accounted for it?"],"leads":[{"id":"L1","title":"ABHD17C depalmitoylase as a lenvatinib-resistance modifier in HCC","mechanism":"ABHD17C is an alpha/beta-hydrolase-domain S-depalmitoylase overexpressed in HCC; its overexpression attenuates lenvatinib-induced apoptosis/cell-cycle arrest and its depletion enhances lenvatinib effect across cell lines, xenografts and patient-derived organoids, with scRNA-seq association to CD8-poor, exhaustion-high tumour microenvironment (PMID:42358063). [KNOWN] ABHD17 enzymes depalmitoylate N-Ras and PSD95, so altered S-acylation cycling plausibly reroutes membrane RAS/MAPK signalling and sustains proliferation under multikinase VEGFR/FGFR blockade. [INFERRED] ABHD17C-high tumours are both TKI-refractory and immune-cold, i.e. a dual-resistance node.","approach":"Genetic epistasis first: ABHD17C knockout vs catalytically dead mutant in lenvatinib-resistant HCC lines to establish hydrolase-dependence; ABE/acyl-RAC palmitoyl-proteomics to identify substrates (test N-RAS, MET, EGFR). Then pharmacology: serine-hydrolase inhibitor tool compounds (palmostatin-class, ABHD17-selective probes) plus lenvatinib in organoids and immunocompetent Hepa1-6/HCC models with CD8 depletion arms. Biomarker deliverable: ABHD17C IHC/RNA cutoff as enrichment marker for lenvatinib benefit. Normal-tissue window: ABHD17 paralogue redundancy predicted mainly neuronal/synaptic liability [SPECULATIVE], must be profiled. Expected resistance: paralogue compensation (ABHD17A/B), ZDH","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42358063","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":11,"lastVisit":1,"lastNote":"New lead from this visit's only mechanistic paper with organoid plus in vivo corroboration; strongest actionable resistance hypothesis in the pack.","history":[{"visit":1,"cycle":11,"status":"NEW","note":"New lead from this visit's only mechanistic paper with organoid plus in vivo corroboration; strongest actionable resistance hypothesis in the pack."}]},{"id":"L2","title":"GPC3/neoantigen-directed antigen-specific immunotherapy for HCC","mechanism":"GPC3 is an oncofetal GPI-anchored proteoglycan re-expressed in most HCC and largely absent from adult hepatocytes [KNOWN], giving a genuine therapeutic window for redirected T cells; AZD5851 is a GPC3-targeted cell therapy in GPC3+ advanced/recurrent HCC (NCT06084884). Complementary antigen-agnostic route: a carrier-free fluorinated-CpG/neoantigen self-assembling nanovaccine drove 2.05-fold enhanced cross-presentation, lymph-node targeting and expansion of antigen-specific CD8+/memory T cells with tumour suppression in prophylactic and therapeutic Hepa1-6 models (PMID:42491306).","approach":"Track AZD5851 dose-escalation safety (on-target hepatic toxicity, CRS) and GPC3 expression thresholds; in parallel test whether TLR9-adjuvanted neoantigen vaccination rescues antigen spreading after CAR-T in GPC3-heterogeneous models. Named resistance routes: GPC3-low/negative subclonal escape, sGPC3 shedding acting as antigen sink, T-cell exhaustion in the immunosuppressive liver TME (potential intersection with the ABHD17C-high phenotype).","level":"LEAD","confidence":0.4,"citations":[{"kind":"NCT","id":"NCT06084884","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42491306","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":11,"lastVisit":1,"lastNote":"New; trial asset plus preclinical vaccine data define a testable antigen-escape combination question rather than a single-agent claim.","history":[{"visit":1,"cycle":11,"status":"NEW","note":"New; trial asset plus preclinical vaccine data define a testable antigen-escape combination question rather than a single-agent claim."}]},{"id":"L3","title":"FAM117B-NAT10 ac4C loop driving JAK-STAT3 as an epitranscriptomic target","mechanism":"FAM117B binds NAT10, blocks its K48-linked ubiquitination and stabilises it, while NAT10 reciprocally supports FAM117B, and the loop activates JAK-STAT3; FAM117B knockdown suppresses proliferation, clonogenicity, invasion and xenograft growth in Huh-7/HepG2 (PMID:42595291). NAT10 is the sole known ac4C mRNA writer [KNOWN], making the loop chemically approachable where FAM117B itself is not.","approach":"Test NAT10 catalytic dependence (remodelin or NAT10 acetyltransferase-dead rescue) for the FAM117B phenotype; ac4C-RIP-seq to identify STAT3-pathway transcripts stabilised by ac4C; epistasis with a JAK1/2 inhibitor (ruxolitinib) to see if STAT3 is the effector arm. Window: NAT10 loss causes laminopathy-like nuclear phenotypes [KNOWN], so a therapeutic index argument is required before any combination proposal.","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"42595291","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":11,"lastVisit":1,"lastNote":"New but single-paper, single-lab, two-cell-line evidence; opened deliberately at low confidence pending independent NAT10/ac4C corroboration.","history":[{"visit":1,"cycle":11,"status":"NEW","note":"New but single-paper, single-lab, two-cell-line evidence; opened deliberately at low confidence pending independent NAT10/ac4C corroboration."}]},{"id":"L4","title":"PD-L1xVEGF bispecific (pumitamig) +/- ipilimumab as first-line HCC, priced against existing IO+VEGF","mechanism":"Unchanged core: single-molecule PD-L1 blockade plus VEGF neutralisation to localise vascular normalisation and Treg/MDSC depletion to PD-L1+ tumour (NCT07291076), with complete VETC as candidate predictive marker (ORR 66% vs 37%; PFS HR 0.42, 95% CI 0.26-0.69; PMID:42067189) and a bleeding-risk benchmark (PMID:42061924). What changed: molecular stratification data now show that 25% CTNNB1ex3/APC and 11% AXIN1/IRF2 subtypes (PMID:42156413) carry distinct immune phenotypes, with Wnt-high tumours immune-cold and IO-resistant (PMID:42237887), and CTNNB1 mutated in 20% of refractory advanced HCC (PMID:41865801). [INFERRED] Any VETC-based enrichment must be tested for confounding by Wnt genotype, ","approach":"As before (mandatory pre-treatment CD34 VETC scoring, grade>=3 bleeding/thromboembolism as first safety endpoint, varix screening, efficacy bar set against atezo-bev depth/duration) plus a new pre-specified two-factor analysis: VETC status x Wnt-pathway genotype (CTNNB1 exon 3, AXIN1, APC, ZNRF3) on ORR/PFS, and a check of whether VETC retains effect within the Wnt-wild-type stratum. Continue the arm-specificity test in the VEGF-free durvalumab-tremelimumab subgroup. Resistance: VEGF-independent angiogenesis (ANG2, FGF), VETC loss under therapy, Wnt-driven CD8 exclusion.","level":"CANDIDATE","confidence":0.44,"citations":[{"kind":"NCT","id":"NCT07291076","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42505057","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42067189","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42061924","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42156413","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42237887","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41865801","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":11,"lastVisit":3,"lastNote":"Strengthened only in analytic specification, not in efficacy: new subtype and Wnt-immune-exclusion evidence adds a required covariate that could explain away the VETC effect, so the lead is now falsifiable in a defined way.","history":[{"visit":3,"cycle":145,"status":"STRENGTHENED","note":"Strengthened only in analytic specification, not in efficacy: new subtype and Wnt-immune-exclusion evidence adds a required covariate that could explain away the VETC effect, so the lead is now falsifiable in a defined way."},{"visit":2,"cycle":66,"status":"STRENGTHENED","note":"Two independent new clinical datasets this visit: a predictive vascular biomarker (PMID:42067189) and a multicentre bleeding-risk benchmark against the VEGF-free comparator (PMID:42061924). Both are retrospective/observational, so this is stratification hypothesis generation, not practice guidance."},{"visit":1,"cycle":11,"status":"NEW","note":"New; the cost-effectiveness paper reframes this class as a differentiation problem and is recorded so the desk does not re-propose undifferentiated IO+VEGF."}]},{"id":"L5","title":"PI3K/AKT-driven ABCG2 efflux as a reversible sorafenib-resistance mechanism","mechanism":"In sorafenib-resistant Huh7-SR and HCCLM3-SR lines, resistance tracks with p-AKT and ABCG2; the flavonoid tectochrysin reportedly binds PI3K and ABCG2 (CETSA/DARTS), lowers ABCG2, restores apoptosis and reverses EMT markers, and resensitises xenografts (PMID:42599637). [INFERRED] The generalisable claim is pathway-level: PI3K/AKT-dependent upregulation of an ATP-binding-cassette efflux pump lowers intracellular sorafenib exposure.","approach":"Decouple the two proposed targets: does a clinical-grade AKT or PI3K inhibitor reduce ABCG2 and restore sorafenib/lenvatinib sensitivity in the same resistant lines, and does ABCG2 knockout abolish the tectochrysin benefit? Measure intracellular drug by LC-MS rather than viability alone. Window/liability: ABCG2 is a physiological BBB/gut/placental barrier transporter [KNOWN], so systemic inhibition carries broad drug-interaction risk. This lead is on probation and will be retired without independent confirmation.","level":"LEAD","confidence":0.2,"citations":[{"kind":"PMID","id":"42599637","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":11,"lastVisit":1,"lastNote":"New at deliberately low confidence: natural-product agent, no pharmacokinetics, target engagement shown only by CETSA/DARTS; kept only because the PI3K-ABCG2 pathway claim is independently testable.","history":[{"visit":1,"cycle":11,"status":"NEW","note":"New at deliberately low confidence: natural-product agent, no pharmacokinetics, target engagement shown only by CETSA/DARTS; kept only because the PI3K-ABCG2 pathway claim is independently testable."}]},{"id":"L6","title":"Tumour vascular architecture (VETC / macrovascular pattern) as a shared delivery-and-response biomarker across anti-VEGF systemic and hepatic-arterial regimens","mechanism":"[INFERRED] HCC response to therapies whose effect depends on tumour perfusion should track with vascular architecture rather than with the agent class. Complete VETC predicted response and PFS under atezolizumab+bevacizumab (PMID:42067189); hepatic arterial infusion chemotherapy plus toripalimab vs plus sorafenib gave near-identical 6-month PFS (63.9% vs 61.1%) but divergent median OS (20.9 vs 16.4 months) in a non-comparative randomised phase 2 (PMID:42266185), where the shared HAIC backbone makes intratumoral drug exposure a function of arterial supply. Histopathological stratifiers - macrovascular vs microvascular invasion, macrotrabecular-massive subtype - are independently prognostic an","approach":"Retrospectively score VETC and MTM subtype on pre-treatment biopsies from HAIC-containing and anti-VEGF-containing cohorts and test interaction with treatment class; correlate with DCE-MRI/CT arterial perfusion parameters to build a non-invasive surrogate. Prospective: VETC-stratified randomisation between HAIC+PD-1 and systemic IO+VEGF in locally advanced disease. Mechanistic: measure intratumoral platinum/fluoropyrimidine and TKI concentration by LC-MS against VETC status in resected or organoid-matched material. Caveat recorded so the desk does not overclaim: PMID:42266185 is non-comparative with essentially equal 6-month PFS, so no superiority of TorHAIC over SoraHAIC may be asserted; th","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42067189","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42266185","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42281878","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":66,"lastVisit":2,"lastNote":"New this visit; unifies the pack's clinical papers into one testable stratification hypothesis rather than three isolated observations, and links to the exposure-limitation logic already in L5.","history":[{"visit":2,"cycle":66,"status":"NEW","note":"New this visit; unifies the pack's clinical papers into one testable stratification hypothesis rather than three isolated observations, and links to the exposure-limitation logic already in L5."}]},{"id":"L8","title":"AXIN1-mutant HCC as a YAP/TAZ-TEAD-dependent subtype for TEAD palmitoylation inhibitors","mechanism":"HCC-associated AXIN1 mutations engineered into liver cancer cells and liver-derived organoids activate Wnt/beta-catenin only weakly (premature stop codons yield N-terminally truncated AXIN1 with partial suppressor activity) yet confer Wnt/R-spondin-independent growth, and Wnt output inversely correlates with YAP/TAZ activity, leaving AXIN1-mutant cells YAP/TAZ-high relative to CTNNB1-mutant (PMID:41550750). Surgical pathology confirms weak/partial Wnt activation in AXIN1 tumours (11/18, weak beta-catenin/glutamine synthetase) with rare tertiary lymphoid structures (PMID:41804058), and integrated multi-omics keeps AXIN1/IRF2 (11%) as a subtype separate from CTNNB1ex3/APC (PMID:42156413). [INF","approach":"Stratify HCC lines/organoids by AXIN1 vs CTNNB1ex3 genotype (isogenic panels as in PMID:41550750) and measure TEAD-luciferase, CTGF/CYR61/AMOTL2 output, then TEAD inhibitor sensitivity vs porcupine inhibitor (predicted inactive, since growth is Wnt-ligand-independent) and vs lenvatinib. Genetic anchor: YAP/TAZ dual knockdown and TEAD1-4 palmitoylation-site mutants to confirm on-target. In vivo: AXIN1-mutant PDX/organoid xenograft with TEAD inhibitor +/- lenvatinib. Resolve the contradiction first: does AXIN1 mutation raise or lower beta-catenin activity (transcriptomic score PMID:42156413 vs IHC/organoid PMID:41804058, PMID:41550750)? Normal-tissue window: YAP/TAZ-TEAD is required for hepato","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"41550750","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41804058","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42156413","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":145,"lastVisit":3,"lastNote":"New this visit; answers half of open question 3 by splitting AXIN1 from CTNNB1 biology and naming a druggable effector (TEAD) that is orthogonal to beta-catenin, which is not directly druggable.","history":[{"visit":3,"cycle":145,"status":"NEW","note":"New this visit; answers half of open question 3 by splitting AXIN1 from CTNNB1 biology and naming a druggable effector (TEAD) that is orthogonal to beta-catenin, which is not directly druggable."}]},{"id":"L9","title":"CTNNB1ex3/Wnt-high status as an exclusion-stratification biomarker for IO-containing first-line HCC","mechanism":"Canonical Wnt hyperactivation (CTNNB1 mutation, or inactivating AXIN1/APC/ZNRF3) occurs in up to 50% of HCC and is associated with CD8+ T-cell exclusion, dendritic-cell repression, MDSC/TAN recruitment and a 'cold' TME, plus sorafenib/lenvatinib resistance via ferroptosis evasion and stemness (PMID:42237887, PMID:41142820); reviews, so mechanism is secondary evidence. Independent primary support for clinical relevance: CTNNB1 was mutated in 20% of 80 refractory advanced HCC in a prospective multicentre WGS/WES/RNA-seq initiative (PMID:41865801), and tertiary lymphoid structures were uncommon except in CTNNB1-mutant cases with additional Wnt hits (PMID:41804058), suggesting immune architectur","approach":"Retrospective first: in atezolizumab-bevacizumab and durvalumab-tremelimumab cohorts with sequencing, test CTNNB1ex3/AXIN1/APC status as a covariate for ORR and PFS, and test interaction with complete VETC status (link to L4/L6) to determine whether the vascular biomarker survives genotype adjustment. Prospective: pre-specify Wnt-pathway genotype as a stratification factor (not exclusion) in ROSETTA HCC-206-type designs; embed paired biopsies for CD8/DC quantification. Therapeutic arm to test only after biology is confirmed: Wnt-high tumours are ligand-independent when CTNNB1 is mutated, so porcupine inhibitors are predicted futile [INFERRED] and the tractable options are beta-catenin/TCF or","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42237887","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41142820","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41865801","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42156413","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":145,"lastVisit":3,"lastNote":"New; converts the pack's Wnt-immune-exclusion literature into a stratification hypothesis for existing IO regimens rather than a speculative Wnt drug, and creates a genotype confounder test for the VETC biomarker in L4/L6.","history":[{"visit":3,"cycle":145,"status":"NEW","note":"New; converts the pack's Wnt-immune-exclusion literature into a stratification hypothesis for existing IO regimens rather than a speculative Wnt drug, and creates a genotype confounder test for the VETC biomarker in L4/L6."}]}],"retired":[{"title":"Plectin cytolinker as the obligate effector of plecstatin anti-invasive activity in mesenchymal HCC","note":"Retired per the probation clause set at visit 2: still one line, one lab, no PK, and the normal-tissue essentiality argument runs against it; recorded in the notebook so the desk does not re-open it.","cycle":145,"ts":"2026-08-19T22:30:36.169Z"}],"nextQueries":["(\"hepatocellular carcinoma\" OR \"liver cancer\") AND (TEAD OR \"YAP\" OR \"TAZ\" OR \"VT3989\" OR \"IK-930\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"DNAJB1-PRKACA\" OR \"fibrolamellar\") AND (inhibitor OR degrader OR kinase OR preclinical OR xenograft) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"hepatocellular carcinoma\") AND (\"S-palmitoylation\" OR \"depalmitoylase\" OR ABHD17 OR ZDHHC) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T22:30:36.169Z"},{"key":"chronic myeloid leukemia","name":"chronic myeloid leukemia","mondo":{"id":"MONDO:0011996","name":"chronic myeloid leukemia"},"genes":[{"label":"ABL1","kind":"causal"},{"label":"BCR","kind":"correlated"},{"label":"RUNX1","kind":"correlated"}],"visits":20,"openQuestions":["Do isogenic e13a3/e14a3 CML models retain full imatinib/ponatinib/olverembatinib sensitivity while losing asciminib potency, confirming a3 as a selectively allosteric liability rather than a general resistance class?","Can targeted nanopore adaptive sampling (PMID:41254115) be validated as a diagnostic gate before asciminib and as a patient-specific genomic-breakpoint MRD assay in FISH-positive/RT-qPCR-negative CML?","Which of the 279 asciminib-resistance mutations lie in SH3/non-kinase regions and remain ponatinib- or olverembatinib-sensitive, i.e. can the mutation-to-agent matrix be published from the DMS atlas?","Does the ELN-BP prognostic score interact with treatment modality (ponatinib+blinatumomab versus early allograft) in lymphoid versus myeloid blast phase, and has it been externally validated?","Does any randomised or prospective dose-reduction/TDM trial in chronic-phase CML exist, and do the ELN 2025 or China 2025 guidelines supply quantitative reduction schedules usable as a comparator arm?","Is the ABL1 E255V neoepitope presented on primary CML cells, and does NCT06904066 admit CML kinase-domain point mutations as participant-specific neoantigens (final pass for L17)?"],"leads":[{"id":"L3","title":"USP28–BCR-ABL–IFITM3 axis as a BCR-ABL-kinase-independent resistance node permitting lower-dose ponatinib","mechanism":"IFITM3 reportedly mediates TKI resistance downstream of a USP28-stabilised BCR-ABL; knockout resensitised K562R cells and, with ponatinib in a ginger-lipid nanocarrier, suppressed resistant xenograft growth (PMID:42582078).","approach":"Unchanged: independent replication in multiple TKI-resistant lines and primary blast-crisis samples +/- T315I before any translational step; pharmacological USP28 inhibition as substitute for gene editing. Deprioritised relative to L5/L6 until replication appears.","level":"LEAD","confidence":0.2,"citations":[{"kind":"PMID","id":"42582078","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":12,"lastVisit":2,"lastNote":"Weakened: a second evidence-bearing visit produced no independent replication of the USP28-IFITM3 axis, and the fresh pack's resistance framing (PMID:41952641) attributes persistence to LSC states/GRNs rather than to single stabilising-deubiquitinase nodes. Still a single laboratory, one resistant line.","history":[{"visit":2,"cycle":24,"status":"WEAKENED","note":"Weakened: a second evidence-bearing visit produced no independent replication of the USP28-IFITM3 axis, and the fresh pack's resistance framing (PMID:41952641) attributes persistence to LSC states/GRNs rather than to single stabilising-deubiquitinase nodes. Still a single laboratory, one resistant line."},{"visit":1,"cycle":12,"status":"NEW","note":"New but deliberately low confidence: single laboratory, one resistant line, CRISPR cargo far from clinic. Normal-tissue caveat — IFITM3 is an interferon-inducible antiviral restriction factor, so systemic loss carries infection risk [INFERRED]."}]},{"id":"L4","title":"Modifiable hERG-mediated QTc risk during nilotinib therapy (curcumin aggravates, nicorandil protects)","mechanism":"Nilotinib blocks hERG/IKr causing dose-dependent QTc prolongation; in telemetered rats curcumin worsened and the KATP opener nicorandil attenuated this (PMID:42474156).","approach":"Human pharmacovigilance analysis of curcumin/turmeric supplement use in nilotinib-treated CML; in vitro hERG patch-clamp with nilotinib +/- curcumin +/- nicorandil in hiPSC-cardiomyocytes before any interventional idea.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42474156","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":12,"lastVisit":1,"lastNote":"New; rat telemetry only, no human data, mechanism of curcumin interaction unspecified in abstract. Hypothesis-generating for supplement-interaction stewardship, not a treatment claim.","history":[{"visit":1,"cycle":12,"status":"NEW","note":"New; rat telemetry only, no human data, mechanism of curcumin interaction unspecified in abstract. Hypothesis-generating for supplement-interaction stewardship, not a treatment claim."}]},{"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","mechanism":"Residual BCR-ABL1+ [SOMATIC] LSCs persist in nearly all DMR patients and CD26+ LSC burden/recurrence does not track molecular relapse (PMID:40116978), so relapse timing appears host-set (low IL-6/MCP-1 predicting relapse, PMID:42121891; clonal CD56+CD57+CD8dim NK-like population with >7-year TFR, PMID:42377752; NK GRN signatures, PMID:41972591). [NEW] STIM1 extended follow-up gives the burden-independent plateau its longest support: molecular recurrence-free survival 37% at 120 months and 35% at 156 months, no progression, 20-year OS 88%, and a late recurrence proven by DNA breakpoint analysis to be the original clone rather than new disease (PMID:41574312). Antigen-directed retrofitting of ","approach":"Observational/biomarker only: at planned cessation, multiplex IL-6/MCP-1 with flow and TCR-seq of CD56+CD57+CD8dim clones and NK maturation subsets, paired with CD26+CD35- LSC quantification so burden and immunity are modelled independently (PMID:40116978, PMID:39503729); test the PMID:42121891 decision tree for specificity/PPV in an independent DMR cohort adjusted for TKI duration and prior interferon; use STIM1-style DNA-breakpoint tracking to distinguish original-clone late recurrence from new disease (PMID:41574312); mine pregnancy-forced discontinuation cohorts. Do NOT propose post-cessation interferon maintenance, peri-cessation IL-6 blockade, or junction-peptide vaccination.","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"42121891","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42377752","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41972591","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41526617","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41373826","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40758938","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41225725","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42557142","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"40116978","verified":true,"isNew":true,"addedVisit":12},{"kind":"PMID","id":"39503729","verified":true,"isNew":true,"addedVisit":12}],"corrobVisits":4,"createdVisit":2,"createdCycle":24,"lastVisit":17,"lastNote":"First new supporting evidence in five visits: 12.8-year STIM1 follow-up shows a hard TFR plateau with no progression and original-clone late relapse, consistent with host-set rather than burden-set relapse timing. The decision tree itself is still unreplicated, so the rise is modest.","history":[{"visit":17,"cycle":171,"status":"STRENGTHENED","note":"First new supporting evidence in five visits: 12.8-year STIM1 follow-up shows a hard TFR plateau with no progression and original-clone late relapse, consistent with host-set rather than burden-set relapse timing. The decision tree itself is still unreplicated, so the rise is modest."},{"visit":12,"cycle":120,"status":"STRENGTHENED","note":"First new evidence in three visits and it supports the load-bearing premise: measured residual LSC burden (CD26+) and its recurrence do not predict molecular relapse in TFR, so relapse control must sit outside clone quantity. Still no independent replication of the IL-6/MCP-1 decision tree itself, hence confidence remains low."},{"visit":4,"cycle":38,"status":"WEAKENED","note":"Weakened again by absence: a third visit with no independent replication of the IL-6/MCP-1 decision tree. Scope clarified by [NEW] PMID:42557142 - interferon survives in CML only as a gestational TKI-free bridge, not as an immune-expansion agent; open question 3 is closed on that basis."},{"visit":3,"cycle":36,"status":"WEAKENED","note":"Weakened by a [NEW] negative phase 3: ENDURE/CML-IX (n=203) found 25-month MRFS 56% with ropeg-IFN vs 59% observation, HR 1.02, P=0.91 (PMID:41526617). The interferon-expansion arm of this lead is retired for unselected post-cessation use; only the biomarker/immune-gating component survives, and it is untested prospectively. Mitigating detail: 95% of relapsers regained >=MMR on restart (median 3 m"},{"visit":2,"cycle":24,"status":"NEW","note":"New this visit; three independent [NEW] immune/TFR datasets converge, but one is a single case report and one is n=6 with an AI pipeline as its real subject. Normal-tissue window: peg-IFN-alpha toxicity (flu-like, depression, cytopenias, autoimmunity) is well characterised and reversible on stop [KNOWN]. Records the negative: anti-IL-6 peri-discontinuation is now disfavoured by the observed low-IL"}]},{"id":"L7","title":"Risk-stratified TKI dose de-escalation as a therapeutic-window strategy in chronic phase","mechanism":"Floor-plus-plateau exposure-response (PMID:40848059); de-escalation safe but not depth-enhancing (PMID:40647447); dasatinib 50 vs 100 mg frontline equivalent with pleural effusion 2.2% vs 25.2% (PMID:41668074); ELN 2025 prefers reduction to switching (PMID:40646132); agent-set window from ASC4FIRST tolerability post hoc (PMID:42389818). [NEW] A second, independent guideline (China 2025) formally recommends TKI dose optimisation based on efficacy and safety, individualised interpretation of molecular milestones, and revised TFR/fertility criteria to minimise toxicity (PMID:41486652).","approach":"Unchanged: immortal-time/selection-bias re-analysis of PMID:41668074 and matched-exposure interrogation of the numerically lower MR4.5 at 50 mg; toxicity/PRO primary endpoint with molecular safety net (>=12 months stable MR4.0, monthly IS PCR, pre-specified re-escalation on MMR loss); two-factor design asking whether allosteric first-line therapy obviates de-escalation or stacks with it. Eligibility requires junction-resolved typing (L18) so the IS denominator is valid, plus diagnosis-time CD26+CD35- burden and ASXL1/RUNX1 status. Both guidelines give principles, not quantitative reduction schedules, so the comparator arm must still be trial-defined.","level":"DOSSIER","confidence":0.81,"citations":[{"kind":"PMID","id":"41510882","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41397287","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42584922","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"41376561","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42394986","verified":true,"isNew":true,"addedVisit":5},{"kind":"PMID","id":"42193014","verified":true,"isNew":true,"addedVisit":5},{"kind":"PMID","id":"40761712","verified":true,"isNew":true,"addedVisit":5},{"kind":"PMID","id":"40647447","verified":true,"isNew":true,"addedVisit":6},{"kind":"PMID","id":"42033491","verified":true,"isNew":true,"addedVisit":6},{"kind":"PMID","id":"41694735","verified":true,"isNew":true,"addedVisit":10},{"kind":"PMID","id":"42209462","verified":true,"isNew":true,"addedVisit":13},{"kind":"PMID","id":"40848059","verified":true,"isNew":false,"addedVisit":13}],"corrobVisits":7,"createdVisit":3,"createdCycle":36,"lastVisit":20,"lastNote":"Independent second-region guideline endorsement of dose optimisation; still no randomised or prospective dose-reduction trial and no quantitative schedules, hence a small rise only.","history":[{"visit":20,"cycle":204,"status":"STRENGTHENED","note":"Independent second-region guideline endorsement of dose optimisation; still no randomised or prospective dose-reduction trial and no quantitative schedules, hence a small rise only."},{"visit":19,"cycle":192,"status":"STRENGTHENED","note":"First patient-level tolerability comparison showing the therapeutic window is agent-dependent as well as dose-dependent; still no randomised dose-reduction trial, so the rise is small."},{"visit":18,"cycle":180,"status":"STRENGTHENED","note":"ELN 2025 guideline explicitly prefers dose reduction over switching, the strongest external endorsement yet; still no randomised dose-reduction trial, so the rise is modest."},{"visit":15,"cycle":156,"status":"WEAKENED","note":"A query written specifically to find a prospective randomised dose-reduction trial with MR4/TFR/PRO endpoints returned none; the tier-limiting gap is now confirmed empty by targeted search, so confidence is trimmed for evidential silence even though the mechanistic base is untouched."},{"visit":14,"cycle":144,"status":"STRENGTHENED","note":"Fifth evidence-bearing visit; first agent-specific dose-comparative cohort with a large toxicity separation and a within-patient reduction series, plus a PRO rationale. Held below 0.8 because the design is observational with unequal follow-up and MR4.5 is numerically lower at 50 mg."},{"visit":13,"cycle":132,"status":"STRENGTHENED","note":"Independent guideline-level endorsement (dose reduction over switching; optimal biologic dose safer and as effective) added on a fourth evidence-bearing visit to an already 10-citation lead that has survived the ELTS-negative and CD26-surrogate kill attempts; promoted, but held at 0.72 because the corroboration is a review and no prospective de-escalation trial exists."},{"visit":12,"cycle":120,"status":"STRENGTHENED","note":"Two new inputs: a flow-implementable diagnosis-time primitive-cell/CD26+CD35- stratifier that predicts 12-month failure, and real-world confirmation that label-dose (never exceeded) asciminib delivers trial-level depth with low toxicity. Also newly bounded: CD26+ LSC counts explicitly excluded as an on-treatment surrogate. Not promoted; still no prospective de-escalation data."},{"visit":10,"cycle":96,"status":"STRENGTHENED","note":"Two new inputs: the asciminib plateau supports the window premise, and a large multi-site study shows the desk's own stratifier (ELTS) is near-useless for molecular response, so the eligibility gate is rewritten around validated bone-marrow cytomorphology. Not promoted further pending prospective de-escalation data."},{"visit":6,"cycle":60,"status":"STRENGTHENED","note":"First head-to-head (retrospective, n=39) comparison of cessation strategies: tapering confers no TFR advantage. Recorded as a negative result so the desk stops proposing taper-to-deepen; safety signal favourable."},{"visit":5,"cycle":48,"status":"STRENGTHENED","note":"Promoted on three [NEW] sources, two of them clinical cohorts (n=53 and n=157) rather than reviews, and one showing 81% TFR persistence after downgrading. Still no randomised de-escalation data and all new cohorts are retrospective and selected for tolerability problems."}]},{"id":"L8","title":"Sequential ATP-site to allosteric switch: asciminib as non-cross-resistant salvage after ponatinib and in T315I disease","mechanism":"Non-overlapping binding sites and largely non-overlapping resistance (PMID:42026180, PMID:42463944, PMID:42042193), with T315I MMR 53.3% and durable responses at 6 years (PMID:42463944). [NEW] Dual functional genomics now defines the failure spectrum prospectively: 279 asciminib-resistance mutations, hotspots inside and outside the kinase domain including SH3, epistasis measured on a Y253H imatinib-resistant background, and a live-cell FRET biosensor linking BCR::ABL1 conformational state to drug sensitivity (PMID:42365381). ELN 2025 keeps these agents sequential (PMID:40646132).","approach":"Build the mutation-to-agent matrix from the DMS/base-editing atlas rather than from case accrual: score atlas-nominated variants (A337V, P465S, F359V/I, T315I compound mutants, SH3-region substitutions) for ponatinib/olverembatinib/dasatinib cross-sensitivity, then validate against paired kinase-domain NGS from ASC4OPT/NCT02081378 non-responders and all 200 mg escalation failures; add a junction-architecture column (L18) and ASXL1 status; use the FRET biosensor to classify clinical variants of unknown significance and NGS-negative failures as conformational versus state-driven.","level":"DOSSIER","confidence":0.82,"citations":[{"kind":"PMID","id":"42090741","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42352456","verified":true,"isNew":true,"addedVisit":4},{"kind":"PMID","id":"42463944","verified":true,"isNew":true,"addedVisit":5},{"kind":"PMID","id":"39996897","verified":true,"isNew":true,"addedVisit":6},{"kind":"PMID","id":"42033491","verified":true,"isNew":true,"addedVisit":6},{"kind":"PMID","id":"41778234","verified":true,"isNew":true,"addedVisit":6},{"kind":"PMID","id":"42026180","verified":true,"isNew":true,"addedVisit":7},{"kind":"NCT","id":"NCT04948333","verified":false,"isNew":false,"addedVisit":7},{"kind":"PMID","id":"41699336","verified":true,"isNew":true,"addedVisit":8},{"kind":"PMID","id":"42042193","verified":true,"isNew":true,"addedVisit":8},{"kind":"PMID","id":"40613032","verified":true,"isNew":true,"addedVisit":8},{"kind":"PMID","id":"41373445","verified":true,"isNew":true,"addedVisit":16}],"corrobVisits":7,"createdVisit":4,"createdCycle":38,"lastVisit":19,"lastNote":"A saturating asciminib resistance map plus an epistasis screen and a conformational-state assay supply the mutation-resolved failure spectrum this lead has lacked for eighteen visits.","history":[{"visit":19,"cycle":192,"status":"STRENGTHENED","note":"A saturating asciminib resistance map plus an epistasis screen and a conformational-state assay supply the mutation-resolved failure spectrum this lead has lacked for eighteen visits."},{"visit":18,"cycle":180,"status":"STRENGTHENED","note":"First atypical-transcript T315I TFR on asciminib plus first primary-resistance case; mutation-resolved failure spectrum still absent, but the resistance taxonomy is now explicitly two-axis (kinase domain plus junction architecture)."},{"visit":16,"cycle":168,"status":"WEAKENED","note":"Fourth consecutive visit with no mutation-resolved asciminib-failure spectrum; the dedicated NGS query returned only a narrative T315I review. Efficacy/safety base untouched, so only a small trim for the persistent tier-limiting gap."},{"visit":12,"cycle":120,"status":"STRENGTHENED","note":"Fifth evidence-bearing visit with new independent corroboration: a 523-patient real-world postmarketing surveillance cohort reproduces trial-level MMR/MR4.0/MR4.5 at label dose with vascular occlusive events at 0.2% and no unexpected signals in elderly/comorbid patients. Residual weakness unchanged: still no mutation-resolved failure spectrum published."},{"visit":8,"cycle":84,"status":"STRENGTHENED","note":"Fourth evidence-bearing visit with new independent corroboration in the hardest settings: asciminib response after dasatinib and ponatinib failure in T315I multi-mutant blast crisis (PMID:41699336) and across three Ph+ acute leukaemias (PMID:42042193); olverembatinib retained activity against T315I+E459K (PMID:40613032). Residual weakness unchanged and explicitly recorded: still zero kinase-domain"},{"visit":7,"cycle":72,"status":"STRENGTHENED","note":"Third evidence-bearing visit with new, independent corroboration: a phase 3b trial (PMID:42026180) replaces inference with prospective salvage efficacy data, and adds a negative sub-result (dose escalation largely futile) that survived my attempt to explain failure as under-exposure. Residual weakness recorded: no NGS at failure, and the reverse-sequence evidence is still one case."},{"visit":6,"cycle":60,"status":"STRENGTHENED","note":"Strengthened by the first documented asciminib-emergent myristoyl-pocket mutation with successful ATP-site rescue, plus review-level confirmation of mutation-specific sensitivity. Held at CANDIDATE, not DOSSIER: the reverse-sequence evidence is a single case report."},{"visit":5,"cycle":48,"status":"STRENGTHENED","note":"Promoted: second evidence-bearing visit with a [NEW] independent, prospective, dose-specified dataset (PMID:42463944) that corroborates the retrospective registry and shows the T315I effect is not merely intolerance-selection. Boundary still open: no mutation spectrum at asciminib failure in either source."},{"visit":4,"cycle":38,"status":"NEW","note":"New from a [NEW] multicentre retrospective (25 Turkish centres). Hypothesis-generating only: non-randomised, n=49, dose not stated in abstract, and the reported cumulative DMR (37.2%) exceeding MMR (32.6%) is internally inconsistent as written - denominators presumably differ; flagged as ambiguous. Resistance boundary to record: no mutation data at asciminib failure in this cohort."}]},{"id":"L9","title":"Concentration-floor (TDM-anchored) de-escalation: reduce exposure to a measured pharmacokinetic threshold, not to a fraction of label dose","mechanism":"Floor-plus-plateau exposure-response with agent-specific thresholds (asciminib quartile analysis PMID:40848059; nilotinib efficacy Cmin and ~1290 ng/mL hyperbilirubinaemia ceiling PMID:40978483; flumatinib Cmax_2h thresholds PMID:42338759). [NEW] Counter-pressure: a simple arbitrary halving of dasatinib (100 to 50 mg) reproduced MMR/MR4/MR4.5 and EFS without any therapeutic drug monitoring (PMID:41668074), so the incremental value of a concentration floor over a flat sub-label dose is now unproven rather than assumed; the only residual signal is the numerically lower MR4.5 at 50 mg, which is where a DMR-specific floor could still matter.","approach":"Reframe as a superiority question: derive an agent-specific Cmin/Cmax_2h floor for MR4.0/MR4.5 from ASC4FIRST/ASC4OPT biobank PK with electronic adherence monitoring to deconfound exposure from relative dose intensity, then compare TDM-guided dosing against fixed halved dosing for DMR attainment and toxicity in the same cohort. Do not port thresholds across agents or transcript types.","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"PMID","id":"42338759","verified":true,"isNew":true,"addedVisit":5},{"kind":"PMID","id":"42412118","verified":true,"isNew":true,"addedVisit":5},{"kind":"PMID","id":"42394986","verified":true,"isNew":true,"addedVisit":5},{"kind":"PMID","id":"40761712","verified":true,"isNew":true,"addedVisit":5},{"kind":"PMID","id":"42026180","verified":true,"isNew":true,"addedVisit":7},{"kind":"PMID","id":"42584922","verified":true,"isNew":false,"addedVisit":8},{"kind":"PMID","id":"40848059","verified":true,"isNew":true,"addedVisit":10},{"kind":"PMID","id":"40978483","verified":true,"isNew":true,"addedVisit":10},{"kind":"PMID","id":"42209462","verified":true,"isNew":true,"addedVisit":13},{"kind":"PMID","id":"41668074","verified":true,"isNew":true,"addedVisit":14}],"corrobVisits":5,"createdVisit":5,"createdCycle":48,"lastVisit":14,"lastNote":"Weakened by the comparator it now has to beat: flat 50 mg dasatinib matched label dose without PK guidance, so TDM must show incremental DMR or toxicity benefit, not merely sub-label feasibility.","history":[{"visit":14,"cycle":144,"status":"WEAKENED","note":"Weakened by the comparator it now has to beat: flat 50 mg dasatinib matched label dose without PK guidance, so TDM must show incremental DMR or toxicity benefit, not merely sub-label feasibility."},{"visit":13,"cycle":132,"status":"STRENGTHENED","note":"Marginal strengthening only: the new review endorses sub-label optimal biologic dosing but contributes no PK; the exposure/adherence confound in every existing dataset still blocks promotion."},{"visit":10,"cycle":96,"status":"STRENGTHENED","note":"Open question 4 closed: the asciminib exposure-response analysis exists and shows a low-exposure penalty with a flat plateau above it, corroborated independently in nilotinib TDM with a toxicity ceiling. Promoted to CANDIDATE on two new, independent, agent-distinct datasets; held below 0.6 because both are regression/retrospective and exposure is confounded with adherence."},{"visit":8,"cycle":84,"status":"WEAKENED","note":"Weakened by targeted absence: a dedicated asciminib PK/exposure-response query returned no new trough-versus-molecular-response data, so the BID>QD trough interpretation remains inference resting on one trial plus one dialysis case."},{"visit":7,"cycle":72,"status":"STRENGTHENED","note":"First schedule-controlled clinical signal supporting the exposure-floor hypothesis (BID > QD at equal daily dose in ASC4OPT); reframes the lead from dose-fraction to trough/schedule. Still no PK-linked molecular-response data published for asciminib, so the trough interpretation is inference."},{"visit":5,"cycle":48,"status":"NEW","note":"New this visit. Introduces the first explicit contradiction to fixed-fraction de-escalation within the programme: exposure-response floors exist for molecular depth, so TDM should gate de-escalation. Evidence is one exploratory single-country TDM study plus one case report."}]},{"id":"L11","title":"HDAC6-selective inhibition plus asciminib: autophagy blockade to maladaptive ISR, MCL-1 loss and BCL-xL-dependent apoptosis in CML","mechanism":"Tool compound 7b sustains alpha-tubulin acetylation at lower concentrations than ricolinostat or nexturastat A, blocks autophagosome maturation and synergises with asciminib in CML lines and primary PBMCs while sparing healthy PBMCs, via p-eIF2alpha/ATF4/CHOP, MCL-1 suppression, PUMA/NOXA, caspase-2 and BCL-xL-dependent apoptosis (PMID:42284888); Beclin 1 phospho/acetyl reprogramming remains title-only (PMID:42480967).","approach":"Unchanged bench specification on primary CD34+CD38- chronic-phase LSCs with ricolinostat/citarinostat substituting for tool compounds, LTC-IC and serial replating versus same-donor normal CD34+ HSPCs, Beclin 1 acetyl/phospho stoichiometry, BH3 profiling before nominating any BH3-mimetic (BCL-xL platelet liability binding, PMID:41596764).","level":"CANDIDATE","confidence":0.32,"citations":[{"kind":"PMID","id":"42284888","verified":true,"isNew":true,"addedVisit":8},{"kind":"PMID","id":"41952641","verified":true,"isNew":false,"addedVisit":8},{"kind":"PMID","id":"42480967","verified":true,"isNew":true,"addedVisit":9},{"kind":"PMID","id":"41899586","verified":true,"isNew":true,"addedVisit":9},{"kind":"PMID","id":"41596764","verified":true,"isNew":true,"addedVisit":9},{"kind":"PMID","id":"40256307","verified":true,"isNew":true,"addedVisit":11}],"corrobVisits":3,"createdVisit":8,"createdCycle":84,"lastVisit":19,"lastNote":"Still no clinical-grade HDAC6 inhibitor data in CML and no LSC (CD34+CD38-) readout anywhere; the source paper itself shows 7b outperforming ricolinostat, which undercuts translatability of the available drugs. One further dedicated empty pass retires it.","history":[{"visit":19,"cycle":192,"status":"WEAKENED","note":"Still no clinical-grade HDAC6 inhibitor data in CML and no LSC (CD34+CD38-) readout anywhere; the source paper itself shows 7b outperforming ricolinostat, which undercuts translatability of the available drugs. One further dedicated empty pass retires it."},{"visit":11,"cycle":108,"status":"WEAKENED","note":"A targeted query for clinical-grade HDAC6 inhibition in CML returned only a TNBC-focused new HDAC6 chemotype (PMID:40256307); no primary CML-LSC data, no ricolinostat/citarinostat CML data, PMID:42480967 still title-only. Weakened for silence; chemistry availability is not corroboration."},{"visit":9,"cycle":92,"status":"STRENGTHENED","note":"Second evidence-bearing visit with independent primary corroboration (PMID:42480967) naming Beclin 1 as the dual-regulated node; promoted to CANDIDATE. Held below 0.5 because the new paper is title-only, there is still no primary CD34+CD38- LSC or clinical-grade HDAC6 agent data, and the BH3 partner remains unidentified."},{"visit":8,"cycle":84,"status":"NEW","note":"New this visit from a single laboratory (in vitro plus one in vivo model, no clinical data); admitted at low confidence because it supplies both a kinase-independent combination partner for asciminib and the apoptotic-priming mechanism that the retired BCL2 lead never had."}]},{"id":"L14","title":"MDM2 degradation (PROTAC) to restore wild-type p53 in TP53-intact CML LSCs alongside BCR-ABL1 blockade","mechanism":"MDM2 PROTAC MD-265 degraded MDM2, restored p53 and killed 105 primary leukaemic stem-cell samples (median IC50 16 nM) with normal HSCs ~100-fold less sensitive and resistance confined to TP53-mutant samples (PMID:41986621). [KNOWN] Chronic-phase CML is near-uniformly TP53-wild-type and BCR-ABL1 suppresses p53 output, making the persistent LSC compartment mechanistically eligible (PMID:41952641), but every dataset remains AML-derived.","approach":"Unchanged extension test: primary CD34+CD38- chronic-phase CML cells +/- imatinib/asciminib with a CRBN-based MDM2 degrader, scoring LTC-IC, serial replating, p21/PUMA induction, MDM2 protein loss and apoptosis versus same-donor normal CD34+ HSPCs, with TP53 sequencing of all samples. Prespecified liabilities: class myelosuppression/thrombocytopenia [KNOWN], selection of TP53-mutant subclones, CRBN loss. Check additivity of PUMA/NOXA induction with the L11 ISR axis.","level":"LEAD","confidence":0.2,"citations":[{"kind":"PMID","id":"41986621","verified":true,"isNew":true,"addedVisit":10},{"kind":"PMID","id":"41952641","verified":true,"isNew":false,"addedVisit":10},{"kind":"PMID","id":"40550748","verified":true,"isNew":true,"addedVisit":10}],"corrobVisits":1,"createdVisit":10,"createdCycle":96,"lastVisit":11,"lastNote":"The query written specifically to find CML MDM2/p53-restoration stem-cell data returned only pan-cancer reviews; the hypothesis remains AML-only extrapolation, so confidence drops.","history":[{"visit":11,"cycle":108,"status":"WEAKENED","note":"The query written specifically to find CML MDM2/p53-restoration stem-cell data returned only pan-cancer reviews; the hypothesis remains AML-only extrapolation, so confidence drops."},{"visit":10,"cycle":96,"status":"NEW","note":"New; the strongest primary-LSC therapeutic-window dataset in this pack (105 samples, 100-fold normal-HSC margin) but generated in AML, with zero CML data, so confidence is capped until CML CD34+CD38- testing is done."}]},{"id":"L17","title":"Drug-selected ABL1 mutation neoepitopes (E255V) as TCR-T targets in multi-TKI-resistant CML — replacing failed fusion-junction vaccination","mechanism":"Fusion-junction vaccination is immunogenic but not cytoreductive (PMID:40333294); HLA-A2-restricted TCRs against ABL1 E255V were raised in humanised mice with T315I peptide non-immunogenic (PMID:39931057). A dedicated immunopeptidomics/HLA-A2 query this visit returned no CML data at all; the only tangentially relevant item is base-edited LCK T316I dasatinib-resistant universal CAR-T (PMID:39935177), a host-rejection workaround, not evidence of ABL1 epitope presentation.","approach":"Unchanged feasibility gate: HLA-A2 typing plus mutation-resolved NGS to size the E255V/HLA-A2 intersection in multi-TKI failure; prove endogenous presentation on primary patient blasts (immunopeptidomics or mutant-peptide-pulsed autologous APC killing); normal-tissue HLA-A2 alloreactivity panel. Determine directly whether NCT06904066 admits CML. Prespecified retirement: one further empty dedicated pass.","level":"LEAD","confidence":0.22,"citations":[{"kind":"PMID","id":"39931057","verified":true,"isNew":true,"addedVisit":17},{"kind":"PMID","id":"40333294","verified":true,"isNew":true,"addedVisit":17},{"kind":"NCT","id":"NCT06904066","verified":true,"isNew":false,"addedVisit":17},{"kind":"PMID","id":"39935177","verified":true,"isNew":true,"addedVisit":18}],"corrobVisits":2,"createdVisit":17,"createdCycle":171,"lastVisit":18,"lastNote":"First dedicated pass for ABL1 neoepitope presentation returned zero relevant primary data; single-laboratory transgenic-mouse TCR work remains the whole evidence base.","history":[{"visit":18,"cycle":180,"status":"WEAKENED","note":"First dedicated pass for ABL1 neoepitope presentation returned zero relevant primary data; single-laboratory transgenic-mouse TCR work remains the whole evidence base."},{"visit":17,"cycle":171,"status":"NEW","note":"New this visit. The pack simultaneously kills the fusion-junction vaccine route with 10-year clinical data and supplies a mutation-restricted alternative with a recruiting platform trial; opened as a separate lead rather than folded into L5 because it is interventional, not gating."}]},{"id":"L18","title":"Transcript-architecture triage: atypical and insertion-bearing BCR::ABL1 fusions as a distinct resistance class and a blind spot in molecular monitoring","mechanism":"Asciminib needs the assembled SH3-SH2-kinase autoinhibited clamp; a3 breakpoints delete ABL1 exon 2 leaving an incomplete SH3 and conferring asciminib resistance, while NUP214 exon 32 reconstitutes a chimeric SH3 and restores sensitivity (PMID:42485989), with SH3-localised resistance hotspots independently mapped by DMS (PMID:42365381). [NEW] Two Ph+ acute-leukaemia cases show a3 disease (e13a3, e1a3) responding to ATP-site dasatinib-based therapy (PMID:41366999, PMID:42064782), consistent with a3 being a selective allosteric liability; a FISH-positive, repeatedly RT-qPCR-negative CML that progressed to lymphoid blast phase and then responded to asciminib (PMID:41869197) instantiates the pri","approach":"Isogenic CML-side panel (e14a2, e13a2, e19a2, e13a3, e1a3, e8a2-SPECC1L, e4a2-CSE1L) in Ba/F3 and CD34+ cells: asciminib versus imatinib/ponatinib/olverembatinib/dasatinib dose-response on WT, T315I and V379I backgrounds, SH3-deletion and alphaI-helix controls, FRET autoinhibition readout (PMID:42365381). Clinically: adopt nanopore adaptive sampling (PMID:41254115) as the junction-resolution assay at diagnosis before any asciminib, TFR or de-escalation pathway; mandatory re-genotyping of every NGS-negative asciminib failure and every FISH-positive/PCR-negative case (PMID:41869197) for a3 and out-of-primer junctions; for confirmed a3 disease default to ATP-site agents and quantify on a patien","level":"DOSSIER","confidence":0.66,"citations":[{"kind":"PMID","id":"41506866","verified":true,"isNew":true,"addedVisit":17},{"kind":"PMID","id":"40999990","verified":true,"isNew":true,"addedVisit":17},{"kind":"PMID","id":"41211450","verified":true,"isNew":true,"addedVisit":17},{"kind":"PMID","id":"40881880","verified":true,"isNew":true,"addedVisit":17},{"kind":"PMID","id":"38965368","verified":true,"isNew":true,"addedVisit":18},{"kind":"PMID","id":"41098098","verified":true,"isNew":true,"addedVisit":18},{"kind":"PMID","id":"42485989","verified":true,"isNew":true,"addedVisit":19},{"kind":"PMID","id":"42365381","verified":true,"isNew":true,"addedVisit":19},{"kind":"PMID","id":"41254115","verified":true,"isNew":true,"addedVisit":20},{"kind":"PMID","id":"41869197","verified":true,"isNew":true,"addedVisit":20}],"corrobVisits":4,"createdVisit":17,"createdCycle":171,"lastVisit":20,"lastNote":"Fourth evidence-bearing visit: a deployable long-read junction assay plus a documented FISH+/PCR-negative case operationalise the monitoring arm, and two a3 case reports give first (indirect, non-CML) support that a3 architecture spares ATP-site sensitivity. Isogenic CML pharmacology still absent, so the rise is modest.","history":[{"visit":20,"cycle":204,"status":"STRENGTHENED","note":"Fourth evidence-bearing visit: a deployable long-read junction assay plus a documented FISH+/PCR-negative case operationalise the monitoring arm, and two a3 case reports give first (indirect, non-CML) support that a3 architecture spares ATP-site sensitivity. Isogenic CML pharmacology still absent, so the rise is modest."},{"visit":19,"cycle":192,"status":"STRENGTHENED","note":"Promoted: the [NEW] chimeric-SH3 rescue experiment plus deletion mapping (PMID:42485989) turns my inferred a2-vs-a3 conformational hypothesis into a mapped structural requirement, corroborated independently by SH3-localised asciminib resistance hotspots (PMID:42365381); third evidence-bearing visit with new independent citations."},{"visit":18,"cycle":180,"status":"STRENGTHENED","note":"Two new atypical-transcript cases with opposite asciminib outcomes convert a monitoring caveat into a falsifiable structural hypothesis (a2 versus a3 dependence of myristoyl-pocket inhibition); second evidence-bearing visit with independent citations."},{"visit":17,"cycle":171,"status":"NEW","note":"New this visit: four converging papers (one assay validation, one review, two case reports) identify transcript architecture as an unhandled axis that also undermines the molecular safety nets assumed by L7 and L5."}]},{"id":"L19","title":"Immunophenotype- and score-stratified blast-phase CML: chemotherapy-sparing ponatinib+blinatumomab for lymphoid BP versus early transplant for myeloid/high-risk","mechanism":"CML mortality concentrates in blast phase, where median OS is 18.9 months but stratifies sharply (97 vs 22 vs 9 months) on six factors available at BP onset — blast percentage, platelet count, age, BP immunophenotype, extramedullary disease and prior CML history (PMID:41714405). [KNOWN] Lymphoid BP is biologically Ph+ ALL-like and CD19+, making it eligible for T-cell-engager plus third-generation ATP-site inhibition, whereas myeloid BP lacks an equivalent antigen and is transplant-dependent. The 2025 Chinese guideline now fixes the lymphoblast threshold defining lymphoid transformation and lists ponatinib, olverembatinib and asciminib as available agents (PMID:41486652); a multi-TKI-intolera","approach":"Retrospectively apply the ELN-BP score to existing ponatinib+blinatumomab cohorts (NCT03147612 framework) and to HLA-mismatched reduced-PTCy transplant series (NCT06001385) to test whether score-by-modality interaction exists; prospectively, stratify at BP onset by immunophenotype and score, allocating CD19+ lymphoid BP to chemotherapy-sparing ponatinib+blinatumomab with mandatory kinase-domain NGS and junction-resolved typing (L18), and myeloid/high-risk BP to induction plus early allografting. Prespecified liabilities: ponatinib arterial-occlusive and hepatic toxicity [KNOWN], blinatumomab CD19-loss/lineage-switch escape [KNOWN], registry-derived score lacking external validation (stated b","level":"LEAD","confidence":0.32,"citations":[{"kind":"PMID","id":"41714405","verified":true,"isNew":true,"addedVisit":20},{"kind":"PMID","id":"41486652","verified":true,"isNew":true,"addedVisit":20},{"kind":"PMID","id":"41869197","verified":true,"isNew":true,"addedVisit":20},{"kind":"NCT","id":"NCT03147612","verified":true,"isNew":false,"addedVisit":20},{"kind":"NCT","id":"NCT06001385","verified":true,"isNew":false,"addedVisit":20}],"corrobVisits":1,"createdVisit":20,"createdCycle":204,"lastVisit":20,"lastNote":"New: first prognostic architecture for CML-BP in this programme's twenty visits, and the phase where the solved-mechanism paradigm fails; hypothesis is currently stratification logic plus borrowed Ph+ ALL biology, not CML-BP trial data.","history":[{"visit":20,"cycle":204,"status":"NEW","note":"New: first prognostic architecture for CML-BP in this programme's twenty visits, and the phase where the solved-mechanism paradigm fails; hypothesis is currently stratification logic plus borrowed Ph+ ALL biology, not CML-BP trial data."}]}],"retired":[{"title":"FBXO3-mediated DUSP9 degradation sustains MAPK output in the persistent CML LSC: FBXO3 inhibition plus ATP-site TKI","note":"Retired: contradicting evidence outranks the single supporting paper — every independent DUSP9 dataset makes DUSP9 a stemness driver, not a brake whose stabilisation would kill LSCs.","cycle":204,"ts":"2026-08-20T01:59:20.795Z"},{"title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","note":"Prespecified retirement fires: third visit of guideline and literature non-endorsement, zero concurrent-dosing data, and the new saturating resistance map gives no evidence of a mutational blind spot that only dual-site occupancy would close.","cycle":192,"ts":"2026-08-20T01:17:59.128Z"},{"title":"CD26 (DPP4) as a CML-restricted surface antigen for antibody- or cell-mediated eradication of the persistent BCR::ABL1+ LSC","note":"Prespecified retirement fired: the dedicated CD26/DPP4 depleting-construct query returned zero relevant primary data, against standing counter-evidence on burden-independence and on DPP4 inhibition supporting haematopoiesis. Method success, recorded to prevent re-proposal.","cycle":156,"ts":"2026-08-19T23:08:54.076Z"},{"title":"STAT5A as a druggable transcriptional node of BCR-ABL1-kinase-independent TKI resistance","note":"Prespecified retirement fired; the fresh STAT-family paper is solid-tumour bioinformatics and does not corroborate the CML claim.","cycle":144,"ts":"2026-08-19T22:26:51.571Z"},{"title":"TIF1beta/TRIM28-SETDB1 chromatin node as a BCR-ABL1-kinase-independent LSC-state dependency","note":"Prespecified retirement condition met: third empty atlas-mining pass. Recorded as a method success, not a failure.","cycle":144,"ts":"2026-08-19T22:26:51.571Z"},{"title":"ILK as a microenvironment-coupled, kinase-independent resistance node in CML LSCs","note":"Prespecified retirement condition met: third visit with zero CML-specific ILK evidence, against a class-level negative on microenvironment targeting. Recorded so the desk does not re-propose niche-adhesion targeting in CML without primary data.","cycle":108,"ts":"2026-08-19T20:23:43.800Z"},{"title":"BCL2 co-dependence confined to multi-TKI/asciminib-resistant CML: venetoclax plus ponatinib as salvage","note":"Retired on both evidential silence (fourth empty visit for PMID:40858806; NCT02689440 still without any readout) and a mechanistic redirection: the apoptotic dependency exposed in primary CML cells this visit is MCL1/BCL-xL, not BCL2.","cycle":84,"ts":"2026-08-19T18:59:08.083Z"},{"title":"BCL2 co-dependence of the TKI-persistent CML clone: dasatinib + venetoclax","note":"Retired for evidential silence: NCT02689440 has been ACTIVE_NOT_RECRUITING without any molecular or LSC readout across three consecutive evidence-bearing visits, and no pack has ever supplied CML-specific BCL2 dependence data. Recorded so the desk does not re-propose it.","cycle":48,"ts":"2026-08-19T16:51:11.593Z"}],"nextQueries":["(\"BCR::ABL1\" OR \"BCR-ABL1\") AND (e13a3 OR e14a3 OR \"exon 3\" OR \"SH3 domain\") AND (asciminib OR allosteric OR Ba/F3 OR isogenic) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"chronic myeloid leukemia\" OR CML) AND (\"blast phase\" OR \"blast crisis\") AND (blinatumomab OR ponatinib OR olverembatinib OR transplantation) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(asciminib AND (resistance OR mutation) AND (ponatinib OR olverembatinib OR \"kinase domain\" OR NGS)) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]"],"updatedAt":"2026-08-20T01:59:20.795Z"},{"key":"mesothelioma","name":"mesothelioma","mondo":{"id":"MONDO:0005065","name":"mesothelioma"},"genes":[{"label":"WT1","kind":"causal"},{"label":"BAP1","kind":"correlated"},{"label":"BCL10","kind":"correlated"}],"visits":3,"openQuestions":["Does TEAD palmitoylation inhibition (AZ'4331-class, VT3989, IK-930) change the VSIG4/CRIg+ cavity macrophage compartment in vivo, or is its mesothelioma activity purely tumour-cell-intrinsic?","Is any TEAD palmitoylation-site inhibitor in first-in-human trials in NF2-altered disease, with reported dose, schedule and renal safety signal?","Do pleural resident macrophages share the C1Q+VSIG4+/SPP1+VSIG4+ ontogeny and CSF1R dependence demonstrated for peritoneal resident macrophages, and does intracavitary CSF1R blockade deplete or merely reprogramme them?","In human pleural mesothelioma cohorts, are NF2 copy-number loss and BAP1 loss co-occurring or mutually exclusive, and does BAP1 status track with MHC-I/B2M loss?","Which promoter-biased transcription factors mediate promoter reinforcement after TEAD inhibition in mesothelioma, and are they druggable (CDK7/9, BET, or the TF itself)?","Does the LAG-3 trial NCT07234058 collect myeloid endpoints (ARG1, VSIG4, SPP1) that could discriminate T-cell-intrinsic from macrophage-mediated ICI resistance, as the sarcomatoid relapse case report implies is needed?"],"leads":[{"id":"L1","title":"TEAD inhibition to reverse NF2-loss-driven resistance to mesothelin CAR T cells in pleural mesothelioma","mechanism":"NF2 [SOMATIC] loss de-represses YAP/TAZ-TEAD; TEAD1-4 cycle rapidly between apo and palmitoylated states, and pan-TEAD palmitoylation inhibition collapses YAP-TEAD binding and TEAD-dependent transcription in Hippo-altered mesothelioma cells (NCI-H226) with monotherapy xenograft activity (PMID:42525965); chemotype landscape now includes PPI disruptors, palmitoylation-pocket ligands and TEAD PROTACs (PMID:42603497). The separate claim that TEAD blockade reverses CRIg+ macrophage-mediated CAR-T/anti-PD-1 resistance remains supported only by PMID:42208538.","approach":"Two-track: (a) tumour-intrinsic — palmitoylation-pocket TEAD inhibitor in NF2-CNV-loss/LATS-mutant selected pleural mesothelioma, intermittent schedule, pharmacodynamics = CTGF/CYR61, TEAD metabolic-labelling palmitoylation assay; (b) sensitiser — layered onto anti-mesothelin TNaive/SCM hYP218 CAR T cells (NCT06885697) with CRIg/VSIG4+ macrophage fraction and CAR-T persistence as co-primary translational endpoints. Resistance: promoter reinforcement (PMID:42410069), TAZ-only activation, mesothelin shedding. Window: renal tubular YAP1/TEAD1-SLC7A5 ferroptosis protection (PMID:41833934) plus intestinal/skin regeneration [KNOWN] argue for intermittent or intracavitary dosing.","level":"CANDIDATE","confidence":0.6,"citations":[{"kind":"PMID","id":"42208538","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06885697","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41833934","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41800759","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42525965","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42603497","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42410069","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":13,"lastVisit":3,"lastNote":"First independent, non-42208538 evidence that TEAD palmitoylation inhibition has mesothelioma activity (PMID:42525965, [NEW]); promoted to CANDIDATE on tumour-intrinsic grounds only. Still zero first-in-human TEAD trial in any pack (Q4 open), and the myeloid-reversal claim is not replicated.","history":[{"visit":3,"cycle":146,"status":"STRENGTHENED","note":"First independent, non-42208538 evidence that TEAD palmitoylation inhibition has mesothelioma activity (PMID:42525965, [NEW]); promoted to CANDIDATE on tumour-intrinsic grounds only. Still zero first-in-human TEAD trial in any pack (Q4 open), and the myeloid-reversal claim is not replicated."},{"visit":2,"cycle":67,"status":"WEAKENED","note":"Fielded 2023-2026 query for mesothelioma x NF2/TEAD/YAP x inhibitor/resistance returned zero papers; absence of any independent replication after a targeted search downgrades this from 0.55 to 0.50. Open questions 1 and 2 remain unanswered."},{"visit":1,"cycle":13,"status":"NEW","note":"New this visit from PMID:42208538, the only mechanistic mesothelioma paper in the pack with in vivo therapeutic reversal data; renal YAP1/TEAD1-SLC7A5 ferroptosis axis (PMID:41833934) imported as the therapeutic-window counterweight. Abstract does not name the TEAD compound or dose - unresolved."}]},{"id":"L2","title":"BAP1-loss-associated EZH2 dependency as a combination scaffold, not monotherapy","mechanism":"BAP1 loss ([SOMATIC] in tumour; [GERMLINE] in BAP1 tumour predisposition syndrome) leaves PRC2/EZH2 H3K27me3 unopposed, silencing tumour suppressors; non-canonical EZH2 roles in DNA repair and immune evasion proposed. Premise remains review-level assertion (PMID:42257802) with no primary synthetic-lethality data in this or the prior pack.","approach":"Only in combination in BAP1-deficient disease: dual EZH1/2 or EZH2i plus platinum-pemetrexed or PD-1 blockade. NCT04104776 lists tulmimetostat with enzalutamide and no BAP1-selected or mesothelioma-specific arm, so it will not read out this hypothesis. Resistance: EZH1 compensation, EED/SUZ12 mutation, BAP1-wild-type subclones. Normal tissue: EZH2 required for haematopoiesis and germinal-centre B cells - cytopenias, secondary T-cell malignancy risk, disqualifying for use in unaffected germline carriers.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42257802","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04104776","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03830229","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":13,"lastVisit":2,"lastNote":"Second consecutive visit with no primary BAP1/EZH2 synthetic-lethality data despite a targeted 2022-2026 query; trial re-listing adds no mesothelioma arm. Recorded for the notebook: single-agent EZH2i gave disease control without meaningful ORR [KNOWN] - do not re-propose as monotherapy.","history":[{"visit":2,"cycle":67,"status":"WEAKENED","note":"Second consecutive visit with no primary BAP1/EZH2 synthetic-lethality data despite a targeted 2022-2026 query; trial re-listing adds no mesothelioma arm. Recorded for the notebook: single-agent EZH2i gave disease control without meaningful ORR [KNOWN] - do not re-propose as monotherapy."},{"visit":1,"cycle":13,"status":"NEW","note":"Opened from the review PMID:42257802; deliberately low confidence because the pack supplies no new efficacy data and prior single-agent results were weak. Germline/somatic distinction anchored to the BAP1 carrier follow-up protocol NCT03830229."}]},{"id":"L3","title":"CRIg+ macrophage / retinoic-acid niche as a cavity-specific immunosuppression target","mechanism":"Human peritoneal cavity contains abundant C1Q+VSIG4+ and SPP1+VSIG4+ resident macrophages at homeostasis that, in tumour, upregulate IL10/VEGF and downregulate antigen-presentation genes; intraperitoneal anti-CSF1R plus anti-PD1 reduces tumour burden and improves survival in vivo (PMID:40246872). VSIG4 = CRIg [KNOWN], so this is cross-tumour corroboration of the CRIg+ cavity niche invoked in PMID:42208538. Independently, identical mesothelioma cell lines are ICT-responsive subcutaneously but refractory intraperitoneally with low IFN/TNF/STAT tone and a non-response signature (PMID:41735480), replicating site-dependence in mesothelioma. Post-ICI mesothelioma relapse shows ARG1/PLA2G7-high TAM","approach":"Repurposing-first: CSF1R inhibitor or anti-CSF1R antibody as intracavitary/loco-regional pre-conditioning before or with PD-1 blockade or mesothelin CAR-T (NCT06885697), tested in peritoneal mesothelioma where the chemo-immunotherapy backbone already exists (NCT05001880); serial cavity fluid and pleural tissue (NCT00715611) for VSIG4/CRIg, C1Q, SPP1, ARG1 multiplex and scRNA-seq. Resistance: monocyte-derived cavity macrophage replenishment, SPP1 axis persistence, IL10/VEGF redundancy (bevacizumab already in NCT05001880). Normal tissue: resident cavity macrophages serve peritoneal/pleural homeostasis and infection control; CSF1R inhibition risks systemic Kupffer/osteoclast effects [KNOWN] - a","level":"CANDIDATE","confidence":0.5,"citations":[{"kind":"PMID","id":"42208538","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05001880","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT00715611","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"40246872","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41735480","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41986072","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":13,"lastVisit":3,"lastNote":"Two independent [NEW] papers: human VSIG4+ cavity-resident macrophage niche with a druggable CSF1R node (PMID:40246872) and cell-line-matched site-dependent ICT failure in mesothelioma (PMID:41735480). Promoted to CANDIDATE; actionable node moves from unidentified chemokine/RAR to CSF1R.","history":[{"visit":3,"cycle":146,"status":"STRENGTHENED","note":"Two independent [NEW] papers: human VSIG4+ cavity-resident macrophage niche with a druggable CSF1R node (PMID:40246872) and cell-line-matched site-dependent ICT failure in mesothelioma (PMID:41735480). Promoted to CANDIDATE; actionable node moves from unidentified chemokine/RAR to CSF1R."},{"visit":2,"cycle":67,"status":"WEAKENED","note":"Same single-source problem as L1 and no answer to question 3 (no chemokine, no RAR isoform, no repurposable antagonist identified). Downgraded 0.35 to 0.30; added NCT00715611 as a source of resected pleural tissue rather than as a therapeutic arm."},{"visit":1,"cycle":13,"status":"NEW","note":"Split from the TEAD lead because the intervention class and expected toxicity differ and may spare renal YAP function; the specific chemokines and RAR isoform are not resolved in the abstract, so this is the most speculative of the three."}]},{"id":"L4","title":"Human correlative platform in BAP1 germline carriers to test the NF2/myeloid resistance model before building drug combinations on it","mechanism":"Programme's mechanistic claims still need human confirmation: NF2 [SOMATIC] CNV loss versus BAP1 [GERMLINE/SOMATIC] loss co-occurrence, MHC-I/B2M status, and the CRIg/VSIG4+ myeloid phenotype. New evidence adds a stratifier: pleural and peritoneal cavities are immunologically distinct compartments in mesothelioma models (PMID:41735480), and the VSIG4+ resident macrophage programme is defined in human peritoneum (PMID:40246872), so cavity of origin must be a covariate rather than pooled.","approach":"Non-interventional correlative endpoints on recruiting cohorts NCT04431024, NCT03830229, NCT00242723, NCT00715611 and NCT05001880 (peritoneal arm as the contrast compartment): paired germline/somatic sequencing with NF2 copy-number calling, BAP1 IHC, HLA class I/B2M IHC, and multiplex VSIG4/C1Q/SPP1/ARG1/CD206 on tissue plus cavity fluid; cfDNA NF2 CNV. Deliverable: go/no-go biomarker set for CAR-T selection (NCT06885697) and for the CSF1R pre-conditioning hypothesis. No epigenetic agent in unaffected germline carriers [KNOWN cytopenia/secondary malignancy risk].","level":"LEAD","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT04431024","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT03830229","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT00242723","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT00715611","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42208538","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41735480","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40246872","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":67,"lastVisit":3,"lastNote":"Assay panel now has defined marker identities (VSIG4, C1Q, SPP1, ARG1) and a mandatory pleural-versus-peritoneal stratification, both from [NEW] papers; core germline/somatic questions from visits 1-2 still unanswered.","history":[{"visit":3,"cycle":146,"status":"STRENGTHENED","note":"Assay panel now has defined marker identities (VSIG4, C1Q, SPP1, ARG1) and a mandatory pleural-versus-peritoneal stratification, both from [NEW] papers; core germline/somatic questions from visits 1-2 still unanswered."},{"visit":2,"cycle":67,"status":"NEW","note":"Opened because the pack's only genuinely new content was three human surveillance/surgical cohorts; with zero new mechanistic papers, the fastest way to move the programme is to demand human confirmation of the mouse model rather than stack more drugs on it."}]},{"id":"L5","title":"Pre-empt promoter-reinforcement resistance to TEAD inhibitors with transcriptional-machinery combinations or TEAD degradation","mechanism":"Mesothelioma cells surviving a pan-TEAD inhibitor restore TEAD target gene expression by promoter reinforcement: enhancer-promoter contacts weaken or are lost while promoter activity recovers, driven by promoter-biased resistance transcription factors, leaving distal elements dispensable (PMID:42410069). Resistance is therefore an adaptive rewiring of transcription rather than only palmitoylation-pocket mutation [INFERRED], which predicts that agents acting at promoters/pause release (CDK7, CDK9, BET) or degradation of TEAD protein (PROTAC modality, PMID:42603497) should be more durable than deeper TEAD occupancy alone [SPECULATIVE].","approach":"In NF2-null mesothelioma lines and PDX (e.g. the NCI-H226 background used for AZ'4331, PMID:42525965): derive TEAD-inhibitor-resistant pools, define the promoter-biased resistance TFs, then test up-front doublets of palmitoylation-site TEAD inhibitor with CDK7i/CDK9i/BETi and with TEAD PROTACs; readouts Micro-C/ATAC at TEAD targets, CTGF/CYR61 rebound kinetics, apo- versus palmitoylated TEAD fraction. Resistance to the combination: general transcriptional toxicity limits, TAZ-independent bypass. Normal tissue: CDK7/9 and BET inhibition are broadly myelosuppressive and GI-toxic [KNOWN], so intermittent scheduling and locoregional TEAD dosing are the only plausible windows.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42410069","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42603497","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42525965","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":146,"lastVisit":3,"lastNote":"Opened because the pack names a concrete, mesothelioma-specific TEAD-inhibitor resistance mechanism before any clinical trial exists - cheapest place to act on it is preclinical combination design, not post hoc.","history":[{"visit":3,"cycle":146,"status":"NEW","note":"Opened because the pack names a concrete, mesothelioma-specific TEAD-inhibitor resistance mechanism before any clinical trial exists - cheapest place to act on it is preclinical combination design, not post hoc."}]}],"retired":[],"nextQueries":["(\"VT3989\" OR \"IK-930\" OR \"TEAD inhibitor\") AND (\"phase 1\" OR \"first-in-human\" OR \"clinical trial\") AND (\"NF2\" OR \"mesothelioma\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"VSIG4\" OR \"CRIg\") AND (\"pleural\" OR \"pleura\" OR \"cavity macrophage\" OR \"resident macrophage\") AND (\"CSF1R\" OR \"depletion\" OR \"immunotherapy\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"mesothelioma\" AND (\"NF2\" AND \"BAP1\") AND (\"co-occurrence\" OR \"mutually exclusive\" OR \"copy number\" OR \"HLA\" OR \"B2M\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"updatedAt":"2026-08-19T22:34:13.854Z"},{"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"},"genes":[{"label":"TNFRSF10B","kind":"causal"},{"label":"ING1","kind":"causal"},{"label":"PTEN","kind":"correlated"}],"visits":3,"openQuestions":["Does DR5 induction by b-AP15/VLX1570 or by an approved proteasome inhibitor plus a multivalent DR5 agonist produce in vivo activity in HNSCC xenografts/PDX, and is that activity abolished in CASP8-mutant or cFLIP-high models?","Is 11q13 FADD/CCND1 amplification (frequent in HPV-negative HNSCC) a positive predictor of death-receptor-pathway sensitivity, and does CASP8 mutation status segregate HNSCC responders from non-responders in any published dataset?","Has petosemtamab reported response rate, duration and Fc-effector/FCGR3A correlatives in HNSCC, and is any innate-checkpoint or NK-engager combination with it in registries?","What are the disclosed targets of AZD6750 (NCT07115043), ABBV-711 (NCT07241039) and BI 765179 (NCT04958239), and do any sit on the myeloid/innate axis L3 depends on?","Are there mechanistic (not commentary) data on acquired resistance and relapse biology after perioperative pembrolizumab in HNSCC - JAK/B2M/MHC-I loss, IFN-signature exhaustion, myeloid re-infiltration - given that L1, L3, L5 and L6 all lay","Does any HNSCC or HPV+ model show that EP2/EP4 or COX-2 blockade increases cDC1 cross-presentation or vaccine-induced CD8 responses (L5), and does an E6*(aa49-110)-directed TCR-T/TCR-mimic programme exist anywhere (L1)?"],"leads":[{"id":"L1","title":"High-avidity HPV16 E6* (aa49-110)-directed TCR-T for HPV+ oropharyngeal SCC; deprioritise E7_11-19","mechanism":"E6/E7 are constitutively expressed viral oncoproteins with no normal-tissue counterpart; patient-derived E6*(aa49-110) TCRs were high-avidity and persisted in an exhausted CD8 compartment in a lung metastasis three years post-therapy while lower-avidity clones including E7_11-19 were lost (PMID:42503644). Independent vaccine literature now states that E6/E7 targeting is constrained by heterogeneous intratumoural antigen expression and that clonality and expression level must be formal antigen-selection parameters (PMID:41571571, PMID:42179134) — the same failure mode as the predicted E6 splice-isoform loss.","approach":"Unchanged construct plan (retro/lentiviral TCR-T or TCR-mimic bispecific, HLA-matched, NFAT-reporter avidity ranking) but add mandatory pre-infusion E6/E7 isoform expression and clonality QC on tumour tissue plus HLA-A LOH and B2M assessment; monitor with HPV DNA rinse (rule-in only) and plasma ctHPV (PMID:42211773, PMID:42565346); pembrolizumab backbone for exhaustion.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42503644","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42211773","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42565346","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41571571","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42179134","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":14,"lastVisit":2,"lastNote":"Dedicated TCR-T/HPV query found no clinical or preclinical E6*-directed programme and no E7_11-19 trial readout — Q1 still open. New antigen-heterogeneity evidence corroborates the predicted escape route, so confidence eases 0.55 to 0.50 and an antigen-QC gate is now part of the design.","history":[{"visit":2,"cycle":68,"status":"WEAKENED","note":"Dedicated TCR-T/HPV query found no clinical or preclinical E6*-directed programme and no E7_11-19 trial readout — Q1 still open. New antigen-heterogeneity evidence corroborates the predicted escape route, so confidence eases 0.55 to 0.50 and an antigen-QC gate is now part of the design."},{"visit":1,"cycle":14,"status":"NEW","note":"New this visit from PMID:42503644 (n=4 single-cell + paired TCR-seq, one longitudinal primary/metastasis pair, nine functionally validated TCRs). Small n; the loss of the clinical E7_11-19 clone is a directional warning, not a formal negative trial."}]},{"id":"L2","title":"PI3K/AKT blockade to resensitise cisplatin-resistant HNSCC in FOXA2/LAMC2-high or PTEN-null tumours","mechanism":"FOXA2 transactivates LAMC2 (ChIP + luciferase) and enriches PI3K/AKT signalling in cisplatin-resistant HNSCC organoids (PMID:42319071); laminin-332/integrin alpha6beta4-FAK at the invasive front is the presumed effector [INFERRED]. The approved-inhibitor landscape is built on activating PIK3CA/AKT1-2/MTOR alterations rather than PTEN loss (PMID:40564038), and PTEN-null stratification evidence sits in prostate cancer (PMID:41525007), not HNSCC [SOMATIC]. Reciprocal ERK1/2 activation is the canonical escape from PI3K-axis blockade (PMID:40943615).","approach":"Select on PIK3CA hotspot plus FOXA2/LAMC2-high rather than PTEN loss; alpelisib or capivasertib + cisplatin in the reported organoid system, with a MEK/ERK inhibitor arm to pre-empt reciprocal activation; test FOXA2/LAMC2 IHC as a platinum-benefit predictor in the banked specimens of NCT02734537 (post-op RT +/- cisplatin, prospective biomarker analysis). For PTEN-null tumours treat PI3Kbeta/SGK1/PARP synthetic lethality as an unproven separate hypothesis. Window: hyperglycaemia, rash, diarrhoea, plus additive toxicity with MEK inhibition [KNOWN].","level":"LEAD","confidence":0.32,"citations":[{"kind":"PMID","id":"42319071","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40564038","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41525007","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40943615","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT02734537","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":14,"lastVisit":2,"lastNote":"Targeted query for HNSCC AKT/PI3K-plus-platinum data returned only reviews; no HNSCC drug-side evidence exists in this pack. PTEN-null stratification is not supported for this disease, so the biomarker is rewritten and confidence drops from 0.40 to 0.32. Gain: a named resistance route (ERK1/2) and a specimen bank to test the biomarker cheaply.","history":[{"visit":2,"cycle":68,"status":"WEAKENED","note":"Targeted query for HNSCC AKT/PI3K-plus-platinum data returned only reviews; no HNSCC drug-side evidence exists in this pack. PTEN-null stratification is not supported for this disease, so the biomarker is rewritten and confidence drops from 0.40 to 0.32. Gain: a named resistance route (ERK1/2) and a specimen bank to test the biomarker cheaply."},{"visit":1,"cycle":14,"status":"NEW","note":"New this visit; single multi-omic paper with organoid and ChIP validation. Drug-side evidence in HNSCC is absent from this pack - next visit must find or fail to find AKT-inhibitor-plus-platinum HNSCC data."}]},{"id":"L3","title":"Macrophage/innate-checkpoint potentiation of cetuximab-mediated ADCP in R/M HNSCC","mechanism":"Cetuximab opsonises EGFR-high HNSCC but ADCP is restrained by CD47-SIRPalpha and by immunosuppressive TAM reprogramming (CCL18/MMP1 axis, PMID:42294496). The Fc-effector arm now has a late-stage molecule: petosemtamab, an EGFR x LGR5 bispecific with enhanced Fc-effector function [KNOWN], sits in the commercial late-stage pipeline with predicted near-term regulatory transition (PMID:41560619), and NK-directed ADCC/engager platforms are argued to be a complementary effector axis to T-cell therapy with a distinct toxicity profile (PMID:42193922, review, nasopharyngeal focus).","approach":"Keep the two live arms (AK117 + cetuximab or + AK104, NCT06508606; BI 770371 + pembrolizumab +/- cetuximab, NCT06806852) and add petosemtamab as the preferred EGFR backbone for any future innate-checkpoint combination. Shared correlative panel: CD47/SIRPalpha IHC, CD68/CD163 density, CD16+ NK infiltration, FCGR2A/FCGR3A polymorphisms, plasma CCL18, LGR5 expression. On-target risks: RBC/platelet clearance and anaemia with CD47 blockade, rash and infusion reactions with dual EGFR-axis engagement [KNOWN].","level":"LEAD","confidence":0.42,"citations":[{"kind":"NCT","id":"NCT06508606","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06806852","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42294496","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41560619","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42193922","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":14,"lastVisit":3,"lastNote":"Strengthened by a named, late-stage, ADCC-enhanced EGFR bispecific (PMID:41560619) and a second effector rationale (PMID:42193922); still no efficacy readout in the pack, and the NK review is not HNSCC-specific, so the rise is modest (0.35 to 0.42).","history":[{"visit":3,"cycle":147,"status":"STRENGTHENED","note":"Strengthened by a named, late-stage, ADCC-enhanced EGFR bispecific (PMID:41560619) and a second effector rationale (PMID:42193922); still no efficacy readout in the pack, and the NK review is not HNSCC-specific, so the rise is modest (0.35 to 0.42)."},{"visit":1,"cycle":14,"status":"NEW","note":"New this visit; trials are phase 1/2 with no efficacy readout yet, and the MTDH support is a systematic review of preclinical work, so this is rationale-level only."}]},{"id":"L4","title":"IRF9 nuclear translocation as a reversible node of apatinib (VEGFR2 TKI) resistance","mechanism":"Apatinib binds IRF9 and promotes RAN-dependent nuclear import; nuclear IRF9 drives JAK-STAT and BCC-pathway programmes, i.e. drug-induced bypass, and higher IRF9 protein predicted resistance in patient material (PMID:42540626). If the mechanism is class-wide rather than apatinib-specific, cabozantinib (VEGFR2/MET) should induce the same nuclear shift [SPECULATIVE].","approach":"Repurpose the lead as a correlative hypothesis: measure IRF9 nuclear/cytoplasmic ratio on paired pre/on-treatment biopsies already mandated in NCT05136196 (cabozantinib + nivolumab, HNSCC cohort) before investing in Oroxin B or RAN-import blockers, which remain tool compounds. IRF9 is an obligate ISGF3 subunit, so systemic inhibition risks blunting IFN and possibly anti-tumour immunity — the window argues against a therapeutic, for a biomarker.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42540626","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05136196","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":1,"createdCycle":14,"lastVisit":2,"lastNote":"Kill-test partly executed: no new mechanistic support appeared, so the therapeutic arm stays unpromoted; the lead survives only as a biomarker hypothesis with an identified clinical specimen source. Confidence held at 0.25.","history":[{"visit":2,"cycle":68,"status":"WEAKENED","note":"Kill-test partly executed: no new mechanistic support appeared, so the therapeutic arm stays unpromoted; the lead survives only as a biomarker hypothesis with an identified clinical specimen source. Confidence held at 0.25."},{"visit":1,"cycle":14,"status":"NEW","note":"New this visit but deliberately held at low confidence: single in vitro study, natural-product tool compound, and a normal-tissue window argument that cuts against it. Flagged for kill-testing next visit."}]},{"id":"L5","title":"Relieving PGE2/VEGF/IL-6-mediated suppression of dendritic-cell cross-presentation to rescue therapeutic HPV E6/E7 vaccination in HPV+ OPSCC","mechanism":"Tumours blunt CD8 priming both by MHC-I downregulation and by secreting PGE2, VEGF, IL-6 and IL-10 that impair DC cross-presentation of exogenous antigen (PMID:41758201); therapeutic HPV vaccines have repeatedly under-delivered clinically despite ideal viral antigens, and next-generation reviews attribute this to antigen and presentation limits rather than target choice (PMID:41571571, PMID:42179134). Blocking the PGE2 arm should restore the cross-presentation step that vaccine platforms depend on [INFERRED].","approach":"Repurposing-first three-arm concept in HPV+ OPSCC: E6/E7 vaccine (peptide or nucleic-acid platform) + pembrolizumab, with or without COX-2 inhibition or an EP2/EP4 antagonist; correlatives: cDC1 density and activation state, MHC-I on tumour, urinary PGE-M, IFN-gamma ELISpot to E6/E7 pools, ctHPV kinetics. Normal-tissue window: prostaglandin signalling maintains gastric mucosal integrity, renal perfusion and platelet function, so COX-2/EP blockade carries GI, renal and cardiovascular risk [KNOWN]. Resistance: VEGF/IL-6 redundancy, MHC-I loss, B2M mutation.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"41758201","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41571571","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42179134","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":68,"lastVisit":2,"lastNote":"New this visit and deliberately modest: all three citations are reviews, none HNSCC-specific for the PGE2 axis, so this is rationale-level only. It is worth carrying because every component is an approved or late-stage agent and it addresses the presentation bottleneck that also constrains L1.","history":[{"visit":2,"cycle":68,"status":"NEW","note":"New this visit and deliberately modest: all three citations are reviews, none HNSCC-specific for the PGE2 axis, so this is rationale-level only. It is worth carrying because every component is an approved or late-stage agent and it addresses the presentation bottleneck that also constrains L1."}]},{"id":"L6","title":"Pharmacological DR5 (TNFRSF10B) induction by DUB/proteasome inhibition to license TRAIL/DR5-agonist apoptosis in HNSCC","mechanism":"HNSCC is largely TRAIL-refractory at baseline; the USP14/UCHL5 inhibitor b-AP15 raises ROS, activates JNK and upregulates DR5/TRAIL-R2, and this DR5 induction is required for the observed TRAIL sensitisation; the same agent inhibits NF-kB survival output and previously sensitised HNSCC cells to TNFa and to TNF-inducing radiation (PMID:42069980) [SOMATIC, TNFRSF10B expression node rather than mutated driver]. DUB/proteostasis targeting is a maturing chemical space with multiple tool and clinical-stage inhibitors (PMID:41891958, PMID:42259777). Approved proteasome inhibitors also induce DR5 and downregulate cFLIP [KNOWN], giving a repurposing surrogate for b-AP15/VLX1570.","approach":"Two-component design: (i) DR5-inducing arm - b-AP15/VLX1570 or a repurposed proteasome inhibitor (bortezomib/carfilzomib) or radiation; (ii) agonist arm - multivalent/hexameric DR5 agonist rather than first-generation TRAIL ligands, which failed clinically for weak receptor clustering [KNOWN]. Mandatory stratification and kill-test in HNSCC lines/PDX: CASP8 loss-of-function (recurrent in HPV-negative HNSCC), 11q13 FADD/CCND1 amplification, cFLIP-L/S and BID/BCL2L1 levels, DR5 O-glycosylation (GALNT14) [KNOWN]; predict CASP8-null lines are resistant despite full DR5 induction - if not, the mechanism is off-pathway. Window: hepatocytes and, for hyperclustering agonists, biliary epithelium are ","level":"LEAD","confidence":0.38,"citations":[{"kind":"PMID","id":"42069980","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41891958","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42259777","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":147,"lastVisit":3,"lastNote":"First disease-context evidence for the Monarch anchor TNFRSF10B after two citation-free visits; answers half of Q3. In vitro single-paper support only, no xenograft data in the abstract, and no CASP8/cFLIP status reported - hence 0.38 and an explicit falsification plan.","history":[{"visit":3,"cycle":147,"status":"NEW","note":"First disease-context evidence for the Monarch anchor TNFRSF10B after two citation-free visits; answers half of Q3. In vitro single-paper support only, no xenograft data in the abstract, and no CASP8/cFLIP status reported - hence 0.38 and an explicit falsification plan."}]}],"retired":[],"nextQueries":["(\"head and neck squamous cell carcinoma\" OR HNSCC) AND (DR5 OR TRAIL OR TNFRSF10B) AND (agonist OR \"caspase-8\" OR CASP8 OR cFLIP OR FADD) AND (xenograft OR \"in vivo\" OR PDX) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(petosemtamab OR (EGFR AND LGR5 AND bispecific) OR \"ADCC-enhanced\") AND (\"head and neck\" OR HNSCC) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"head and neck\" OR HNSCC) AND (\"acquired resistance\" OR relapse) AND (pembrolizumab OR \"PD-1\") AND (B2M OR JAK1 OR JAK2 OR \"MHC class I\" OR \"interferon signature\" OR myeloid) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T22:37:42.130Z"},{"key":"adrenocortical carcinoma","name":"adrenocortical carcinoma","mondo":{"id":"MONDO:0006639","name":"adrenal cortex carcinoma"},"genes":[{"label":"TP53","kind":"correlated"},{"label":"ZNRF3","kind":"correlated"},{"label":"CTNNB1","kind":"correlated"},{"label":"CDKN2A","kind":"correlated"},{"label":"TERT","kind":"correlated"},{"label":"PRKAR1A","kind":"correlated"}],"visits":3,"openQuestions":["Do responders in NCT02721732, NCT03333616 and NCT06900595 concentrate in the immunomodulatory subtype of PMID:42550593, and is HLA class II copy loss enriched in non-responders?","Is hypercortisolism predictive of ICI failure independently of molecular subtype, or was the prior cortisol signal confounded by the immune-suppressed subtype?","Does whole-genome doubling / copy-neutral LOH status (PMID:42265438) co-segregate with the cell-cycle-altered subtype, and does it predict WEE1/PKMYT1/ATR/KIF18A sensitivity in ACC models?","What fraction of CDK4-amplified or CDKN2A-deleted ACC retains RB1, and can CDK4/6-inhibitor exposure be sustained on concurrent mitotane?","In ZNRF3-mutant ACC specifically, is the tumour immune microenvironment T-cell-enriched (consistent with PMID:42236114) or excluded, and is SCD expression correspondingly low?","Are on-treatment biopsies from NCT06900595 yielding any evidence of MET/AXL bypass or Treg re-expansion after cabozantinib plus cemiplimab?"],"leads":[{"id":"L1","title":"Adaptive WEE1 induction as the actionable vulnerability of TP53-mutant ACC after RSK1/multikinase inhibition","mechanism":"Truncal global LOH followed by whole-genome doubling and copy-neutral LOH occurs in 7/9 advanced ACC patients as a single catastrophic, evolutionarily conserved event (PMID:42265438), and an independent cohort defines a 22% cell-cycle-altered subtype marked by chromosomal instability and cell-cycle gene overexpression (PMID:42550593). With TP53 loss removing the G1/S checkpoint [KNOWN], such aneuploid, CIN-high cells depend on WEE1/PKMYT1-mediated CDK1 restraint and on ATR to tolerate replication stress; RSK1/multikinase inhibition by OTSSP167 induced compensatory WEE1 in TP53-mutant ACC lines (PMID:42601067). Aneuploid cells also acquire KIF18A dependency [KNOWN].","approach":"Stratify H295R/CUACC1/CUACC9 and PDX by ploidy/WGD status before testing adavosertib, a PKMYT1 inhibitor, ceralasertib and a KIF18A inhibitor; readouts pCDK1-Y15, gamma-H2AX, pHH3, micronuclei, cGAS-STING output. Use the PMID:42550593 CCA transcriptional signature as the inclusion filter and ask whether CD/steroid-high tumours are resistant. Clinic-ready upstream substitute remains platinum-etoposide (NCT03583710). Resistance: CCNE1/CDC25 rewiring, adaptive ATR-CHK1 signalling.","level":"LEAD","confidence":0.44,"citations":[{"kind":"PMID","id":"42601067","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03583710","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42550593","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42265438","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":15,"lastVisit":3,"lastNote":"Two new independent ACC datasets supply the missing context: a CIN/cell-cycle-altered subtype (22%) and truncal WGD in 7/9 patients. Still zero ACC-specific WEE1/PKMYT1/ATR dependency data, so the rise is modest and the lead is now explicitly subtype-conditional.","history":[{"visit":3,"cycle":148,"status":"STRENGTHENED","note":"Two new independent ACC datasets supply the missing context: a CIN/cell-cycle-altered subtype (22%) and truncal WGD in 7/9 patients. Still zero ACC-specific WEE1/PKMYT1/ATR dependency data, so the rise is modest and the lead is now explicitly subtype-conditional."},{"visit":2,"cycle":69,"status":"WEAKENED","note":"A query aimed squarely at WEE1/adavosertib/RSK1/MELK in ACC returned zero ACC-relevant papers this visit; the pack's cell-cycle content (YBX1 PMID:42196325, TONSL PMID:42002539/PMID:41817780, AARS1 PMID:41952148, RNF40 PMID:42059264) is pan-cancer bioinformatics in other tumour types with no ACC validation. Two visits, still one primary report and abstract-only RSK1 attribution, so confidence fall"},{"visit":1,"cycle":15,"status":"NEW","note":"New from PMID:42601067 — first mechanistic in vivo dataset in the pack; couples the dominant somatic anchor (TP53) to a druggable adaptive checkpoint. Discounted for single-group data, abstract-only RSK1 attribution, and OTSSP167's poor clinical track record."}]},{"id":"L2","title":"VEGFR/MET TKI plus PD-1 blockade as the practical immunotherapy backbone in advanced ACC","mechanism":"ACC is largely MSS with modest TMB [KNOWN]; anti-angiogenic kinase inhibition normalises vasculature and blunts VEGF-driven myeloid suppression to permit T-cell entry [INFERRED]. PMID:42550593 shows ~24% of ACC form an immunomodulatory subtype with enriched immune signalling and favourable outcomes, versus 40% immune-suppressed with TCR-pathway downregulation and recurrent HLA class II deletion — a plausible explanation for the reproducible small responder fraction across unselected ICI trials, and PMID:42106259 records durable unselected benefit with nivolumab/ipilimumab in rare tumours including ACC in SWOG DART.","approach":"Follow NCT06900595 (cabozantinib+cemiplimab) and retro-annotate NCT02721732/NCT03333616 archival tissue with the PMID:42550593 four-subtype classifier plus HLA-II copy number; primary question is whether responders concentrate in IM and are absent from IS. Add HLA class II loss and TCR-signalling downregulation to the prespecified resistance panel alongside HGF/MET bypass and Treg re-expansion. Drop 'WNT-driven T-cell exclusion' as an assumed resistance route pending ACC data (see PMID:42236114).","level":"LEAD","confidence":0.46,"citations":[{"kind":"NCT","id":"NCT06900595","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42158873","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT02721732","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03333616","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT02867592","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42550593","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42106259","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":15,"lastVisit":3,"lastNote":"Gains a concrete, testable enrichment biomarker (IM subtype; HLA-II intact) and independent evidence of a durable unselected responder tail. Also loses a wrong assumption: WNT activation is not established as an exclusion mechanism in ACC.","history":[{"visit":3,"cycle":148,"status":"STRENGTHENED","note":"Gains a concrete, testable enrichment biomarker (IM subtype; HLA-II intact) and independent evidence of a durable unselected responder tail. Also loses a wrong assumption: WNT activation is not established as an exclusion mechanism in ACC."},{"visit":1,"cycle":15,"status":"NEW","note":"New. Trial infrastructure now exists (NCT06900595); PMID:42158873 supplies a genomically annotated durable partial response with triple therapy but is n=1 and confounded by lenvatinib plus dual checkpoint blockade."}]},{"id":"L3","title":"Tumour-derived cortisol as a targetable immune-evasion axis: GR antagonism to enable checkpoint therapy","mechanism":"Unchanged mechanism (glucocorticoid signalling on T cells and myeloid cells; PMID:42433381, PMID:42590935, PMID:40736645), but its scope narrows: PMID:42550593 finds a discrete cortisol-driven subtype in only 14% of ACC, while the immune-suppressed subtype (40%, worst DFS) is defined by TCR downregulation and HLA-II deletion rather than steroidogenic activation. Cortisol therefore looks like a subtype-restricted and possibly systemic-only contributor, not the general driver of MSS-ACC checkpoint resistance [INFERRED].","approach":"Reframe as a biomarker-selected question: test relacorilant (safety database NCT03604198) or steroidogenesis inhibition plus anti-PD-1 only in cortisol-secreting/CD-subtype models and patients, and formally ask in archival ICI cohorts whether hypercortisolism predicts failure independently of subtype. Retain mandatory adrenal-reserve testing and the mitotane monitoring caveat (PMID:42065769, PMID:40736645).","level":"CANDIDATE","confidence":0.42,"citations":[{"kind":"PMID","id":"42590935","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42158873","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03604198","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05286814","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42433381","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40736645","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42065769","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42550593","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":15,"lastVisit":3,"lastNote":"First ACC transcriptomic partition that separates steroid-high from immune-cold biology assigns the two to different, mostly non-overlapping subtypes; the immune-cold majority is antigen-presentation-defective. Contradicting evidence outranks the prior inference, so confidence falls and the hypothesis is narrowed to the CD subtype.","history":[{"visit":3,"cycle":148,"status":"WEAKENED","note":"First ACC transcriptomic partition that separates steroid-high from immune-cold biology assigns the two to different, mostly non-overlapping subtypes; the immune-cold majority is antigen-presentation-defective. Contradicting evidence outranks the prior inference, so confidence falls and the hypothesis is narrowed to the CD subtype."},{"visit":2,"cycle":69,"status":"STRENGTHENED","note":"Promoted on two new independent ACC-specific sources this visit: PMID:42433381 names glucocorticoid signalling plus myeloid suppression as a defining feature of the immune-depleted ACC microenvironment, and PMID:40736645 supplies prevalence, prognostic weight, first-line steroidogenesis-inhibitor pharmacology, GR-antagonist monitoring limits and an explicit ICI-combination rationale. Confidence he"},{"visit":1,"cycle":15,"status":"NEW","note":"New and deliberately speculative — mechanistic scaffolding is a review plus a case report; needs cohort-level correlation between hypercortisolism and checkpoint failure before it earns candidacy."}]},{"id":"L4","title":"Replacement-dose glucocorticoid stewardship as a modifiable determinant of checkpoint-inhibitor efficacy in ACC","mechanism":"Most advanced ACC patients receive mitotane, which induces CYP3A4 and raises cortisol-binding globulin, so hydrocortisone replacement is routinely supraphysiologic and cortisol/ACTH monitoring is unreliable (PMID:40736645); ICI can additionally destroy residual adrenal tissue via immune adrenalitis (PMID:42065769). Exogenous glucocorticoid is systemic GR agonism on the same T-cell and myeloid compartments that PMID:42433381 identifies as glucocorticoid-suppressed in ACC, so replacement dose and schedule may be an unmeasured confounder that blunts PD-1 blockade [INFERRED], and steroid exposure could mimic the tumour-derived cortisol effect in L3 [SPECULATIVE].","approach":"Retrospective, hypothesis-generating analysis of ACC ICI cohorts (NCT02721732, NCT03333616, NCT06900595) capturing cumulative hydrocortisone-equivalent dose, mitotane co-exposure and irAE-related steroid pulses against ORR/PFS; preclinically, compare anti-PD-1 efficacy in adrenalectomised ACC-bearing mice under physiologic versus supraphysiologic corticosterone replacement, reading FKBP5/TSC22D3 induction in TILs. Test whether mineralocorticoid-dominant replacement or lowest-effective hydrocortisone preserves T-cell function. Treat NCT05286814 (systemic dexamethasone with PDS01ADC) as the natural experiment for the antagonism prediction. Research hypothesis only; not a management recommendat","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42065769","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40736645","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42433381","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT05286814","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT02721732","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":69,"lastVisit":2,"lastNote":"New from PMID:42065769, which shows ICI precipitating adrenal crisis in a mitotane-pretreated ACC patient and forces the desk to separate tumour-derived cortisol (L3) from iatrogenic glucocorticoid exposure. Deliberately low confidence: entirely inferential, no cohort data, and confounded because sicker patients receive more steroid.","history":[{"visit":2,"cycle":69,"status":"NEW","note":"New from PMID:42065769, which shows ICI precipitating adrenal crisis in a mitotane-pretreated ACC patient and forces the desk to separate tumour-derived cortisol (L3) from iatrogenic glucocorticoid exposure. Deliberately low confidence: entirely inferential, no cohort data, and confounded because sicker patients receive more steroid."}]},{"id":"L5","title":"CDK4/6 inhibition in the CDK4-amplified / CDKN2A-deleted cell-cycle-altered ACC subtype","mechanism":"PMID:42550593 identifies focal CDK4 amplification and a 22% cell-cycle-altered subtype with cell-cycle gene overexpression and chromosomal instability, and explicitly proposes CDK4/6 inhibition for it; CDKN2A is a Monarch-anchored correlated/[SOMATIC] alteration in ACC, and CDKN2A loss plus CDK4 gain with intact RB1 is the canonical setting for palbociclib/ribociclib/abemaciclib sensitivity [KNOWN]. Truncal WGD (PMID:42265438) may co-select for CDK4/6 dependence in the same tumours [SPECULATIVE].","approach":"Genotype-select ACC lines/PDX for CDK4 amplification or CDKN2A deletion with intact RB1; test CDK4/6i monotherapy and combinations with mitotane, with a WEE1/PKMYT1 inhibitor, and with anti-PD-1 (CDK4/6i-induced senescence/antigen presentation) [KNOWN]. Critical translational caveat: mitotane is a potent CYP3A4 inducer (PMID:40736645) and will lower exposure of CYP3A4-cleared CDK4/6 inhibitors, so PK-guided dosing or a mitotane-free arm is required. Resistance: RB1 loss, CCNE1/CDK2 activation, TERT-amplified proliferative escape.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42550593","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42265438","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40736645","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":148,"lastVisit":3,"lastNote":"New from PMID:42550593: the most directly repurposable signal in this pack, with an approved drug class, an ACC-derived selection biomarker, and a named drug-drug interaction hazard. Untested in ACC, hence LEAD.","history":[{"visit":3,"cycle":148,"status":"NEW","note":"New from PMID:42550593: the most directly repurposable signal in this pack, with an approved drug class, an ACC-derived selection biomarker, and a named drug-drug interaction hazard. Untested in ACC, hence LEAD."}]},{"id":"L6","title":"ZNRF3-Wnt-SCD lipid axis as an immune-metabolic modifier in ACC, with SCD inhibition in ZNRF3-intact tumours","mechanism":"A genome-wide CRISPR screen shows ZNRF3 loss under glucose restriction activates Wnt and transcriptionally represses SCD, and that this lipid rewiring increases T-cell infiltration and cytotoxicity and synergises with checkpoint blockade in preclinical models (PMID:42236114). ACC carries ZNRF3 mutation in ~10% and CTNNB1 in ~15% (PMID:42550593). If transferable, ZNRF3-mutant ACC would be immunologically favourable rather than T-cell-excluded — inverting the desk's prior assumption — and SCD would become a druggable node in ZNRF3-intact/Wnt-quiet ACC [INFERRED/SPECULATIVE; non-ACC models only].","approach":"Score SCD expression and Wnt target genes against the four PMID:42550593 subtypes and against CD8 infiltration in ACC cohorts; ask directly whether ZNRF3-mutant ACC segregates with the IM rather than IS subtype. Preclinically, test an SCD1 inhibitor plus anti-PD-1 in immunocompetent ACC models stratified by ZNRF3/CTNNB1 status, reading TIL cytotoxicity and membrane lipid saturation. This lead also functions as a falsification test for any future 'WNT activation excludes T cells in ACC' proposal.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42236114","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42550593","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":148,"lastVisit":3,"lastNote":"New and deliberately low confidence: mechanism is pan-cancer with no ACC validation, but it contradicts the assumed direction of WNT-immune coupling used in L2/L3 and must be resolved before any porcupine/tankyrase proposal is made.","history":[{"visit":3,"cycle":148,"status":"NEW","note":"New and deliberately low confidence: mechanism is pan-cancer with no ACC validation, but it contradicts the assumed direction of WNT-immune coupling used in L2/L3 and must be resolved before any porcupine/tankyrase proposal is made."}]}],"retired":[],"nextQueries":["(\"adrenocortical carcinoma\" AND (CDK4 OR CDK6 OR palbociclib OR ribociclib OR abemaciclib OR CDKN2A)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"adrenocortical carcinoma\" AND (\"whole genome doubling\" OR aneuploidy OR \"chromosomal instability\" OR WEE1 OR PKMYT1 OR KIF18A OR ATR)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"adrenocortical carcinoma\" AND (\"HLA class II\" OR \"antigen presentation\" OR \"immune subtype\" OR \"tumor microenvironment\" OR \"single-cell\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T22:41:20.700Z"},{"key":"neuroblastoma","name":"neuroblastoma","mondo":{"id":"MONDO:0005072","name":"neuroblastoma"},"genes":[{"label":"MYCN","kind":"correlated"},{"label":"ALK","kind":"correlated"},{"label":"LIN28B","kind":"correlated"},{"label":"LMO1","kind":"correlated"},{"label":"HACE1","kind":"correlated"},{"label":"PHOX2B","kind":"correlated"}],"visits":3,"openQuestions":["What acquired ALK resistance genotypes (compound mutations, MYCN/MDM2 or RAS-MEK bypass) appear at lorlatinib progression in neuroblastoma, and is the MYCN-amplified failure pattern in PMID:42499277 reproduced in larger series such as NANT/","Does ALK inhibition itself alter GD2 density, MHC-I and TAM M1/M2 ratio in ALK-aberrant neuroblastoma in vivo, i.e. is lorlatinib a legitimate immunotherapy partner rather than just a cytoreductor?","Is METTL3- or IGF2BP2-driven GD2 restoration in MES cells quantitatively sufficient for dinutuximab ADCC and GD2.CAR lysis, and how does it compare head-to-head with EZH2/DNMT re-differentiation (L3)?","Can FECH/heme-directed metabolic conditioning (linsitinib, N-methyl protoporphyrin IX) be applied ex vivo during CAR manufacture, and does it also improve NK-cell persistence relevant to L1?","Is the ALK/USP7/SOX9/MFAP2 lactate-TAM axis druggable downstream of ALK — USP7 inhibitors, MCT1/4 or lactate-export blockade — for ALK-wild-type MYCN-amplified tumours?","Are LIN28B, LMO1, HACE1 or PHOX2B tractable beyond lineage/predisposition markers, and which are germline versus somatic in neuroblastoma?"],"leads":[{"id":"L1","title":"Allogeneic umbilical-cord-blood NK cells to restore ADCC on an anti-GD2 backbone","mechanism":"Anti-GD2 mAbs kill via FcgammaRIIIa-mediated NK ADCC; dose-intensive induction chemotherapy depletes and exhausts patient NK cells, and intratumoral NK density correlates with anti-GD2 response. UCB-derived NK cells expanded ex vivo show higher cytotoxicity, persistence, lower checkpoint and higher memory-like marker expression; anti-GD2 induces a high-activating/low-inhibitory receptor phenotype and remodels the TME toward immune activation.","approach":"Add ex vivo expanded/activated UCB-NK infusions to dinutuximab (NCT06172296) or hu14.18K322A+temozolomide/irinotecan (NCT07549321) in relapsed/refractory and consolidation settings; prespecify FCGR3A-158V/F genotype, baseline intratumoral NK infiltration and GD2 (ST8SIA1) expression as stratifiers; add MDSC/TAM-directed agents if myeloid suppression dominates. Expected resistance: GD2 antigen loss or heterogeneity, TGF-beta/adenosine-mediated NK suppression, KIR-ligand match, NK rejection by recipient immunity.","level":"LEAD","confidence":0.6,"citations":[{"kind":"PMID","id":"42216567","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41827873","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06172296","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07549321","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":16,"lastVisit":1,"lastNote":"Founding lead from PMID:42216567 (preclinical-to-clinical UCB-NK + anti-GD2 synergy; only 2 patients, uncontrolled) framed against the resistance taxonomy in PMID:41827873.","history":[{"visit":1,"cycle":16,"status":"NEW","note":"Founding lead from PMID:42216567 (preclinical-to-clinical UCB-NK + anti-GD2 synergy; only 2 patients, uncontrolled) framed against the resistance taxonomy in PMID:41827873."}]},{"id":"L2","title":"Multi-antigen CAR-T against GPC2/B7-H3 with TGF-beta blockade for MHC-I-low MYCN-amplified disease","mechanism":"MYCN amplification [SOMATIC] with MHC-I downregulation and low TMB disfavours MHC-restricted immunity, so MHC-independent GPC2/B7-H3 CAR targeting plus dTBRII armouring addresses the dominant TME node. New this visit: the IGF1R/IR inhibitor linsitinib, via off-target inhibition of ferrochelatase (FECH), lowers intracellular heme, reduces glycolytic ATP and activation/exhaustion marker expression, and drives central-memory differentiation with improved in vivo persistence of GD2.CAR T cells in neuroblastoma models (PMID:42587334); GPC2 is reported highly expressed in MYCN-amplified tumours (PMID:41750126).","approach":"Track NCT05650749 and NCT07172958; add a metabolic-conditioning arm — linsitinib or selective FECH inhibition (N-methyl protoporphyrin IX class) applied ex vivo during CAR manufacture and/or peri-infusion — to GPC2 and B7-H3 constructs, with central-memory fraction, mitochondrial/glycolytic flux and persistence as prespecified biomarkers; combine with L2's dTBRII armouring and pair with METTL3 priming where antigen is MES-suppressed. Windows: GPC2 fetal/neural-restricted [KNOWN]; B7-H3 broad normal expression is the main on-target off-tumour risk; systemic FECH inhibition risks protoporphyria-like photosensitivity, favouring ex vivo conditioning [INFERRED]. Resistance: antigen downregulation","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"NCT","id":"NCT05650749","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07172958","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41827873","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42587334","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41750126","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":16,"lastVisit":3,"lastNote":"Strengthened by NEW PMID:42587334, which supplies an independent, repurposable (clinical-stage linsitinib) route to fix CAR-T persistence — the failure mode this lead previously only named; GPC2 antigen rationale weakly reinforced by the NEW review PMID:41750126.","history":[{"visit":3,"cycle":149,"status":"STRENGTHENED","note":"Strengthened by NEW PMID:42587334, which supplies an independent, repurposable (clinical-stage linsitinib) route to fix CAR-T persistence — the failure mode this lead previously only named; GPC2 antigen rationale weakly reinforced by the NEW review PMID:41750126."},{"visit":1,"cycle":16,"status":"NEW","note":"New lead; rationale is the MYCN-MHC-I/low-TMB argument in PMID:41827873 matched to the two active CAR trials in the pack, one of which uniquely carries TGF-beta blockade."}]},{"id":"L3","title":"EZH2/DNMT-mediated reactivation of TrkA/TrkC differentiation with pre-emptive TrkB blockade","mechanism":"In neuroblastoma NTRK loci are rarely mutated; TrkA/TrkC (adrenergic, differentiation-competent, favourable-outcome) expression is silenced by promoter methylation, PRC2/EZH2 chromatin repression, MYCN-driven transcriptional silencing and enhancer rewiring, while BDNF-TrkB autocrine loops mark mesenchymal-like therapy-resistant states. Relieving PRC2/DNA-methylation repression should push cells back along the ADRN-MES continuum toward a differentiation-competent state.","approach":"Test EZH2 inhibition (tazemetostat [KNOWN, approved for other indications]) with or without low-dose DNMT inhibition in MYCN-amplified and MES-enriched neuroblastoma models, reading out NTRK1/NTRK3 re-expression, differentiation, and surface MHC-I/GD2 synthase [INFERRED]; combine with a pan-Trk inhibitor (entrectinib/larotrectinib class) to close the predicted BDNF-TrkB escape route. Normal-tissue window: EZH2 and PRC2 are required in haematopoiesis and germinal-centre B cells, so myelosuppression and lymphoid effects bound the dose.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"41977421","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":16,"lastVisit":1,"lastNote":"New lead from PMID:41977421; single review citation only, so it needs independent primary corroboration before promotion.","history":[{"visit":1,"cycle":16,"status":"NEW","note":"New lead from PMID:41977421; single review citation only, so it needs independent primary corroboration before promotion."}]},{"id":"L4","title":"Alpha-emitter radiopharmaceuticals and the ADRN-state dependence of NET-mediated uptake","mechanism":"[211At]MABG enters cells via the norepinephrine transporter SLC6A2, an adrenergic-lineage gene; high-LET alpha emission is less oxygen-dependent than beta emission, but MES/therapy-resistant states are predicted to be intrinsically low-uptake, making state plasticity an on-target escape route.","approach":"Continue to follow NCT07767630 for dose-finding and marrow toxicity; the SSTR2-directed hedge is currently untestable in neuroblastoma because NCT06479811 lists no neuroblastoma cohort, so the SSTR2 arm is parked pending an in-indication vehicle. Retain the preclinical ask: quantify SLC6A2 and SSTR2 across ADRN/MES states and test whether EZH2/DNMT re-differentiation (L3) raises NET-mediated uptake.","level":"LEAD","confidence":0.35,"citations":[{"kind":"NCT","id":"NCT07767630","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06479811","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41977421","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":16,"lastVisit":2,"lastNote":"Weakened: re-pull confirms NCT06479811 has no neuroblastoma indication, so the lineage-orthogonal SSTR2 hedge has no clinical vehicle in this disease; the only in-indication anchor remains a data-free early phase 1. No new evidence this visit.","history":[{"visit":2,"cycle":70,"status":"WEAKENED","note":"Weakened: re-pull confirms NCT06479811 has no neuroblastoma indication, so the lineage-orthogonal SSTR2 hedge has no clinical vehicle in this disease; the only in-indication anchor remains a data-free early phase 1. No new evidence this visit."},{"visit":1,"cycle":16,"status":"NEW","note":"New lead; trial-anchored with no efficacy data yet (early phase 1, recruiting) - explicitly speculative on the NET/ADRN coupling."}]},{"id":"L5","title":"FcgammaR-genotype and ADRN/MES antigen stratification nested inside the frontline dinutuximab phase 3","mechanism":"Anti-GD2 efficacy is FcgammaRIIIa-dependent ADCC; germline FCGR3A-158V/F and FCGR2A-131H/R alter IgG1 affinity, and ST8SIA1-driven GD2 density plus ADRN-to-MES switching alter antigen availability. If both axes are measured in a randomised frontline population, the ADCC-deficient subgroup can be defined prospectively rather than inferred from n=2 salvage series.","approach":"Use the existing biospecimen and serial bone-marrow collection in NCT06172296 to genotype FCGR3A-158V/F and FCGR2A-131H/R [GERMLINE] and to run single-cell/RNA scoring of ADRN vs MES programmes with paired quantification of ST8SIA1/GD2, GPC2, CD276 and SLC6A2 on marrow disease at diagnosis, end-induction and relapse. Prespecified hypothesis: 158F carriers and MES-shifted disease have inferior EFS on dinutuximab and are the enrichment population for NK augmentation (L1) or MHC-independent CAR targeting (L2). Normal tissue: FcgammaRIIIa is expressed on NK cells, monocytes and macrophages, so genotype is a host, not tumour, variable.","level":"LEAD","confidence":0.35,"citations":[{"kind":"NCT","id":"NCT06172296","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41827873","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42216567","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":70,"lastVisit":2,"lastNote":"Derived, not corroborated: built from already-cited resistance taxonomy plus the correlative infrastructure visible in the NCT06172296 record. Created to convert open questions 1 and 3 into something answerable without a new trial.","history":[{"visit":2,"cycle":70,"status":"NEW","note":"Derived, not corroborated: built from already-cited resistance taxonomy plus the correlative infrastructure visible in the NCT06172296 record. Created to convert open questions 1 and 3 into something answerable without a new trial."}]},{"id":"L6","title":"Lorlatinib in ALK-aberrant neuroblastoma stratified by MYCN status, combined with anti-GD2 to exploit ALK-driven myeloid reprogramming","mechanism":"Activating ALK alterations [SOMATIC] (F1174L, R1275Q, fusions, amplification) drive proliferation and, non-cell-autonomously, recruit USP7 to stabilise SOX9, which transactivates MFAP2 to boost glycolysis and lactate/immunosuppressive factor secretion and polarise TAMs to M2; lorlatinib reverses this in vitro and in vivo, and MFAP2 overexpression rescues tumour growth (PMID:42603656). Clinically, 3/5 heavily pretreated ALK-aberrant patients had partial responses, but both MYCN-amplified progressors failed rapidly, implying MYCN amplification uncouples ALK-kinase blockade from response (PMID:42499277) [INFERRED].","approach":"Prospective ALK-aberrant cohort with mandatory MYCN status stratification and paired progression biopsies for compound-mutation and MFAP2/lactate readouts; preclinically, test lorlatinib + dinutuximab/hu14.18K322A (NCT07549321) or lorlatinib + UCB-NK (L1) in ALK-mutant MYCN-amplified PDX, reading TAM M1/M2 ratio, lactate, GD2 density and MHC-I; in MYCN-amplified disease pair lorlatinib with a MYCN-directed or MEK-directed agent rather than expecting monotherapy benefit. Normal tissue: ALK expression is largely restricted to developing neural tissue in adults, giving a favourable window; lorlatinib CNS penetration is an asset for CNS relapse but carries neurocognitive/lipid toxicity [KNOWN]. ","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"42499277","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42603656","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT07549321","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":149,"lastVisit":3,"lastNote":"First ALK lead in this programme; created from two independent NEW items this visit — a 5-patient clinical series showing MYCN-dependent heterogeneity of lorlatinib response, and a mechanistic paper making lorlatinib a myeloid-reprogramming agent, which merges open question 5 into the ALK axis.","history":[{"visit":3,"cycle":149,"status":"NEW","note":"First ALK lead in this programme; created from two independent NEW items this visit — a 5-patient clinical series showing MYCN-dependent heterogeneity of lorlatinib response, and a mechanistic paper making lorlatinib a myeloid-reprogramming agent, which merges open question 5 into the ALK axis."}]},{"id":"L7","title":"METTL3/IGF2BP2-HMGA2-FOSL1 blockade to reverse MES-state GD2 suppression and restore anti-GD2/CAR sensitivity","mechanism":"HMGA2 is a MES-enriched regulator that maintains MES chromatin accessibility, cisplatin resistance, invasion and, critically, suppression of GD2; it cooperates with FOSL1/AP-1-RUNX super-enhancers and is supported post-transcriptionally by the m6A reader IGF2BP2, with METTL3-dependent methylation favouring and ALKBH5 demethylation opposing the MES program. METTL3 inhibition with STM2457 reduced MES chromatin activity, re-sensitised MES cells to cisplatin and increased GD2 expression (DOI:10.21203/rs.3.rs-10306203/v1).","approach":"In ADRN/MES isogenic lines and MES-shifted PDX, quantify whether STM2457-induced GD2 reaches densities sufficient for dinutuximab-mediated ADCC and GD2.CAR lysis (functional ADCC assay, not just flow MFI), with parallel readout of GPC2, CD276 and SLC6A2 to see whether one agent broadens both immunotherapy (L1/L2) and NET-directed radiopharmaceutical (L4) windows; compare against EZH2/DNMT re-differentiation (L3) head-to-head. Normal tissue: METTL3 is required for HSC self-renewal and neural development [KNOWN], so marrow and CNS toxicity bound dosing; scheduling as pulsed antigen-priming rather than continuous exposure is the obvious mitigation [SPECULATIVE]. Resistance: METTL3-independent H","level":"LEAD","confidence":0.4,"citations":[{"kind":"DOI","id":"10.21203/rs.3.rs-10306203/v1","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41827873","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":149,"lastVisit":3,"lastNote":"New lead from the only fresh item that offers a pharmacologic handle on antigen escape itself; capped at 0.4 because the sole primary source is a non-peer-reviewed preprint and no ADCC/CAR functional rescue is shown.","history":[{"visit":3,"cycle":149,"status":"NEW","note":"New lead from the only fresh item that offers a pharmacologic handle on antigen escape itself; capped at 0.4 because the sole primary source is a non-peer-reviewed preprint and no ADCC/CAR functional rescue is shown."}]}],"retired":[],"nextQueries":["(neuroblastoma AND (lorlatinib OR \"ALK inhibitor\") AND (resistance OR \"compound mutation\" OR MYCN)) AND (FIRST_PDATE:[2024-01-01 TO 2026-12-31])","neuroblastoma AND (METTL3 OR IGF2BP2 OR HMGA2 OR FOSL1) AND (\"cell state\" OR mesenchymal OR GD2)","neuroblastoma AND (USP7 OR SOX9 OR MFAP2 OR lactate OR \"tumor-associated macrophage\") AND (\"anti-GD2\" OR dinutuximab OR CAR)"],"updatedAt":"2026-08-19T22:44:45.619Z"},{"key":"medulloblastoma","name":"medulloblastoma","mondo":{"id":"MONDO:0007959","name":"medulloblastoma"},"genes":[{"label":"CTNNB1","kind":"causal"},{"label":"PTCH2","kind":"causal"},{"label":"ELP1","kind":"correlated"},{"label":"SUFU","kind":"correlated"},{"label":"GPR161","kind":"correlated"},{"label":"BRCA2","kind":"correlated"}],"visits":3,"openQuestions":["In the same orthotopic MYC-amplified MB model, does CDK9 (+/- CDK7) inhibition outperform TOP1/ATR-directed replication-stress agents, and is any CDK9 inhibitor CNS-penetrant at active exposures?","Is MCL1 loss the proximal effector of CDK9i in Myc-MB, and does BCL2L1/MCL1 rebalancing or ABCB1 efflux drive resistance?","Does selective MET inhibition (savolitinib/capmatinib) reproduce the anti-SHH-MB effect of tivantinib in vivo, or is tivantinib's activity tubulin-mediated and MET-independent?","Final attempt: any primary data that ELP1 loss in SHH-MB creates a measurable ISR/GCN2/PERK or tRNA-modification vulnerability?","In the PBTA germline cohort, which cancer-predisposition genes are P/LP in medulloblastoma specifically, and is BRCA2/DDR carriage frequent enough to justify a PARP/platinum stratum?","Does DFMO/ODC1 dependency in MB have primary mechanistic support via eIF5A hypusination, and what is the polyamine-transport salvage route?"],"leads":[{"id":"L1","title":"TOP1-directed replication-stress payloads in MYC/MYCN-amplified Group 3/4 MB","mechanism":"MYC/MYCN amplification elevates origin firing and transcription-replication conflict [KNOWN]; TOP1 trapping by SN-38 converts this into irreparable fork collapse [INFERRED]. P7 (PMID:40759474) extends a parallel rationale to ATR/CHK1/WEE1 in TP53-mutant tumours, relevant to TP53-mutant SHH-MB, but contains no MB primary data [KNOWN limitation].","approach":"Keep tracking NCT06161519 (amplification-gated PLX038) and NCT04337177 as the tolerability comparator, but the lead's fate now depends on a direct in vivo comparison against CDK9/CDK7 inhibition in the same MYC-amplified orthotopic model, with SLFN11 and ABCG2 as pre-specified resistance biomarkers.","level":"LEAD","confidence":0.4,"citations":[{"kind":"NCT","id":"NCT06161519","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04337177","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40759474","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":17,"lastVisit":3,"lastNote":"Weakened by contrast, not by contradiction: OQ2 resolved in favour of transcription-CDK targeting, which now has primary MB data while this lead remains trial-registration-only after three visits. P7 adds only a generic DDR rationale.","history":[{"visit":3,"cycle":150,"status":"WEAKENED","note":"Weakened by contrast, not by contradiction: OQ2 resolved in favour of transcription-CDK targeting, which now has primary MB data while this lead remains trial-registration-only after three visits. P7 adds only a generic DDR rationale."},{"visit":1,"cycle":17,"status":"NEW","note":"New this visit; opened because NCT06161519 is amplification-gated rather than histology-gated, making it the most mechanistically interpretable active trial in the pack."}]},{"id":"L2","title":"Polyamine depletion (DFMO/ODC1) as molecular-risk-stratified maintenance","mechanism":"ODC1 is a direct MYC transcriptional target; irreversible ODC1 inhibition depletes putrescine/spermidine, limiting eIF5A hypusination and MYC-driven translational output [KNOWN]","approach":"Track NCT04696029 (DFMO maintenance in molecular high/very-high-risk and relapsed MB); next visit seek primary MB data on ODC1/AMD1 dependency and on eIF5A/hypusination as the effector node; anticipate resistance via polyamine transporter (SLC3A2/ATP13A3) uptake salvage","level":"LEAD","confidence":0.4,"citations":[{"kind":"NCT","id":"NCT04696029","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":17,"lastVisit":1,"lastNote":"New this visit; trial-only evidence so far, no primary MB mechanism paper in this pack — confidence capped accordingly.","history":[{"visit":1,"cycle":17,"status":"NEW","note":"New this visit; trial-only evidence so far, no primary MB mechanism paper in this pack — confidence capped accordingly."}]},{"id":"L3","title":"Secretory-pathway (ARF1/GBF1) disruption destabilises CD133 and collapses Group 3 MB stem cells","mechanism":"Brefeldin A induces ER stress and structural disruption of the stemness receptor CD133, reducing clonogenicity, downregulating PI3K/AKT/mTOR and impairing intercellular communication in Group 3 MB lines; effect is most plausibly GBF1/ARF1-mediated block of ER-Golgi transport rather than direct CD133 engagement [INFERRED]","approach":"Validate the in-silico-nominated approved BFA mimetics in orthotopic Group 3 xenografts with limiting-dilution neurosphere assays; measure surface CD133 by flow plus proteostasis markers (ATF4/CHOP); window concern: GBF1/ARF1 are essential for normal secretory tissue and Purkinje/neuronal trafficking, so tumour selectivity must be demonstrated before any advancement","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42443895","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":17,"lastVisit":1,"lastNote":"New this visit; only primary MB mechanism paper in the pack, but compounds are computational-only and BFA itself is undevelopable — deliberately low confidence.","history":[{"visit":1,"cycle":17,"status":"NEW","note":"New this visit; only primary MB mechanism paper in the pack, but compounds are computational-only and BFA itself is undevelopable — deliberately low confidence."}]},{"id":"L4","title":"Metabolic radiosensitisation tested under clinically faithful fractionated craniospinal irradiation","mechanism":"Focal or whole-brain irradiation of orthotopic MB fails to prevent spinal relapse, so radiosensitiser efficacy is uninterpretable without CSI; complex-III/OXPHOS inhibition by atovaquone lowers tumour oxygen consumption and reoxygenates hypoxic niches, increasing radiation-induced DNA damage [KNOWN for the OXPHOS-reoxygenation mechanism]","approach":"Run atovaquone (NCT06624371) and other candidate sensitisers in the 7-model fractionated-CSI platform (PMID:42502578) using recurrence pattern and gammaH2AX/pATM IHC as endpoints; couple to reduced-volume CTV_2340 planning (PMID:42425418) where tumour-selective sensitisation is most valuable","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42502578","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06624371","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42425418","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":17,"lastVisit":1,"lastNote":"New this visit; P5 changes what counts as a credible preclinical radiosensitiser experiment and retrospectively devalues focal-irradiation-only combination data.","history":[{"visit":1,"cycle":17,"status":"NEW","note":"New this visit; P5 changes what counts as a credible preclinical radiosensitiser experiment and retrospectively devalues focal-irradiation-only combination data."}]},{"id":"L6","title":"Antigen-agnostic total-tumour-RNA DC vaccine + xenogeneic-primed adoptive lymphocyte transfer under PD-1 blockade in MB","mechanism":"MB has low mutational burden and no MB-validated surface antigen (GD2/B7-H3/HER2 evidence in this pack is glioma-derived at best) [KNOWN]; total tumour RNA-loaded DC vaccination templates a polyclonal response without requiring a defined epitope, and lymphodepletion plus autologous HSC support supplies the homeostatic-proliferation niche needed for adoptive lymphocyte engraftment, with pembrolizumab relieving PD-1-mediated exhaustion of the transferred product [INFERRED]","approach":"Track NCT06514898 for immune-correlative rather than radiographic endpoints (TCR-clonotype expansion, post-HSC lymphocyte reconstitution kinetics, intratumoural CD8 density on any re-resection); pre-specify tumour MHC-I/B2M expression by subgroup, since MYC-amplified Group 3 antigen-presentation loss is the predicted primary resistance route [SPECULATIVE], with PD-L1-independent myeloid suppression as the secondary route","level":"LEAD","confidence":0.25,"citations":[{"kind":"NCT","id":"NCT06514898","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":71,"lastVisit":2,"lastNote":"New this visit; first primary MB immunotherapy protocol seen by the desk and a partial answer to OQ4 — the antigen is tumour RNA, not GD2/B7-H3/HER2. Phase 1, no efficacy data, so confidence capped.","history":[{"visit":2,"cycle":71,"status":"NEW","note":"New this visit; first primary MB immunotherapy protocol seen by the desk and a partial answer to OQ4 — the antigen is tumour RNA, not GD2/B7-H3/HER2. Phase 1, no efficacy data, so confidence capped."}]},{"id":"L7","title":"Genotype-matched kinase inhibition at MB relapse: RET and MET as screenable but unquantified alterations","mechanism":"Relapsed MB is genomically divergent from diagnosis [KNOWN]; selpercatinib offers direct inhibition only if activating RET fusions/mutations occur at non-trivial frequency, which remains unmeasured in MB [KNOWN gap].","approach":"Seek relapse-MB sequencing series reporting RET fusion/mutation frequency by subgroup; if <1-2%, close the lead and rely on molecular tumour board routes (NCT05057702, NCT04320888) without an MB-specific claim. RET is required for enteric neurogenesis and nephrogenesis - a real pediatric window concern.","level":"LEAD","confidence":0.12,"citations":[{"kind":"NCT","id":"NCT04320888","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT03598244","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT05057702","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":71,"lastVisit":3,"lastNote":"The MET half moved to its own lead on new primary data; the RET half received no evidence for a second consecutive visit and is now on notice for retirement.","history":[{"visit":3,"cycle":150,"status":"WEAKENED","note":"The MET half moved to its own lead on new primary data; the RET half received no evidence for a second consecutive visit and is now on notice for retirement."},{"visit":2,"cycle":71,"status":"NEW","note":"New this visit; three newly surfaced trials enrol MB only by eligibility, not by stated MB biology. Opened deliberately low as a prevalence question, not yet a therapeutic hypothesis."}]},{"id":"L8","title":"CDK9 (P-TEFb) inhibition, synergistic with CDK7, collapses the Myc core regulatory circuit in MYC-amplified Group 3 MB","mechanism":"MYC amplification builds a core regulatory circuit of enhancer-promoter loops that amplifies pro-survival transcription; Myc itself is undruggable, but processive elongation through those loops requires CDK9/P-TEFb-mediated Ser2 phosphorylation of RNA Pol II [KNOWN]. Eight pooled CRISPR-Cas9 screens across three labs converge on CDK9 as a conserved dependency in Myc-MB, primary-patient Hi-C maps the enhancer-promoter contacts disrupted by inhibition, and CDK9i downregulates Myc-driven programmes with antitumour effect in vitro and in xenografts; CDK7 co-inhibition (initiation-side) is synergistic (PMID:40372972). Short-lived transcripts (MCL1, MYC itself) are the proximal effectors [INFERRED","approach":"Prosecute in orthotopic MYC-amplified models (D425/D283, MB002) with a selective CDK9i (AZD4573/enitociclib class) +/- a CDK7i, reading out Pol II Ser2P ChIP, nascent-transcript (SLAM-seq) loss of Myc target modules, and MCL1 protein decay; pre-specify BCL2L1/MCL1 rebalancing, ABCB1 efflux and CDK9-independent elongation as resistance routes; measure CNS penetration explicitly since no CDK9i has published MB brain exposure. Normal-tissue window: P-TEFb is globally required for transcription, so selectivity must be shown as a therapeutic index versus proliferating gut/marrow and developing cerebellum, not as target absence.","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"40372972","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":150,"lastVisit":3,"lastNote":"New this visit and immediately the strongest mechanistic lead in the programme: genetic (8 screens), structural (primary Hi-C) and in vivo evidence in the correct subgroup. Opened at 0.55 rather than higher because no CNS-penetrant CDK9i is named and there is no pediatric trial in the pack.","history":[{"visit":3,"cycle":150,"status":"NEW","note":"New this visit and immediately the strongest mechanistic lead in the programme: genetic (8 screens), structural (primary Hi-C) and in vivo evidence in the correct subgroup. Opened at 0.55 rather than higher because no CNS-penetrant CDK9i is named and there is no pediatric trial in the pack."}]},{"id":"L9","title":"c-MET/HGF autocrine signalling in SHH-alpha/beta medulloblastoma - real dependency, misleading pharmacology","mechanism":"c-MET and its ligand HGF are highly co-expressed in SHH-MB with SHH-alpha and SHH-beta highest, and siRNA knockdown of c-MET reduces proliferation, indicating an autocrine dependency rather than an amplification-driven one (PMID:41729336). Critically, the best-killing agent tivantinib acts via prolonged mitotic arrest then apoptosis, whereas the selective inhibitors crizotinib and foretinib produce only mitotic slippage rescued into death by navitoclax - consistent with tivantinib's documented tubulin/antimitotic off-target activity [KNOWN], meaning cytotoxicity may be largely MET-independent [INFERRED].","approach":"Falsify before advancing: test selective MET inhibitors (savolitinib per NCT03598244, capmatinib) versus tivantinib in orthotopic SHH-MB PDX with pMET/pERK pharmacodynamics; if only tivantinib works, reclassify it as an antimitotic and pursue the vincristine-tivantinib and mitotic-slippage/navitoclax combinations on their own terms. Normal-tissue window: MET drives cerebellar granule precursor migration and hepatocyte/muscle regeneration, so chronic pediatric dosing needs growth and hepatic monitoring; navitoclax carries dose-limiting thrombocytopenia [KNOWN].","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"41729336","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT03598244","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":150,"lastVisit":3,"lastNote":"Split out of L7 because the evidence type changed: this is now subgroup-resolved expression plus a knockdown dependency in MB cells, but the same paper's pharmacology argues the lead drug is off-target - a built-in contradiction that caps confidence.","history":[{"visit":3,"cycle":150,"status":"NEW","note":"Split out of L7 because the evidence type changed: this is now subgroup-resolved expression plus a knockdown dependency in MB cells, but the same paper's pharmacology argues the lead drug is off-target - a built-in contradiction that caps confidence."}]}],"retired":[{"title":"Subgroup-differential BBB integrity as the determinant of CNS drug exposure in MB","note":"Retired on scheduled null: a confirmed absence of data, not a refutation, but the desk should not spend further queries here.","cycle":150,"ts":"2026-08-19T22:48:19.129Z"}],"nextQueries":["\"medulloblastoma\" AND (CDK9 OR \"P-TEFb\" OR AZD4573 OR enitociclib OR MCL1)","\"medulloblastoma\" AND (ELP1 OR Elongator OR \"integrated stress response\" OR GCN2 OR hypusination OR eIF5A)","(\"medulloblastoma\" AND (germline OR \"cancer predisposition\") AND (BRCA2 OR PARP OR \"second hit\"))"],"updatedAt":"2026-08-19T22:48:19.129Z"},{"key":"retinoblastoma","name":"retinoblastoma","mondo":{"id":"MONDO:0008380","name":"retinoblastoma"},"genes":[{"label":"RB1","kind":"causal"},{"label":"MYCN","kind":"correlated"}],"visits":3,"openQuestions":["Were any retinoblastoma models (WERI-Rb1, Y79, RB1-/- cone-precursor organoids) included in the TRIP13/Aurora A Rb-deficient panel, and what were the AURKAi IC50s relative to other Rb-null lineages?","What are TRIP13, AURKA and GSDME expression levels in retinoblastoma primaries and vitreous seeds, and is GSDME silenced (which would abolish the pyroptotic arm)?","Is there any clinical-grade TRIP13 inhibitor or degrader, or must the combination be reformulated as AURKAi plus an alternative SAC-prolonging partner (e.g. MPS1 or KIF11 modulation)?","What intravitreal or intra-arterial exposure is achievable for alisertib-class Aurora A inhibitors relative to melphalan/topotecan, and is ocular toxicity to proliferating retinal tissue prohibitive?","What is the measured GPC2 surface density and positivity frequency in retinoblastoma primaries, vitreous seeds and CSF deposits, and does it track with MYCN amplification?","Does the TGF-beta-high, immunosuppressive invasive-RB subtype (PMID:41238845) predict failure of unarmoured CAR T or checkpoint blockade, and is HLA class I retained in these tumours?"],"leads":[{"id":"L1","title":"CDK7 / transcriptional-CDK inhibition as synthetic lethality with RB1 loss and MYCN amplification in retinoblastoma","mechanism":"Unchanged: RB-E2F collapse plus MYCN amplification in the RB1-proficient minority predicts E2F/MYCN transcriptional addiction (PMID:41782059, PMID:42212122); CDK7 inhibition should preferentially kill cells lacking the RB brake [INFERRED]. CDK7 is required for basal transcription in all proliferating tissue, so the window would be schedule plus local ocular delivery.","approach":"Unchanged, but demoted in priority behind the AURKA/TRIP13 axis: any further investment requires a primary CDK7/CDK9/CDK12 experiment in an RB1-null retinoblastoma model.","level":"LEAD","confidence":0.2,"citations":[{"kind":"PMID","id":"41782059","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42212122","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07633756","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT01783535","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04040205","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42013305","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":18,"lastVisit":3,"lastNote":"Third consecutive evidence-bearing visit with no primary transcriptional-CDK data in any RB1-null retinoblastoma model, while a competing RB1-loss synthetic lethality (PMID:42013305 [NEW]) now has xenograft support. 0.40 to 0.20; pre-committed retirement at visit 4 absent primary data.","history":[{"visit":3,"cycle":151,"status":"WEAKENED","note":"Third consecutive evidence-bearing visit with no primary transcriptional-CDK data in any RB1-null retinoblastoma model, while a competing RB1-loss synthetic lethality (PMID:42013305 [NEW]) now has xenograft support. 0.40 to 0.20; pre-committed retirement at visit 4 absent primary data."},{"visit":2,"cycle":73,"status":"WEAKENED","note":"Two consecutive sweeps returned no primary CDK7/CDK9/CDK12 data in any RB1-null retinoblastoma model; NCT07633756 remains a lineage-distant leiomyosarcoma read-through. NCT04040205 [NEW] adds only a negative anchor (CDK-pathway-selected abemaciclib presupposes intact RB1), reinforcing the choice of transcriptional over cell-cycle CDKs but supplying no positive retinoblastoma evidence. Confidence 0"},{"visit":1,"cycle":18,"status":"NEW","note":"New this visit. NCT07633756 selects patients by RB1-negative status for a CDK7 inhibitor, giving a clinical precedent for RB1-loss-selective transcriptional-CDK targeting that is directly transferable in principle to retinoblastoma; P1/P10 supply the RB1/MYCN transcriptional-addiction rationale. Explicitly preferred over CDK4/6 inhibition, which is mechanistically undercut by RB1 loss [KNOWN]."}]},{"id":"L2","title":"GPC2-directed CAR T cells for metastatic/extraocular retinoblastoma","mechanism":"GPC2 is a MYCN-transactivated surface glycoprotein with restricted postnatal normal expression [KNOWN]; MYCN dysregulation is documented in retinoblastoma (PMID:41782059). New this visit: the retinoblastoma immune microenvironment does contain innate and adaptive infiltrates with PD-1/PD-L1/CTLA-4 expression modulated by chemotherapy (PMID:42187581), and invasive tumours show an immunosuppressive bulk subtype with TGF-beta-high cone-precursor subpopulations and increased fibroblast-CP crosstalk (PMID:41238845) - permissive for trafficking but a defined suppressive barrier for any cell product [INFERRED].","approach":"Unchanged priority on antigen frequency: quantify GPC2 surface density on enucleation specimens, vitreous seeds and CSF/metastatic deposits banked in NCT01109394/NCT03050268 and correlate with MYCN status; add TGF-beta pathway blockade or dominant-negative TGF-betaRII armouring to the CAR design given PMID:41238845, and profile PD-L1 as a combination anchor. Pre-specify antigen-low escape, ocular sanctuary exclusion, developing-CNS on-target toxicity.","level":"LEAD","confidence":0.38,"citations":[{"kind":"NCT","id":"NCT05650749","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41782059","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT01109394","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03050268","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42187581","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41238845","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":18,"lastVisit":3,"lastNote":"Open question 3 partially answered by two [NEW] papers: immune infiltration and checkpoint expression exist in retinoblastoma (PMID:42187581) and invasive disease carries a TGF-beta-rich immunosuppressive TME (PMID:41238845). Trafficking plausibility up, suppression barrier now explicit; still zero retinoblastoma GPC2 expression data, so only 0.35 to 0.38.","history":[{"visit":3,"cycle":151,"status":"STRENGTHENED","note":"Open question 3 partially answered by two [NEW] papers: immune infiltration and checkpoint expression exist in retinoblastoma (PMID:42187581) and invasive disease carries a TGF-beta-rich immunosuppressive TME (PMID:41238845). Trafficking plausibility up, suppression barrier now explicit; still zero retinoblastoma GPC2 expression data, so only 0.35 to 0.38."},{"visit":2,"cycle":73,"status":"WEAKENED","note":"NCT05650749 [NEW status change] is now ENROLLING_BY_INVITATION, so the only clinical vehicle enrolling metastatic retinoblastoma is closed-access; combined with a second visit yielding no retinoblastoma GPC2 expression data, the antigen-frequency gap must now be closed from tissue banks. 0.40 to 0.35."},{"visit":1,"cycle":18,"status":"NEW","note":"New this visit. NCT05650749 explicitly enrols metastatic retinoblastoma, so the clinical vehicle already exists; the open scientific gap is retinoblastoma-specific GPC2 expression data, which the pack does not provide."}]},{"id":"L5","title":"TRIP13 + Aurora A co-inhibition as mitotic synthetic lethality in RB1-null retinoblastoma","mechanism":"Biallelic RB1 loss [GERMLINE first hit / SOMATIC second hit] abolishes the G1 brake and raises mitotic load; Aurora A inhibition induces mitotic arrest, and loss of TRIP13 (AAA+ ATPase that recycles MAD2/p31comet to silence the spindle assembly checkpoint [KNOWN]) prolongs that arrest, producing mitotic DNA damage and concurrent apoptotic plus GSDME-mediated pyroptotic death selectively in Rb-deficient cells, with in vivo efficacy using a clinically relevant Aurora A inhibitor and inducible TRIP13 degradation (PMID:42013305). RB1-status-dependent rather than MYCN-dependent, so it should cover the RB1-null majority (PMID:41782059) [INFERRED]. Normal tissue: AURKA is required in all proliferat","approach":"Confirm RB1-null retinoblastoma models were not tested in the source paper, then run alisertib-class AURKAi with TRIP13 knockdown/degradation in WERI-Rb1, Y79 and CRISPR RB1-/- cone-precursor organoids versus RB1-proficient MYCN-amplified comparators; read out mitotic duration by live-cell imaging, gammaH2AX, caspase-3 and GSDME cleavage; profile TRIP13/AURKA/GSDME mRNA and protein in primary enucleation specimens and vitreous seeds; benchmark achievable intravitreal/systemic exposure against melphalan/topotecan standards and the topotecan-carboplatin backbone (NCT01783535). Resistance to pre-specify: AURKA gatekeeper mutations, GSDME silencing abolishing pyroptosis, p31comet-independent che","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42013305","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41782059","verified":true,"isNew":false,"addedVisit":3},{"kind":"NCT","id":"NCT01783535","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":151,"lastVisit":3,"lastNote":"First genotype-anchored RB1-loss synthetic lethality in this programme with in vivo data; created new and placed above L1. Key unresolved caveat from abstract only: retinoblastoma models themselves may not have been tested.","history":[{"visit":3,"cycle":151,"status":"NEW","note":"First genotype-anchored RB1-loss synthetic lethality in this programme with in vivo data; created new and placed above L1. Key unresolved caveat from abstract only: retinoblastoma models themselves may not have been tested."}]}],"retired":[{"title":"Sunitinib repurposing (multi-RTK inhibition) validated in CRISPR retinal organoid retinoblastoma models","note":"Retired as pre-committed at visit 2: a third sweep produced no primary paper, no RB1/MYCN status for the organoid models and no target deconvolution. Notebook rule: do not re-open without a primary paper naming the RTK dependency and the model genotype.","cycle":151,"ts":"2026-08-19T22:51:32.987Z"},{"title":"PTM-enzyme pharmacology (ubiquitin/SUMO/acetylation circuits) around the RB-E2F axis, with immunotherapy combination","note":"Retired as pre-committed at visit 1: no named E3 ligase, DUB or SUMO E1/E2 with a demonstrated retinoblastoma genetic dependency appeared in this pack. Notebook rule: do not re-open without a CRISPR/degrader screen hit in an RB1-null retinoblastoma model.","cycle":73,"ts":"2026-08-19T18:19:41.980Z"}],"nextQueries":["(\"TRIP13\" OR \"AURKA\" OR \"Aurora A\" OR \"alisertib\") AND (\"retinoblastoma\" OR \"RB1\" OR \"Rb-deficient\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"retinoblastoma\") AND (\"GPC2\" OR \"glypican-2\" OR \"B7-H3\" OR \"GD2\" OR \"surfaceome\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"retinoblastoma\") AND (\"intravitreal pharmacokinetics\" OR \"intra-arterial chemotherapy\" OR \"vitreous concentration\" OR \"ocular pharmacokinetics\") AND SRC:MED AND PUB_YEAR:[2015 TO 2026]"],"updatedAt":"2026-08-19T22:51:32.988Z"},{"key":"wilms tumor","name":"Wilms tumor","mondo":{"id":"MONDO:0006058","name":"Wilms tumor"},"genes":[{"label":"BRCA2","kind":"causal"},{"label":"GPC3","kind":"causal"},{"label":"TRIM28","kind":"causal"},{"label":"WT1","kind":"causal"},{"label":"REST","kind":"correlated"},{"label":"POU6F2","kind":"correlated"},{"label":"DIS3L2","kind":"correlated"},{"label":"CTR9","kind":"correlated"},{"label":"TRIP13","kind":"correlated"},{"label":"H19","kind":"correlated"}],"visits":3,"openQuestions":["Which Wilms tumor PDX model(s) responded to vobramitamab duocarmazine in PMID:41941262, at what B7-H3 IHC/protein level, and is there a pediatric expansion cohort of NCT03729596?","What is B7-H3 protein prevalence and intensity across WT blastemal, epithelial, stromal and anaplastic components in primary human pathology series?","What is the frequency of somatic TP53 mutation and 1q gain in relapsed/blastemal-predominant WT, and do TP53-mutant WT models show WEE1/ATR inhibitor sensitivity?","What is the Wilms tumor stratum outcome (ORR, PFS, MET/AXL/VEGFR correlates) of cabozantinib in NCT02867592 — still unretrieved after two visits?","Does NCT04616560 report a HER2 IHC/ISH entry threshold or any WT responses, and is HER2 protein detectable at all in primary WT?","Do TRIM28-, DIS3L2- or CTR9-mutant WT define a distinct dependency, and are the reported cases germline or somatic?"],"leads":[{"id":"L1","title":"IL-15/IL-21-armored GPC3 CAR-T against onco-fetal GPC3 in Wilms tumor","mechanism":"Unchanged: somatic onco-fetal GPC3 re-expression on blastemal/epithelial WT with cytokine armoring for persistence [INFERRED]; postnatal GPC3 restriction is the claimed window [KNOWN].","approach":"Deprioritise relative to B7-H3 until a primary human WT GPC3 IHC series exists; if a WT cohort in NCT04715191 is pursued, require GPC3 IHC screening and soluble-GPC3 sink monitoring.","level":"LEAD","confidence":0.32,"citations":[{"kind":"NCT","id":"NCT04715191","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":19,"lastVisit":3,"lastNote":"Second consecutive IHC-directed search returned no WT GPC3 protein prevalence data, while the competing B7-H3 hypothesis gained in vivo WT evidence; relative priority drops.","history":[{"visit":3,"cycle":152,"status":"WEAKENED","note":"Second consecutive IHC-directed search returned no WT GPC3 protein prevalence data, while the competing B7-H3 hypothesis gained in vivo WT evidence; relative priority drops."},{"visit":2,"cycle":74,"status":"WEAKENED","note":"Targeted search for WT GPC3/B7-H3 human expression data returned nothing this visit; lead still has no primary human prevalence citation, so confidence trimmed and the evidence gap made explicit."},{"visit":1,"cycle":19,"status":"NEW","note":"New lead; GPC3 KG anchor plus an actively recruiting pediatric solid-tumour CAR-T trial with a cytokine-armoring design."}]},{"id":"L2","title":"B7-H3 CAR-T combined with TGF-beta-insensitive (dTbetaRII) antigen-specific T cells for relapsed embryonal WT","mechanism":"B7-H3/CD276 is expressed across pediatric embryonal tumours [KNOWN] and is now functionally validated in Wilms tumor xenografts, where an anti-B7-H3 ADC produced objective responses while an isotype-matched control ADC with identical linker/payload did not (PMID:41941262) — antigen-dependent killing, not payload effect. dTbetaRII should shield effectors from TGF-beta-rich blastemal stroma [INFERRED]. Resistance: antigen-low subclones, CAR exhaustion, TGF-beta-independent myeloid suppression.","approach":"Track the WT subgroup in NCT07172958; obtain B7-H3 IHC intensity/prevalence across primary WT blastemal, epithelial and stromal components and in anaplastic WT; assay tumour TGF-beta1/pSMAD2 pre/post and pair CAR persistence with antigen density.","level":"CANDIDATE","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT07172958","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41941262","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":19,"lastVisit":3,"lastNote":"First WT-specific in vivo evidence that B7-H3 is a sufficient target antigen, with an isotype-ADC control; upgraded from inference-only pan-pediatric expression.","history":[{"visit":3,"cycle":152,"status":"STRENGTHENED","note":"First WT-specific in vivo evidence that B7-H3 is a sufficient target antigen, with an isotype-ADC control; upgraded from inference-only pan-pediatric expression."},{"visit":2,"cycle":74,"status":"WEAKENED","note":"Same null retrieval as L1 — no WT-specific B7-H3 prevalence data surfaced; confidence trimmed pending IHC evidence."},{"visit":1,"cycle":19,"status":"NEW","note":"New lead from an actively recruiting phase 1 explicitly in relapsed/refractory embryonal tumours."}]},{"id":"L3","title":"ATRA plus hypomethylating agent to force differentiation through the CRABP2/RARB switch in blastemal WT","mechanism":"Retinoic acid signalling is bidirectional in WT: ATRA can induce differentiation, but cytoplasmic retention of CRABP2 and RARB promoter methylation block nuclear RAR output and sustain the undifferentiated blastemal state (PMID:42492627). Restoring nuclear RA signalling with a DNMT inhibitor should convert ATRA from inert to differentiating [INFERRED/SPECULATIVE]. Normal tissue: RA signalling is required for nephrogenesis, so risk is limited in postnatal kidney but includes classic retinoid toxicities [KNOWN].","approach":"Test ATRA +/- azacitidine or decitabine in WT patient-derived xenografts/organoids stratified by CRABP2 subcellular localisation and RARB methylation; readouts = epithelial differentiation markers, loss of blastemal SIX2/CITED1.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42492627","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":19,"lastVisit":1,"lastNote":"New lead; review-level mechanism only (no primary WT data in pack), so preclinical validation precedes any translational claim.","history":[{"visit":1,"cycle":19,"status":"NEW","note":"New lead; review-level mechanism only (no primary WT data in pack), so preclinical validation precedes any translational claim."}]},{"id":"L4","title":"WT1-directed TCR-T repurposing — window-limited, held at low confidence","mechanism":"WT1 is the founding WT gene [GERMLINE causal] and is frequently retained/overexpressed somatically, making it an intracellular antigen for HLA-A*02:01-restricted TCR-T (NCT07645469 in MRD+ AML). Counterweight: WT1 protein is functionally required in podocytes, mesothelium and visceral adipose-derived stem cells, where it controls PRDM16/UCP1 via UBC9 (PMID:42125880), predicting on-target renal and metabolic toxicity in children with a single remaining kidney.","approach":"Before any WT proposal: quantify WT1 epitope presentation in WT vs normal pediatric kidney; measure podocyte injury markers in the AML TCR-T cohort as a human safety surrogate.","level":"LEAD","confidence":0.22,"citations":[{"kind":"NCT","id":"NCT07645469","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42125880","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":19,"lastVisit":1,"lastNote":"New but deliberately constrained; the normal-tissue WT1 dependency documented this visit is the argument against, and is recorded so the desk does not over-promote it.","history":[{"visit":1,"cycle":19,"status":"NEW","note":"New but deliberately constrained; the normal-tissue WT1 dependency documented this visit is the argument against, and is recorded so the desk does not over-promote it."}]},{"id":"L5","title":"CACNA1E amplification as a relapse-risk biomarker in favourable-histology WT","mechanism":"Review-level report that CACNA1E amplification/overexpression correlates with relapse in favourable-histology WT; Cav2.3-mediated Ca2+ influx drives WNT/Ca2+ signalling and chemoresistance in other tumours (PMID:42327581). Druggability is poor — no selective Cav2.3 antagonist, and dihydropyridines/verapamil hit cardiac and vascular channels [KNOWN].","approach":"Use as stratification variable, not a target: test CACNA1E copy number against relapse in existing favourable-histology cohorts; only then explore Ca2+-signalling dependency (siRNA, WNT7B readout) in WT lines.","level":"LEAD","confidence":0.2,"citations":[{"kind":"PMID","id":"42327581","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":19,"lastVisit":1,"lastNote":"New; low confidence because the WT claim is secondary within a pan-cancer review and the pharmacology has no therapeutic window.","history":[{"visit":1,"cycle":19,"status":"NEW","note":"New; low confidence because the WT claim is secondary within a pan-cancer review and the pharmacology has no therapeutic window."}]},{"id":"L6","title":"Cabozantinib as MET/VEGFR2/AXL blockade in recurrent Wilms tumor — readout-ready repurposing","mechanism":"Multi-RTK inhibition (MET, VEGFR2, AXL, RET [KNOWN]) targets the angiogenic and mesenchymal-invasive axis of blastemal/relapsed WT rather than a single WT driver; VEGF-driven vascularity and HGF/MET-supported invasion are the presumed dependencies [INFERRED]. Normal tissue: VEGFR2 blockade causes hypertension, proteinuria and impaired growth-plate/renal reserve — a sharp window issue in children with one remaining kidney [KNOWN]. Expected resistance: bypass FGFR/ANG2 angiogenic switching, MET-independent relapse.","approach":"Extract the Wilms-tumor stratum outcome from NCT02867592 (already ACTIVE_NOT_RECRUITING) — objective response, PFS, and any MET/AXL/VEGFR biomarker correlates; if responses cluster, define an IHC/RNA predictor (MET, AXL, phospho-MET) in archival WT and design a cabozantinib + topotecan/irinotecan relapse arm with protocolised BP and renal monitoring.","level":"LEAD","confidence":0.32,"citations":[{"kind":"NCT","id":"NCT02867592","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":74,"lastVisit":2,"lastNote":"New this visit: first WT-inclusive trial of an approved agent found in the programme; closed accrual means a real human readout may already exist, making this the fastest-maturing lead on the desk.","history":[{"visit":2,"cycle":74,"status":"NEW","note":"New this visit: first WT-inclusive trial of an approved agent found in the programme; closed accrual means a real human readout may already exist, making this the fastest-maturing lead on the desk."}]},{"id":"L7","title":"Trastuzumab deruxtecan as antigen-anchored topoisomerase-I payload delivery in relapsed WT (not HER2 addiction)","mechanism":"Unchanged: HER2 as docking antigen for the DXd topo-I payload with bystander diffusion [INFERRED]; cardiac/pulmonary HER2 sets the window [KNOWN].","approach":"Still need the NCT04616560 HER2 IHC/ISH entry threshold and WT-arm responses; if HER2 prevalence in WT remains undocumented, formally pivot the ADC concept to B7-H3 (see new lead) and retire the HER2 framing.","level":"LEAD","confidence":0.28,"citations":[{"kind":"NCT","id":"NCT04616560","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41941262","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":74,"lastVisit":3,"lastNote":"A targeted HER2/ERBB2 IHC query again returned no WT prevalence data; meanwhile a competing ADC target in the same tumour type acquired xenograft efficacy data, so the HER2 hypothesis loses ground on comparative grounds.","history":[{"visit":3,"cycle":152,"status":"WEAKENED","note":"A targeted HER2/ERBB2 IHC query again returned no WT prevalence data; meanwhile a competing ADC target in the same tumour type acquired xenograft efficacy data, so the HER2 hypothesis loses ground on comparative grounds."},{"visit":2,"cycle":74,"status":"NEW","note":"Promoted from open question to formal lead; reframed mechanistically as payload delivery rather than oncogene targeting, which is the honest reading and sets a falsifiable test (HER2 prevalence in WT)."}]},{"id":"L8","title":"B7-H3-directed antibody-drug conjugate (vobramitamab duocarmazine) as the fastest B7-H3 route into relapsed Wilms tumor","mechanism":"Antigen-anchored delivery of a duocarmycin DNA-alkylating payload to B7-H3+ WT cells; WT xenografts responded to a single 6 mg/kg dose of vobra duo while the CD20 control ADC with identical linker/payload did not (PMID:41941262), and the same agent has manageable toxicity and responses in adult mCRPC phase I/II [per PMID:41941262]. Normal tissue: B7-H3 is low in most normal adult/pediatric tissues, so the window is payload-driven — expect myelosuppression and mucosal toxicity [KNOWN]. Resistance: ABCB1/efflux, antigen-low escape, alkylator-repair (NER/HR) upregulation [INFERRED].","approach":"Identify which WT model(s) responded and their B7-H3 protein level to define an IHC cut-off; test vobra duo against WT PDX panels stratified by histology (blastemal vs epithelial vs anaplastic) and in combination with irinotecan/topotecan; seek a pediatric expansion cohort rather than a de novo trial; pre-specify B7-H3 IHC screening on archival relapse biopsies.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"41941262","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":152,"lastVisit":3,"lastNote":"New modality lead separated from the CAR-T hypothesis: an off-the-shelf ADC avoids autologous manufacturing and has direct WT xenograft efficacy data.","history":[{"visit":3,"cycle":152,"status":"NEW","note":"New modality lead separated from the CAR-T hypothesis: an off-the-shelf ADC avoids autologous manufacturing and has direct WT xenograft efficacy data."}]},{"id":"L9","title":"TP53-mutant / 1q-gain chemoresistant Wilms tumor as a separable stratum for replication-stress (WEE1 or ATR) synthetic lethality","mechanism":"A bilateral blastemal-predominant WT with somatic TP53 p.R273H, 1q gain and 16q deletion progressed through VAD chemotherapy, staged nephron-sparing surgery, radiotherapy and oral targeted therapy (PMID:42254928), consistent with intrinsic chemoresistance of TP53-altered WT. p53 loss abolishes the G1/S checkpoint and shifts survival onto G2/M and replication-stress checkpoints, predicting sensitivity to WEE1 (adavosertib) or ATR inhibition, especially combined with a topo-I or anthracycline backbone [KNOWN paradigm / INFERRED for WT]. Normal tissue: WEE1/ATR are needed in all proliferating tissue, so dose-limiting myelosuppression in pretreated children is the window problem [KNOWN]. Resista","approach":"Genotype archival high-risk/anaplastic and blastemal-predominant WT for TP53 status and 1q gain; test adavosertib or an ATR inhibitor +/- irinotecan in TP53-mutant versus TP53-wildtype WT PDX/organoids with gamma-H2AX, pCDK1-Y15 and micronucleus readouts; define whether TP53 status prospectively separates relapse risk independent of histology.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42254928","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":152,"lastVisit":3,"lastNote":"Single case report only — hypothesis-generating, not prevalence evidence; recorded because it is the first concrete WT TP53/1q-gain chemoresistance datapoint in this programme and it anchors open question 6.","history":[{"visit":3,"cycle":152,"status":"NEW","note":"Single case report only — hypothesis-generating, not prevalence evidence; recorded because it is the first concrete WT TP53/1q-gain chemoresistance datapoint in this programme and it anchors open question 6."}]}],"retired":[],"nextQueries":["(\"Wilms tumor\" OR nephroblastoma) AND (\"B7-H3\" OR CD276) AND (immunohistochemistry OR \"antibody-drug conjugate\" OR xenograft)","(\"Wilms tumor\" OR nephroblastoma) AND (TP53 OR \"1q gain\") AND (chemoresistance OR relapse OR WEE1 OR ATR OR adavosertib)","cabozantinib AND (\"Wilms tumor\" OR nephroblastoma OR \"rare tumors\") AND (\"phase 2\" OR \"objective response\" OR NCT02867592)"],"updatedAt":"2026-08-19T22:54:58.786Z"},{"key":"osteosarcoma","name":"osteosarcoma","mondo":{"id":"MONDO:0009807","name":"osteosarcoma"},"genes":[{"label":"CHEK2","kind":"causal"},{"label":"RB1","kind":"causal"},{"label":"TP53","kind":"correlated"}],"visits":3,"openQuestions":["Do ATRX-wildtype but functionally ALT-positive osteosarcoma models retain SMARCAL1 dependency, or is the synthetic lethality restricted to ATRX-loss genotypes (PMID:41520142 vs PMID:42330800)?","What is the sensitivity of ALT+ osteosarcoma PDX to ATR inhibitors, and does ALT status predict resistance to doxorubicin/cisplatin/radiation as PMID:41148828 implies?","Can a C-circle or APB assay be standardised on FFPE osteosarcoma biopsies to serve as a clinical stratification biomarker, given sequencing's failure to call ALT?","Does duocarmycin payload from a B7-H3 ADC produce measurable bystander killing in mosaic low/high-H-score osteosarcoma models, and would an extracellular-release linker outperform the internalising design?","What fraction of relapsed osteosarcoma patients meet ALC/CD3 apheresis thresholds for autologous B7-H3 CAR-T, and does prior chemotherapy intensity predict failure?","Is ALT positivity associated with greater immune infiltration or immunotherapy response in osteosarcoma, as the glioblastoma/chondrosarcoma paradox suggests?"],"leads":[{"id":"L1","title":"KIF18A inhibition as CIN/whole-genome-doubling-selective synthetic lethality in osteosarcoma","mechanism":"TP53 (~80%) and RB1 (~40%) loss with chromothripsis in >70% of osteosarcoma (PMID:42326738) makes the CIN/WGD substrate for KIF18A dependency highly prevalent [SOMATIC]. KIF18A loss in WGD/CIN cells triggers aberrant spindle assembly, SAC-dependent mitotic arrest and death, with SAC deficiency rescuing growth (PMID:42328720); KIF18A is dispensable in normal diploid tissue [KNOWN]. Stress-induced polyploidy is a general adaptive response to genotoxic insult (PMID:42190013), so cytotoxic therapy may itself manufacture the WGD state and hence the dependency [INFERRED].","approach":"Quantify AM-1882-class sensitivity against WGD status, CIN score and SAC gene integrity across ploidy-annotated osteosarcoma PDX; test sequential doxorubicin/radiation priming followed by KIF18A inhibition versus concurrent dosing; control opioid exposure in CIN/micronucleus biomarker assays because morphine blunted doxorubicin-induced DNA and chromosomal damage in MG63 while being genotoxic alone (PMID:42565507); profile resistance via MAD1/MAD2/BUB1B loss and near-diploid reversion.","level":"LEAD","confidence":0.62,"citations":[{"kind":"PMID","id":"42328720","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42326738","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42190013","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42565507","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":20,"lastVisit":2,"lastNote":"Only marginally strengthened: no new KIF18A-specific osteosarcoma data. What is NEW is disease-level substrate prevalence (chromothripsis >70%) and a polyploidy-as-stress-response framing that yields a testable sequencing hypothesis, plus a logged assay confounder (morphine).","history":[{"visit":2,"cycle":75,"status":"STRENGTHENED","note":"Only marginally strengthened: no new KIF18A-specific osteosarcoma data. What is NEW is disease-level substrate prevalence (chromothripsis >70%) and a polyploidy-as-stress-response framing that yields a testable sequencing hypothesis, plus a logged assay confounder (morphine)."},{"visit":1,"cycle":20,"status":"NEW","note":"New this visit from PMID:42328720: isogenic WGD-vs-parental selectivity, SAC-dependence rescue, and xenograft activity without cytotoxic-level toxicity make this the desk's strongest mechanistic entry point into undruggable suppressor loss."}]},{"id":"L2","title":"B7-H3 (CD276) antigen-density-stratified targeting with companion immunoPET selection","mechanism":"Unchanged antigen rationale (PMID:42251292, PMID:40937367, NCT07774533). New operational layer: autologous MNC apheresis for CAR-T manufacture across paediatric solid, brain and haematologic tumours is feasible but gated on peripheral ALC >=300/uL and CD3 >=150/uL, with disease group and baseline lymphocyte counts predicting whether collection targets are met (PMID:42241897) — heavily pretreated relapsed osteosarcoma is precisely the lymphodepleted setting where an autologous B7-H3 CAR-T arm may fail before antigen density matters [INFERRED].","approach":"Retain lesion-level PET SUV vs IHC H-score concordance and prospective SUV threshold definition; add pre-enrolment lymphocyte adequacy screening and apheresis-timing relative to cytotoxic cycles as a feasibility endpoint; where apheresis fails, route patients to ADC (L6) rather than cell therapy; continue paired-biopsy assessment of chemotherapy-induced B7-H3 modulation.","level":"CANDIDATE","confidence":0.64,"citations":[{"kind":"NCT","id":"NCT07774533","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42366590","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42251292","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40937367","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41941262","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42326738","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42241897","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":20,"lastVisit":3,"lastNote":"Only operationally strengthened by NEW paediatric apheresis feasibility data defining a manufacturing gate for the CAR-T arm; no new antigen-density or imaging-correlation data, so deliberately held at CANDIDATE rather than promoted.","history":[{"visit":3,"cycle":153,"status":"STRENGTHENED","note":"Only operationally strengthened by NEW paediatric apheresis feasibility data defining a manufacturing gate for the CAR-T arm; no new antigen-density or imaging-correlation data, so deliberately held at CANDIDATE rather than promoted."},{"visit":2,"cycle":75,"status":"STRENGTHENED","note":"Promoted: two independent NEW inputs this visit — a 133-sample two-centre pre-treatment IHC cohort quantifying osteosarcoma B7-H3 density, and a review tying response to IHC overexpression — convert the assumed antigen into a graded, measurable biomarker."},{"visit":1,"cycle":20,"status":"NEW","note":"New: an osteosarcoma-specific imaging trial converts B7-H3 from an assumed antigen into a measurable, patient-selection variable; no efficacy data yet, so confidence is capped."}]},{"id":"L3","title":"Locally delivered IL-12 via membrane-anchored tumour-targeted T/TIL cells against the immunosuppressive osteosarcoma TME","mechanism":"Cold, myeloid-dominated osteosarcoma TIME rationale unchanged (PMID:42326738, PMID:42366590). New: in 55 osteosarcoma patients receiving neoadjuvant immunotherapy, quantitative MRI histogram features (normalised T1WI percentiles, kurtosis, coefficient of variation) discriminated good (necrosis rate >=90%) from poor responders where RECIST 1.1 was limited (PMID:42273091), giving attIL12 trials a non-size-based efficacy readout suited to immune-mediated response patterns [INFERRED].","approach":"Track NCT05621668/NCT06474676 for bone-sarcoma readouts; adopt quantitative MRI histogram endpoints alongside paired-biopsy TAM M1/M2, Treg/MDSC fractions and intratumoural IFN-gamma; test baseline T-cell infiltrate and, newly, functional ALT status (PMID:41148828 immunogenicity hypothesis) as response predictors; anticipate IFN-gamma-driven PD-L1/IDO1 resistance.","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT06474676","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05621668","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42366590","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42326738","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40937367","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42273091","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41148828","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":20,"lastVisit":3,"lastNote":"Marginal: still no osteosarcoma efficacy readout from either attIL12 trial, but a NEW prospective imaging study supplies a validated response metric for these trials and an ALT-based candidate predictor.","history":[{"visit":3,"cycle":153,"status":"STRENGTHENED","note":"Marginal: still no osteosarcoma efficacy readout from either attIL12 trial, but a NEW prospective imaging study supplies a validated response metric for these trials and an ALT-based candidate predictor."},{"visit":2,"cycle":75,"status":"STRENGTHENED","note":"Modest strengthening only: a NEW independent review corroborates the myeloid-dominated cold TIME that this vehicle targets, but there is still zero osteosarcoma efficacy readout from either trial."},{"visit":1,"cycle":20,"status":"NEW","note":"New: two MDACC trials give a concrete clinical vehicle for the cold-TME problem articulated in the immunotherapy review; osteosarcoma-specific efficacy unreported."}]},{"id":"L4","title":"USP7 as a p53-independent non-oncogene dependency in osteosarcoma","mechanism":"Sarcoma cells hijack the ubiquitin-proteasome system to stabilise oncogenic drivers and inactivate suppressors; USP7 is highlighted as an emerging deubiquitinase vulnerability including in osteosarcoma (PMID:42556483). The canonical USP7-MDM2-p53 axis is likely irrelevant in TP53-null osteosarcoma [INFERRED], so activity must come from other substrates.","approach":"Define the osteosarcoma USP7 substrate set by ubiquitin-remnant proteomics in TP53-null vs TP53-wild-type lines; test selective USP7 inhibitors for p53-status-independent killing; check overlap with KIF18A/mitotic dependencies.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42556483","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":20,"lastVisit":1,"lastNote":"New but review-level and substrate-agnostic; held at low confidence and flagged for pre-emptive falsification (if activity is purely p53-dependent, retire for osteosarcoma).","history":[{"visit":1,"cycle":20,"status":"NEW","note":"New but review-level and substrate-agnostic; held at low confidence and flagged for pre-emptive falsification (if activity is purely p53-dependent, retire for osteosarcoma)."}]},{"id":"L5","title":"FZD1/TCF7L1 Wnt-dependent osteosarcoma cancer stem cells and homoharringtonine repurposing","mechanism":"Single-cell and longitudinal transcriptomics implicate TCF7L1 transcriptional activity and FZD1-Wnt/beta-catenin signalling in osteosarcoma cancer stem cell self-renewal and therapy resistance, with FZD1 expression tracking clinical malignancy; homoharringtonine emerged as an active agent against OCSCs (PMID:42472087).","approach":"Deconvolute drug from delivery: test free homoharringtonine (approved as omacetaxine [KNOWN]) against FZD1-high vs FZD1-low osteosarcoma spheroids and PDX; validate FZD1 as a delivery/biomarker axis independent of the UM206 nanoplatform; assess normal-tissue Wnt dependence (bone remodelling, gut crypt) as the window constraint.","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"42472087","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":20,"lastVisit":1,"lastNote":"New; efficacy is confounded by a bespoke pH/GSH-responsive nanocarrier, so the repurposing claim needs free-drug validation before advancing.","history":[{"visit":1,"cycle":20,"status":"NEW","note":"New; efficacy is confounded by a bespoke pH/GSH-responsive nanocarrier, so the repurposing claim needs free-drug validation before advancing."}]},{"id":"L6","title":"B7-H3 antibody-drug conjugate (vobramitamab duocarmazine) as antigen-directed cytotoxic delivery in osteosarcoma","mechanism":"Antigen-directed activity of vobra duo in osteosarcoma xenografts (isotype-matched control ADC inactive) plus high B7-H3 density in sarcoma (PMID:41941262, PMID:42251292) is now complemented by explicit linker pharmacology: non-internalising ADCs with tumour-microenvironment-activated extracellular cleavage were developed precisely to overcome antigen loss, tumour heterogeneity and impaired endocytosis, generating cytotoxic diffusion across antigen-negative cells (PMID:41866709). This supplies the mechanistic route by which a duocarmycin payload could cover the ~45% of low-H-score osteosarcoma lesions [INFERRED].","approach":"Mixed high/low-H-score co-culture and mosaic PDX to quantify bystander fraction for duocarmycin payload; compare internalisation-dependent versus protease/redox-activated extracellular-release linker variants on the same B7-H3 antibody to test whether heterogeneity, not affinity, limits response; measure B7-H3 internalisation rate in osteosarcoma lines as a predictive parameter; 68Ga-B7-H3 PET (NCT07774533) for lesion-level selection; resistance via antigen downregulation, lysosomal processing defects, ABC-transporter efflux.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"41941262","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42251292","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT07774533","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41866709","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":75,"lastVisit":3,"lastNote":"Strengthened mechanistically (not clinically) by a NEW review giving concrete linker chemistries for extracellular/bystander payload release, converting the lead's key inference about low-antigen lesions into a testable design choice. No new osteosarcoma efficacy data, so held below CANDIDATE.","history":[{"visit":3,"cycle":153,"status":"STRENGTHENED","note":"Strengthened mechanistically (not clinically) by a NEW review giving concrete linker chemistries for extracellular/bystander payload release, converting the lead's key inference about low-antigen lesions into a testable design choice. No new osteosarcoma efficacy data, so held below CANDIDATE."},{"visit":2,"cycle":75,"status":"NEW","note":"New this visit; separated from L2 because ADC pharmacology (bystander payload, catabolism) sets a different antigen-density threshold than CAR-T engagement, and this is the fastest repurposing route given an existing adult clinical programme."}]},{"id":"L7","title":"PARP inhibition as radiosensitiser (including high-LET) in unresectable/axial osteosarcoma with STING-mediated immune conversion","mechanism":"PARPi radiosensitisation with cGAS-STING activation remains mechanistically sound (PMID:42228304) and osteosarcoma's chromothripsis/TP53 loss context is permissive (PMID:42326738), but ALT-positive cancers are classically resistant to DNA-damaging therapies despite high replication stress (PMID:41148828), and ALT is functionally present in ~63% of osteosarcomas (PMID:42330800). A disease-wide PARPi+radiation hypothesis is therefore no longer defensible; the sensitive population is plausibly the ALT-negative/telomerase-positive minority [INFERRED].","approach":"Re-scope preclinical testing: stratify osteosarcoma PDX/orthotopic models by functional ALT (C-circle) before olaparib/talazoparib plus photon or carbon-ion irradiation; treat ALT+ models as a prespecified resistance arm rather than excluding them; retain RAD51-foci functional HR readout since osteosarcoma is not BRCA-driven; test the counter-hypothesis from PMID:41148828 that ALT-associated instability raises immunogenicity, i.e. whether ALT+ tumours respond better to STING-dependent immune conversion or attIL12 combination than to the cytotoxic component.","level":"LEAD","confidence":0.22,"citations":[{"kind":"PMID","id":"42228304","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42326738","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41148828","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42330800","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":75,"lastVisit":3,"lastNote":"Weakened by contradicting evidence: ALT positivity is linked to DNA-damaging-therapy resistance and is the majority phenotype in osteosarcoma, so the unstratified radiosensitisation claim is undercut. Survives only as an ALT-stratified hypothesis.","history":[{"visit":3,"cycle":153,"status":"WEAKENED","note":"Weakened by contradicting evidence: ALT positivity is linked to DNA-damaging-therapy resistance and is the majority phenotype in osteosarcoma, so the unstratified radiosensitisation claim is undercut. Survives only as an ALT-stratified hypothesis."},{"visit":2,"cycle":75,"status":"NEW","note":"New this visit from a radiosensitisation review; osteosarcoma-specific evidence is absent, so this is an inference from genome-instability context and must be falsified in bone-sarcoma models before advancing."}]},{"id":"L8","title":"ALT-directed synthetic lethality (SMARCAL1, replication-stress DDR nodes) selected by functional C-circle/APB assay, not ATRX genotype, in osteosarcoma","mechanism":"Functional ALT is present in 62.9% of 342 patient-derived osteosarcomas, yet ATRX/DAXX mutation and TOP3A amplification occur at substantially lower frequency, so ALT activation in this disease is largely non-mutational (chromatin/epigenetic/replication-stress driven) and cannot be inferred from sequencing (PMID:42330800). ALT tumours depend on recombination-based telomere synthesis with APBs, extrachromosomal telomeric repeats, telomere fragility and mitotic DNA synthesis — a defined set of DDR dependencies (PMID:41480636). SMARCAL1, an annealing helicase that localises to APBs, is a highly specific CRISPR synthetic-lethal vulnerability in ATRX-deficient ALT glioma lines and xenografts (PMI","approach":"Genotype-blind functional ALT calling (C-circle assay, APB immuno-FISH, telomere-length heterogeneity) across osteosarcoma cell-line and PDX panels; test SMARCAL1 knockdown/degradation and ATR pathway inhibition for selective killing in ALT+ vs ALT- lines, explicitly comparing ATRX-mutant vs ATRX-wildtype ALT+ models to see if dependency tracks the phenotype or the genotype; mine DepMap sarcoma lines for SMARCAL1/BLM/FANCM/SLX4/TOP3A co-dependency clusters; read out telomeric DNA damage, APB dissolution and telomere loss; anticipate resistance via telomerase reactivation or switch of recombination pathway; define window against bone-marrow and fracture-healing regenerative compartments given","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42330800","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41520142","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41480636","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41148828","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41120592","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":153,"lastVisit":3,"lastNote":"New this visit from three convergent ALT inputs: a 342-tumour osteosarcoma prevalence/discordance analysis, a mechanistic ALT-DDR review, and the first concrete synthetic-lethal node (SMARCAL1). Held at 0.5 because the SMARCAL1 data are glioma-derived and the osteosarcoma ALT majority is ATRX-wildtype.","history":[{"visit":3,"cycle":153,"status":"NEW","note":"New this visit from three convergent ALT inputs: a 342-tumour osteosarcoma prevalence/discordance analysis, a mechanistic ALT-DDR review, and the first concrete synthetic-lethal node (SMARCAL1). Held at 0.5 because the SMARCAL1 data are glioma-derived and the osteosarcoma ALT majority is ATRX-wildtype."}]}],"retired":[],"nextQueries":["(\"osteosarcoma\" OR \"bone sarcoma\") AND (SMARCAL1 OR FANCM OR SLX4 OR BLM OR \"C-circle\" OR \"ALT-associated PML\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"osteosarcoma\" AND (\"ATR inhibitor\" OR berzosertib OR ceralasertib OR \"replication stress\" OR \"telomere maintenance\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"osteosarcoma\" OR \"bone sarcoma\") AND (\"B7-H3\" OR CD276) AND (\"antigen density\" OR bystander OR \"CAR T\" OR apheresis) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-19T22:58:37.042Z"},{"key":"ewing sarcoma","name":"Ewing sarcoma","mondo":{"id":"MONDO:0012817","name":"Ewing sarcoma"},"genes":[{"label":"EWSR1","kind":"causal"},{"label":"ERG","kind":"correlated"},{"label":"ETV1","kind":"correlated"},{"label":"ETV4","kind":"correlated"},{"label":"FLI1","kind":"correlated"},{"label":"SMARCA5","kind":"correlated"}],"visits":3,"openQuestions":["What is the distribution of SLFN11, ABCG2/BCRP and B7-H3 protein expression across matched Ewing sarcoma primaries and metastases, and does SLFN11-high status predict TOP1-payload ADC or irinotecan benefit?","Are there any registered TOP1-payload ADC trials (B7-H3, GD2, LINGO1, HER3 directed) that enrol Ewing sarcoma or paediatric bone sarcoma cohorts?","Has any BET inhibitor been tested clinically in EWSR1-fusion sarcoma, and does BETi lower measured EWSR1::FLI1 target-gene output in ES models at tolerable exposures?","Which agents constitute the arms of NCT06820957 in newly diagnosed metastatic ES, and can fusion-dose, SLFN11 and pCHK1 correlatives be embedded now that FDG-PET/CT (PMID:42590965) frees up marrow-sampling burden?","Has fusion-induced ATM hypofunction (PMID:41811428) been replicated independently, and has any ATR-inhibitor cohort actually enrolled ES patients?","Does genetic ATG5/ATG7/Beclin-1 ablation restore PARPi killing in ES, and does the same axis blunt ATR inhibitors?"],"leads":[{"id":"L1","title":"ATR inhibition as synthetic lethality against fusion-induced ATM hypofunction in FET-rearranged sarcoma","mechanism":"EWSR1::FLI1 [SOMATIC] and other FET fusions are recruited to DSBs and impair ATM activation, making the compensatory ATR axis a collateral dependency in FET-fusion PDX models (PMID:41811428). Still a single-report mechanism.","approach":"Unchanged: basket ATR-inhibitor testing in EWSR1/FUS/TAF15-fusion sarcoma with pATM/pCHK1/gammaH2AX PD on serial biopsies, combinations with topo-I poisons (NCT04337177) or gemcitabine, marrow-toxicity-limited since ATR is essential in normal proliferating tissue [KNOWN]. Next step is literature-independent: seek any ES arm in ATR-inhibitor registries and quantify fusion-dose-dependent ATM hypofunction.","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"41811428","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04337177","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":21,"lastVisit":2,"lastNote":"Dedicated Europe PMC searches for ES + named ATR inhibitors and for ES/FET + SLFN11/STAG2/replication stress/ATM (2023-2026) returned zero papers; absence of corroboration after a targeted search warrants a small decrement, and the null queries are recorded so they are not repeated verbatim.","history":[{"visit":2,"cycle":76,"status":"WEAKENED","note":"Dedicated Europe PMC searches for ES + named ATR inhibitors and for ES/FET + SLFN11/STAG2/replication stress/ATM (2023-2026) returned zero papers; absence of corroboration after a targeted search warrants a small decrement, and the null queries are recorded so they are not repeated verbatim."},{"visit":1,"cycle":21,"status":"NEW","note":"New this visit from PMID:41811428 [NEW]; strongest mechanistic anchor in the pack because the vulnerability derives directly from the disease-defining fusion and was tested in PDX, not only cell lines."}]},{"id":"L2","title":"PARP inhibitor monotherapy is dead in Ewing sarcoma; only autophagy-blockade combinations are worth revisiting","mechanism":"Unchanged: PARPi-induced autophagy correlates with reduced killing in WE-68/SK-ES-1 (PMID:42215796), causality untested. Generic reviews of Beclin-1/PI3KC3 as an autophagy node (PMID:39650649) and of PARPi combination formulation (PMID:40806481) contain no ES data and do not corroborate the axis.","approach":"Unchanged and now explicitly gated: no clinical proposal without ATG5/ATG7 or Beclin-1 genetic ablation restoring PARPi killing in ES models. Retain as a permanent negative-evidence entry against single-agent olaparib.","level":"LEAD","confidence":0.27,"citations":[{"kind":"PMID","id":"42215796","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"39650649","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":21,"lastVisit":3,"lastNote":"A targeted ES + (ATG5/ATG7/autophagy/hydroxychloroquine) + PARP query returned only non-ES reviews; the causal experiment demanded at visit 1 still does not exist in the literature, so confidence decrements again.","history":[{"visit":3,"cycle":154,"status":"WEAKENED","note":"A targeted ES + (ATG5/ATG7/autophagy/hydroxychloroquine) + PARP query returned only non-ES reviews; the causal experiment demanded at visit 1 still does not exist in the literature, so confidence decrements again."},{"visit":1,"cycle":21,"status":"NEW","note":"Recorded primarily as a negative-evidence entry so the desk never re-proposes olaparib monotherapy; the combination hypothesis is retained at low confidence pending causal autophagy experiments."}]},{"id":"L3","title":"B7-H3 CAR T cells armoured against TGF-beta signalling for relapsed/refractory Ewing sarcoma","mechanism":"Unchanged: low-TMB paediatric bone sarcoma with a TGF-beta-rich immunosuppressive TME (PMID:42366590) treated with dTbetaRII-expressing antigen-specific T cells plus B7-H3 CAR T cells (NCT07172958). New this visit: the manufacturing precondition is empirically supported — autologous mononuclear apheresis succeeded across paediatric solid-tumour and brain-tumour diagnoses using ALC >=300/uL and CD3+ >=150/uL suitability thresholds (PMID:42241897), so lymphopenia in heavily pretreated ES patients is a manageable rather than disqualifying obstacle.","approach":"As before, plus: prospectively record pre-apheresis ALC/CD3 in relapsed ES candidates to define the collection window before further chemotherapy, and require paired metastatic-site biopsies for B7-H3 density and homogeneity (the unanswered question). Resistance: antigen heterogeneity/downregulation, CAR exhaustion, myeloid exclusion.","level":"LEAD","confidence":0.43,"citations":[{"kind":"PMID","id":"42366590","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07172958","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42241897","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":21,"lastVisit":3,"lastNote":"Small increment for feasibility only: new paediatric solid-tumour apheresis data remove a practical objection, but no ES response or antigen-density data exist yet, so this stays a LEAD.","history":[{"visit":3,"cycle":154,"status":"STRENGTHENED","note":"Small increment for feasibility only: new paediatric solid-tumour apheresis data remove a practical objection, but no ES response or antigen-density data exist yet, so this stays a LEAD."},{"visit":1,"cycle":21,"status":"NEW","note":"New this visit; the only immunotherapy lead in the pack that engineers against its own predicted resistance mechanism rather than relying on checkpoint blockade in a low-TMB tumour."}]},{"id":"L4","title":"Polyamine depletion (DFMO + polyamine transport inhibition) exploiting EWSR1::FLI1-driven ODC1","mechanism":"ODC1 is a direct EWSR1::FLI1 target and ES cells are polyamine-dependent [KNOWN]; DFMO escape via upregulated uptake is blocked by AMXT 1501 (NCT06465199). Methionine restriction lowers SAM, the aminopropyl donor for spermidine/spermine synthesis, so dietary methionine reduction is a mechanistically orthogonal squeeze on the same pathway [INFERRED]; a feasibility trial of a methionine-reduced diet in solid tumours is now open (NCT07628634).","approach":"Follow NCT06465199 sarcoma cohorts for ES signal with tumour/plasma polyamine and EWSR1::FLI1 signature readouts; preclinically combine DFMO/AMXT 1501 with methionine restriction and with ATR inhibition (L1). Window: ODC1 activity in gut crypt epithelium, DFMO ototoxicity, and cachexia risk of dietary restriction in paediatric patients [KNOWN].","level":"LEAD","confidence":0.38,"citations":[{"kind":"NCT","id":"NCT06465199","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07628634","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":1,"createdCycle":21,"lastVisit":2,"lastNote":"Only a mechanistic extension, not ES data: NCT07628634 is new in this pack but is a non-ES feasibility diet study, so the confidence increment is deliberately minimal and the lead remains at LEAD level.","history":[{"visit":2,"cycle":76,"status":"STRENGTHENED","note":"Only a mechanistic extension, not ES data: NCT07628634 is new in this pack but is a non-ES feasibility diet study, so the confidence increment is deliberately minimal and the lead remains at LEAD level."},{"visit":1,"cycle":21,"status":"NEW","note":"New this visit; clinical-stage repurposing route with a plausible direct link to the fusion transcriptional programme, but no ES-specific human data yet in the pack."}]},{"id":"L5","title":"Cabozantinib as an approved multikinase backbone in relapsed Ewing sarcoma, to be combined rather than escalated alone","mechanism":"Unchanged (VEGFR2/MET/AXL blockade of the vascular-stromal compartment, NCT02243605).","approach":"Unchanged, but deprioritised: do not build combination proposals on this backbone until ES-specific ORR/PFS and the biomarker analysis are actually reported.","level":"LEAD","confidence":0.35,"citations":[{"kind":"NCT","id":"NCT02243605","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT04337177","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":76,"lastVisit":3,"lastNote":"A dedicated Europe PMC query for ES/EWSR1 with cabozantinib/VEGFR2/AXL/MET (2022-2026) returned zero ES-specific papers, and NCT02243605 remains ACTIVE_NOT_RECRUITING with no posted results; targeted-search silence warrants a decrement. Query recorded so it is not repeated verbatim.","history":[{"visit":3,"cycle":154,"status":"WEAKENED","note":"A dedicated Europe PMC query for ES/EWSR1 with cabozantinib/VEGFR2/AXL/MET (2022-2026) returned zero ES-specific papers, and NCT02243605 remains ACTIVE_NOT_RECRUITING with no posted results; targeted-search silence warrants a decrement. Query recorded so it is not repeated verbatim."},{"visit":2,"cycle":76,"status":"NEW","note":"First ES-dedicated approved-agent repurposing trial to enter this programme; created because repurposing routes reach patients fastest and because it supplies a plausible combination backbone for the DDR leads."}]},{"id":"L6","title":"Disulfiram/copper-driven proteotoxic stress (CuET-p97/NPL4) with liposomal doxorubicin in refractory sarcoma","mechanism":"The disulfiram-copper metabolite CuET inhibits the p97/NPL4 segregase, causing poly-ubiquitinated protein aggregation, heat-shock response overload and nucleolar stress [KNOWN]; fusion-driven transcriptional addiction and high biosynthetic load in ES plausibly sensitise it to proteostasis collapse and to anthracycline co-exposure [SPECULATIVE]. Trial combines disulfiram, copper gluconate and liposomal doxorubicin in treatment-refractory sarcomas (NCT05210374).","approach":"Track NCT05210374 for any ES-histology responses and require correlative markers of proteotoxic stress (poly-Ub aggregates, HSF1 targets, NPL4 immunostaining). Preclinically test CuET in ES lines/PDX against fusion-high vs fusion-low states and for synergy with topo-II and with ATR inhibition. Normal-tissue window: hepatic and neurologic toxicity of disulfiram plus copper loading, additive cardiotoxicity with anthracycline [KNOWN]. Resistance: copper efflux (ATP7A/B), glutathione/metallothionein buffering.","level":"LEAD","confidence":0.25,"citations":[{"kind":"NCT","id":"NCT05210374","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":76,"lastVisit":2,"lastNote":"New from this visit's trial pack; logged at low confidence purely so the desk tracks the disulfiram-copper route and does not reinvent it, since no ES-specific preclinical or clinical data are in the pack.","history":[{"visit":2,"cycle":76,"status":"NEW","note":"New from this visit's trial pack; logged at low confidence purely so the desk tracks the disulfiram-copper route and does not reinvent it, since no ES-specific preclinical or clinical data are in the pack."}]},{"id":"L7","title":"Antigen-directed TOP1-payload ADCs in SLFN11-high Ewing sarcoma, ABCG2-screened and ATR-potentiated","mechanism":"Response to tumour-targeted TOP1 poisons is governed by surface-epitope density, proliferation index, SLFN11 expression, HR deficiency and ABCG2/BCRP efflux, and is mechanistically potentiated by PARP/ATR/CHK1/ATM inhibition (PMID:42092629). Ewing sarcoma is the archetypal SLFN11-high, highly proliferative, irinotecan-sensitive paediatric tumour [KNOWN] and carries dense B7-H3/CD276 surface antigen (PMID:42366590), so an ADC delivers a payload the tumour is already primed to fail at repairing, at higher intratumoural exposure than oral irinotecan [INFERRED]. Fusion-driven replication stress plus impaired ATM activation (PMID:41811428) predicts additive killing with ATR inhibition [INFERRED/S","approach":"Quantify SLFN11 (IHC/RNA) and ABCG2 across ES primaries and metastases alongside B7-H3 density; test B7-H3- or GD2-directed exatecan/deruxtecan-class ADCs in ES PDX versus free VAL-413/temozolomide (NCT04337177) as comparator, then ADC + low-dose ATR inhibitor with pCHK1/gammaH2AX PD. Resistance routes: SLFN11 epigenetic silencing (reversible by EZH2/HDAC inhibition [KNOWN]), ABCG2 upregulation, antigen loss, payload-independent HR restoration. Window: interstitial lung disease and marrow suppression of TOP1-payload ADCs, plus normal B7-H3 expression in some epithelia [KNOWN].","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42092629","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42366590","verified":true,"isNew":false,"addedVisit":3},{"kind":"PMID","id":"41811428","verified":true,"isNew":false,"addedVisit":3},{"kind":"NCT","id":"NCT04337177","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":154,"lastVisit":3,"lastNote":"Created from the one genuinely informative new paper: a determinants-of-response framework for TOP1-payload ADCs that maps onto ES biology (SLFN11-high, B7-H3-high) and supplies both a patient-selection biomarker and a rational ATR combination, tying L1 and L3 together.","history":[{"visit":3,"cycle":154,"status":"NEW","note":"Created from the one genuinely informative new paper: a determinants-of-response framework for TOP1-payload ADCs that maps onto ES biology (SLFN11-high, B7-H3-high) and supplies both a patient-selection biomarker and a rational ATR combination, tying L1 and L3 together."}]},{"id":"L8","title":"BET inhibition to collapse EWSR1::FLI1 transcriptional output, combined with CHK1/ATR inhibition","mechanism":"BET proteins are epigenetic readers coupling transcription to cell cycle and DDR; BET inhibitors disrupt transcriptional programmes driven by oncogenic sarcoma fusion proteins, uncouple transcription from replication kinetics, and show preclinical efficacy alone or with CHK1, HDAC or PI3K inhibitors (PMID:40138251). In ES the undruggable EWSR1::FLI1 [SOMATIC] transcription factor is thus attacked indirectly, and the resulting transcription-replication conflict is expected to be lethal in a background of fusion-impaired ATM activation (PMID:41811428) [INFERRED].","approach":"Test BETi (e.g. clinical-stage BD1/BD2-selective agents) in EWSR1::FLI1-high versus fusion-low ES lines/PDX with fusion-signature RNA-seq as the on-target PD marker; then BETi + CHK1i or + ATR inhibitor at intermittent schedules. Expected resistance: BRD4 phosphorylation/SPOP-dependent stabilisation, kinome-mediated MYC restoration, WNT reactivation [KNOWN]. Window: BETi thrombocytopenia and GI toxicity plus overlapping marrow toxicity with DDR inhibitors is the limiting constraint in paediatric patients [KNOWN].","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"40138251","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41811428","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":154,"lastVisit":3,"lastNote":"New from a sarcoma-specific BET review in this pack; logged at modest confidence because the review reports no ES-specific clinical efficacy and BETi have repeatedly failed on tolerability, but it is the only route in the pack that targets fusion output itself and it is mechanistically continuous with L1.","history":[{"visit":3,"cycle":154,"status":"NEW","note":"New from a sarcoma-specific BET review in this pack; logged at modest confidence because the review reports no ES-specific clinical efficacy and BETi have repeatedly failed on tolerability, but it is the only route in the pack that targets fusion output itself and it is mechanistically continuous with L1."}]}],"retired":[],"nextQueries":["(\"Ewing sarcoma\" OR EWSR1) AND (SLFN11 OR ABCG2 OR \"antibody-drug conjugate\" OR deruxtecan OR exatecan) AND PUB_YEAR:[2021 TO 2026] AND SRC:MED","(\"Ewing sarcoma\" OR \"EWSR1-FLI1\" OR \"EWS-FLI1\") AND (BRD4 OR \"BET inhibitor\" OR JQ1 OR ZEN-3694 OR mivebresib) AND SRC:MED","(\"Ewing sarcoma\") AND (B7-H3 OR CD276) AND (immunohistochemistry OR \"antigen density\" OR metastasis) AND SRC:MED"],"updatedAt":"2026-08-19T23:02:10.768Z"},{"key":"rhabdomyosarcoma","name":"rhabdomyosarcoma","mondo":{"id":"MONDO:0005212","name":"rhabdomyosarcoma"},"genes":[{"label":"PAX3","kind":"causal"},{"label":"PAX7","kind":"causal"},{"label":"SLC67A1","kind":"causal"},{"label":"FOXO1","kind":"causal"},{"label":"DICER1","kind":"causal"},{"label":"TP53","kind":"correlated"},{"label":"NF1","kind":"correlated"}],"visits":3,"openQuestions":["In one matched orthotopic RMS PDX panel (fusion-positive and fusion-negative), how do vobramitamab duocarmazine, a B7-H3-TOP1 ADC, and 3A11-exatecan rank on EFS, and does ranking track calibrated antigen molecules/cell or internalisation ha","Are RMS lines/PDXs SLFN11-high or SLFN11-low, and does SLFN11/ABCG2 status predict exatecan- or DXd-payload ADC response — i.e. is a companion Dx feasible for RMS ADC trials?","What is the hepatobiliary/bile-acid and skeletal-muscle toxicity profile of FGFR4-directed ADCs at efficacious doses, given normal FGF19-FGFR4 signalling, and does it differ from FGFR4 CAR-T (NCT06865664)?","Does FGFR4 surface density differ systematically between PAX3/PAX7-FOXO1-positive and fusion-negative RMS, and is FGFR4 a direct fusion target gene?","Does ADC pretreatment lower B7-H3 or FGFR4 surface density enough to compromise subsequent CAR-T against the same antigen (sequencing question for L2 and the FGFR4 programme)?","Any posted readout for temsirolimus plus VAC/VI in intermediate-risk RMS (NCT02567435) — if negative, formally close mTOR-plus-chemotherapy as dead ground?"],"leads":[{"id":"L1","title":"CD28-costimulated L1CAM-CAR T cells for moderate-/low-antigen-density, fusion-positive RMS","mechanism":"L1CAM is relatively tissue-restricted across RMS lines/PDXs and enriched in fusion-positive disease, and CD28-based L1CAM.III exceeds clinical 4-1BB CE7 in cytotoxicity, IFN-gamma, expansion and tumour control. [SPECULATIVE] L1CAM as a direct PAX3-FOXO1 target gene remains untested.","approach":"Reposition as contingency only: test L1CAM.III exclusively in B7-H3-low and FGFR4-low RMS PDXs identified by calibrated antigen-density flow, against vobra duo and 3A11-exatecan as active comparators. CNS/adrenal medulla/renal tubule cross-reactivity remains the window argument. Resistance: antigen-density downshift, L1CAM-negative outgrowth, CD28-driven exhaustion, TGF-beta stroma.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42336095","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41709231","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42288687","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41941262","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42447867","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":22,"lastVisit":3,"lastNote":"Third consecutive visit with no new RMS L1CAM data, while two competing antigens now have controlled in vivo efficacy in RMS models. Retained one more visit purely as the antigen-low contingency; retire next visit absent matched-model comparison data.","history":[{"visit":3,"cycle":155,"status":"WEAKENED","note":"Third consecutive visit with no new RMS L1CAM data, while two competing antigens now have controlled in vivo efficacy in RMS models. Retained one more visit purely as the antigen-low contingency; retire next visit absent matched-model comparison data."},{"visit":2,"cycle":77,"status":"WEAKENED","note":"Weakened, not retired: an L1CAM-fielded query returned no new RMS L1CAM data this visit, and the 2026 paediatric therapeutic development workshop priority list names B7-H3/CD276 and FGFR4 but not L1CAM, so the comparative case for L1CAM must now be won in matched models."},{"visit":1,"cycle":22,"status":"NEW","note":"New this visit: first dataset in the programme giving construct-resolved L1CAM CAR potency with a B7-H3 comparator and healthy-tissue profiling."}]},{"id":"L2","title":"Armoured / multi-antigen CAR platform to break the immune-cold, TGF-beta-suppressed RMS microenvironment","mechanism":"RMS CAR failure is driven by antigen heterogeneity plus TME suppression rather than binder affinity; counter-engineering options are dnTGFBRII, IL-15/IL-21 co-expression, and now wild-type FOXO1 overexpression in the CAR T cell, reported to improve metabolic fitness and stem-like persistence in solid tumours. [INFERRED] FOXO1 transgene armouring is mechanistically independent of the [SOMATIC] PAX3/PAX7-FOXO1 tumour fusion and does not risk fusion-mimetic signalling in T cells.","approach":"Composite arms in RMS PDX: (i) B7-H3 CAR + dnTGFBRII T cells (NCT07172958), (ii) IL-15/IL-21-armoured backbone (NCT04715191) on B7-H3 or L1CAM binders, (iii) FOXO1-overexpressing CAR arm with Tscm phenotyping and serial rechallenge, (iv) dual L1CAM+B7-H3 CAR against single-antigen escape. Resistance: cytokine-driven dysfunction/CRS in paediatric patients, MDSC/TAM suppression independent of IL-15, antigen-negative escape.","level":"CANDIDATE","confidence":0.5,"citations":[{"kind":"PMID","id":"41709231","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42172443","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07172958","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04715191","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41770377","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42012754","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":22,"lastVisit":2,"lastNote":"New this visit: an independent 2026 review of armoured CAR-T in paediatric solid tumours including RMS, plus a FOXO1 review supplying a concrete new armouring modality (FOXO1 overexpression for CAR-T persistence) not previously in the programme.","history":[{"visit":2,"cycle":77,"status":"STRENGTHENED","note":"New this visit: an independent 2026 review of armoured CAR-T in paediatric solid tumours including RMS, plus a FOXO1 review supplying a concrete new armouring modality (FOXO1 overexpression for CAR-T persistence) not previously in the programme."},{"visit":1,"cycle":22,"status":"NEW","note":"New this visit: two recruiting paediatric phase 1 armouring platforms plus review-level confirmation that TME suppression, not binder affinity, is the dominant RMS CAR failure mode."}]},{"id":"L3","title":"Osimertinib repurposing against a MYLK4-CDKAL1 stemness/chemoresistance axis in RMS","mechanism":"Osimertinib is reported to inhibit MYLK4-mediated phosphorylation of CDKAL1, suppressing stemness and chemoresistance in RMS — i.e. an EGFR-independent off-target kinase effect. [INFERRED] the actionable node is MYLK4 kinase activity, not EGFR.","approach":"Genetic validation first: MYLK4 CRISPR knockout and phospho-dead/phospho-mimetic CDKAL1 rescue in fusion-positive and fusion-negative lines; then osimertinib + vincristine/actinomycin-D/cyclophosphamide in PDX with serial limiting-dilution sphere assays. Window question is central: MYLK4 is cardiac/skeletal-muscle-enriched [KNOWN], so cardiac and myofibre toxicity readouts are mandatory. Resistance routes: MYLK4-independent stemness programmes, MYLK1/2 redundancy, EGFR-pathway-agnostic escape.","level":"LEAD","confidence":0.22,"citations":[{"kind":"PMID","id":"41565624","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":22,"lastVisit":1,"lastNote":"New but deliberately low confidence: single 2026 Letter, abstract only, no visible potency/PK/selectivity data and an unresolved muscle-kinase therapeutic window.","history":[{"visit":1,"cycle":22,"status":"NEW","note":"New but deliberately low confidence: single 2026 Letter, abstract only, no visible potency/PK/selectivity data and an unresolved muscle-kinase therapeutic window."}]},{"id":"L4","title":"B7-H3/CD276 antibody-drug conjugate and antibody-guided delivery in RMS","mechanism":"B7-H3 is surface-expressed on fusion-positive and fusion-negative RMS; MGA271-IRDye800 showed antigen-dependent tumour enrichment (T:B 5.6 at 144 h in orthotopic RH30 vs 2.7 isotype), and vobramitamab duocarmazine (DAR ~2.7, duocarmycin) induced objective responses in RMS and other paediatric solid tumour xenografts after a single 6 mg/kg dose while a linker/payload-matched anti-CD20 control ADC (SYD988) did not — antigen-dependent, not payload-nonspecific, activity [INFERRED]. [KNOWN] B7-H3 has restricted but non-zero normal-tissue expression, so payload and DAR govern the window; clinical maturation of the class is independent (ifinatamab deruxtecan in late-stage pipeline).","approach":"Benchmark duocarmycin vs TOP1 (exatecan/DXd) vs MMAE payloads on the same B7-H3 binder in orthotopic fusion-positive (RH30/RH4) and fusion-negative RMS PDX; calibrated flow for B7-H3 molecules/cell plus internalisation/recycling kinetics to test whether RMS is internalisation-permissive or requires extracellular-release/non-internalising linker chemistry; MGA271-IRDye800 as companion PD/biodistribution and fluorescence-guided resection readout; combine with vincristine/irinotecan backbone. Resistance: intratumoural B7-H3 heterogeneity and antigen-low escape, slow internalisation, ABCB1/ABCG2 payload efflux, normal-tissue on-target uptake, cross-resistance with B7-H3 CAR-T.","level":"CANDIDATE","confidence":0.62,"citations":[{"kind":"PMID","id":"42276839","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42288687","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41941262","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41560619","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42426296","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41866709","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":77,"lastVisit":3,"lastNote":"Promoted: first control-ADC-matched in vivo efficacy of a B7-H3 ADC in RMS xenografts (PMID:41941262), plus independent workshop endorsement (PMID:42426296) and late-stage class maturation (PMID:41560619). Partly answers open question 1 — RMS B7-H3 biology is ADC-permissive for a bystander-capable alkylator payload even before density is quantified.","history":[{"visit":3,"cycle":155,"status":"STRENGTHENED","note":"Promoted: first control-ADC-matched in vivo efficacy of a B7-H3 ADC in RMS xenografts (PMID:41941262), plus independent workshop endorsement (PMID:42426296) and late-stage class maturation (PMID:41560619). Partly answers open question 1 — RMS B7-H3 biology is ADC-permissive for a bystander-capable alkylator payload even before density is quantified."},{"visit":2,"cycle":77,"status":"NEW","note":"New lead created from the first in vivo RMS antibody-biodistribution dataset for B7-H3 plus independent field-level prioritisation of B7-H3 ADCs; separates the non-cellular B7-H3 axis from the CAR platform in L2."}]},{"id":"L5","title":"Direct ablation of the PAX3/PAX7-FOXO1 fusion: siRNA nanocarrier delivery and degrader routes","mechanism":"PAX3-FOXO1 [SOMATIC] is the initiating and maintenance driver of alveolar RMS and is not a conventional small-molecule target. Partially glycosylated fourth-generation poly(propylene imine) dendrimers (PPI-M3-20, PPI-Lac-27) formed stable dendriplexes with PAX3-FOXO1 siRNA, reduced RH30 viability and migration, and on intratumoral dosing inhibited tumour growth with suppression of PAX3-FOXO1 and downstream transcriptional programmes in tumour tissue. Caveat that outranks the positive: the empty PPI-M3-20 vector alone also significantly reduced tumour mass, so target-specific contribution is unresolved from the abstract. Complementary chemical routes flagged by workshop consensus are P300/CBP","approach":"Require carrier-controlled, systemically dosed experiments: scrambled-siRNA dendriplex versus PAX3-FOXO1 siRNA dendriplex versus empty vector, with matched biodistribution and dose-response, in fusion-positive versus fusion-negative RMS PDX (fusion-negative as on-target specificity control); RNA-seq to confirm collapse of the fusion signature rather than generic cytotoxicity; in parallel benchmark P300/CBP degrader sensitivity against the same signature. Resistance: incomplete knockdown with rapid transcriptional rebound, hepatic/RES sequestration of dendriplexes, fusion-independent escape states, immunogenicity of repeat nanocarrier dosing.","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"42425239","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42288687","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":77,"lastVisit":2,"lastNote":"New but deliberately low confidence: single 2026 report, intratumoral administration only, and vector-alone antitumour activity confounds attribution; retained because direct fusion targeting is independently named a top field priority.","history":[{"visit":2,"cycle":77,"status":"NEW","note":"New but deliberately low confidence: single 2026 report, intratumoral administration only, and vector-alone antitumour activity confounds attribution; retained because direct fusion targeting is independently named a top field priority."}]},{"id":"L6","title":"FGFR4-targeted ADC (3A11-exatecan) for fusion-positive and fusion-negative RMS","mechanism":"FGFR4 is a lineage-restricted RTK highly expressed in RMS. Two ADCs built on the high-affinity 3A11 antibody — the identical binder in an NCI CAR-T trial for relapsed/refractory RMS (NCT06865664) — are rapidly internalised and produce FGFR4-dependent cytotoxicity; in vivo the exatecan (TOP1) conjugate outperformed MMAE, giving durable control in fusion-negative RMS559 and fusion-positive RH4 CDX and in an RMS PDX, and eradicating relapsed FGFR4+ breast xenografts on retreatment (PMID:42447867). [INFERRED] rapid internalisation makes FGFR4 mechanistically better suited to classical intracellular-release ADCs than B7-H3 may be. [KNOWN] normal FGFR4 function is hepatic FGF19-mediated bile-acid ","approach":"Confirm binder-shared logic: quantify FGFR4 molecules/cell and internalisation half-time across a fusion-stratified RMS line/PDX panel and correlate with exatecan-ADC IC50; orthotopic (not only subcutaneous) fusion-positive and fusion-negative PDX efficacy with bile-acid/ALT/liver-histology and myofibre regeneration toxicology; head-to-head exatecan-FGFR4-ADC vs vobra duo vs B7-H3-TOP1 ADC in the same PDX panel; test sequential ADC-then-FGFR4-CAR-T for antigen-density interference. Resistance: FGFR4 downregulation or antigen-low escape, FGFR1/2 or RAS-pathway bypass signalling, ABCG2-mediated exatecan efflux, SLFN11-low insensitivity to TOP1 payloads.","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"42447867","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT06865664","verified":false,"isNew":false,"addedVisit":3},{"kind":"PMID","id":"41749943","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42288687","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":155,"lastVisit":3,"lastNote":"New lead from the first FGFR4 ADC dataset in RMS; strategically important because the binder is already clinical-stage as a CAR, and because it directly rivals B7-H3 for the same patients. Workshop priority lists and the 2026 RMS therapy review independently name FGFR4.","history":[{"visit":3,"cycle":155,"status":"NEW","note":"New lead from the first FGFR4 ADC dataset in RMS; strategically important because the binder is already clinical-stage as a CAR, and because it directly rivals B7-H3 for the same patients. Workshop priority lists and the 2026 RMS therapy review independently name FGFR4."}]},{"id":"L7","title":"Payload-and-biomarker layer: TOP1-payload ADCs plus ATR/CHK1/PARP1 inhibition, stratified by SLFN11 and ABCG2 in RMS","mechanism":"In RMS xenografts the exatecan conjugate beat MMAE on the same FGFR4 binder (PMID:42447867), pointing to TOP1 poisons as the preferred RMS payload class. Response determinants for tumour-targeted TOP1 poisons are high surface antigen, high proliferative index, SLFN11 expression, HRD/BRCAness and low ABCG2/BCRP efflux, with mechanistic rationale for combining with PARP, ATR, CHK1 or ATM inhibitors (PMID:42092629). [INFERRED] RMS is proliferative and frequently TP53-altered [SOMATIC], so replication-stress checkpoint dependency is plausible, but SLFN11 and ABCG2 status in RMS is unmeasured in this pack — this is a testable stratification hypothesis, not an established one.","approach":"Profile SLFN11 (IHC/RNA), ABCG2/ABCB1, Ki67 and HRD signatures across fusion-positive and fusion-negative RMS lines and PDXs; test whether SLFN11 status predicts exatecan/DXd-ADC response; then low-dose ADC plus selective ATR or CHK1 inhibitor, and selective PARP1 inhibitor, in SLFN11-low PDXs to resensitise; monitor overlapping myelosuppression as the dose-limiting interaction. Resistance: SLFN11 promoter methylation-driven loss on treatment, ABCG2 upregulation, schedule-dependent additive marrow toxicity forcing subtherapeutic ADC dosing.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42092629","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42447867","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42426296","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":155,"lastVisit":3,"lastNote":"New cross-cutting lead: it converts payload choice and combination design for both L4 and the FGFR4 lead into an explicit, measurable biomarker programme. Deliberately low confidence — no RMS SLFN11/ABCG2 data exist in the pack.","history":[{"visit":3,"cycle":155,"status":"NEW","note":"New cross-cutting lead: it converts payload choice and combination design for both L4 and the FGFR4 lead into an explicit, measurable biomarker programme. Deliberately low confidence — no RMS SLFN11/ABCG2 data exist in the pack."}]}],"retired":[],"nextQueries":["(rhabdomyosarcoma OR \"soft tissue sarcoma\") AND (SLFN11 OR ABCG2 OR \"schlafen 11\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","FGFR4 AND (rhabdomyosarcoma OR sarcoma) AND (toxicity OR hepatotoxicity OR \"bile acid\" OR \"antigen density\" OR internalization) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"B7-H3\" OR CD276 OR FGFR4) AND (rhabdomyosarcoma) AND (\"molecules per cell\" OR quantitative OR \"antigen density\" OR \"CAR T\" AND ADC) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-19T23:05:43.745Z"},{"key":"atypical teratoid rhabdoid tumor","name":"atypical teratoid rhabdoid tumor","mondo":{"id":"MONDO:0020560","name":"atypical teratoid rhabdoid tumor"},"genes":[{"label":"SMARCA4","kind":"correlated"},{"label":"SMARCB1","kind":"correlated"}],"visits":3,"openQuestions":["In isogenic SMARCB1-null ATRT lines, does CHD3/CHD4 depletion phenocopy corin (shared hyper-accessibility, PARD3B induction, MYC-output loss) or is it additive — and does either state resemble or oppose PHIP loss?","Is PARD3B derepression a lethal effector in SMARCB1-null (SMARCA4-retained) cells at all, or does residual SWI/SNF activity abolish the CHD3 brake dependency?","Does PHIP depletion in ATRT models transform or expand normal murine HSPCs (PHF6-network stemness derepression), i.e. is there any survivable therapeutic window for PHIP degradation in infants?","Does an EZH2 degrader plus CNS-penetrant CDK4/6 inhibitor (abemaciclib) combination outperform either agent in orthotopic ATRT PDX, and is it tolerable in infant-equivalent models?","What is quantitative B7-H3 surface density across ATRT subgroups versus TME myeloid/endothelial B7-H3, and do differentiation-inducing epigenetic agents raise or lower it?","Does corin (or any CoREST/NuRD-directed agent) achieve pharmacologically active CNS exposure in orthotopic ATRT?"],"leads":[{"id":"L1","title":"CoREST complex inhibition (corin; bifunctional LSD1/HDAC1-2) to restore differentiation programmes in SMARCB1-deficient ATRT","mechanism":"SMARCB1-null cells retain enhancers/promoters held closed by CoREST (RCOR/LSD1/HDAC1-2); pharmacologic CoREST inhibition substitutes for lost SWI/SNF opposition, driving accessibility at neuronal/synaptic genes, differentiation and apoptosis, with RCOR2-knockdown phenocopy and desensitisation confirming on-target dependency (PMID:42479134) and subgroup-agnostic activity (PMID:41289204). Newly supported in principle: in SWI/SNF-deficient cells, removing a repressive remodeller (CHD3/NuRD) is lethal through toxic derepression rather than protective (PMID:42174139) — an independent genotype but the same directional logic [INFERRED].","approach":"Orthotopic CNS exposure/PK for corin; dose-response across ATRT-MYC/SHH/TYR with ATAC/RNA-seq differentiation PD markers; combinations with EZH2 degrader, alisertib (PMID:41289204) and radiation dose-sparing (PMID:42296837); include PARD3B and MYC-signature readouts to test whether corin and CHD3 loss converge on the same toxic-derepression programme. Window: LSD1/HDAC1-2 are needed for neurogenesis and haematopoiesis [KNOWN]; infant median age 18 months (PMID:42453193) mandates neurodevelopmental and marrow endpoints. Resistance: CoREST-independent repression (NuRD/PRC2 compensation), LSD1-independent HDAC re-silencing.","level":"LEAD","confidence":0.58,"citations":[{"kind":"PMID","id":"42479134","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41289204","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42453193","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42296837","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42174139","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":23,"lastVisit":3,"lastNote":"Directional corroboration from a new genotype: relief of chromatin repression is lethal in SWI/SNF-deficient cancer (PMID:42174139). Still no ATRT CNS PK, so no promotion.","history":[{"visit":3,"cycle":157,"status":"STRENGTHENED","note":"Directional corroboration from a new genotype: relief of chromatin repression is lethal in SWI/SNF-deficient cancer (PMID:42174139). Still no ATRT CNS PK, so no promotion."},{"visit":1,"cycle":23,"status":"NEW","note":"New this visit from PMID:42479134: first mechanism-matched epigenetic lead with genetic target validation (RCOR2 knockdown phenocopy/desensitisation) plus in vivo survival extension in orthotopic ATRT."}]},{"id":"L2","title":"Repeated intracerebroventricular B7-H3 CAR T cells for recurrent/refractory ATRT","mechanism":"B7-H3 (CD276) is expressed at high surface density on paediatric CNS embryonal tumours with limited normal-tissue expression (PMID:41073827, PMID:40801642); ICV delivery bypasses the BBB. ATRT is genomically quiet, so surface-antigen-directed cellular therapy is better matched than mutation-dependent approaches [INFERRED]. New caveat: B7-H3 is also on TME myeloid cells, abnormal tumour endothelium and CAFs, so CAR T will remodel (and be consumed by) the microenvironment, with context-dependent, partly contradictory immunobiology (PMID:41073827).","approach":"BrainChild-03 Arm B (NCT04185038) gave feasibility, no DLTs, MTD 10x10^7 CAR T/dose over 181+ infusions incl. 5 ATRT patients (PMID:42503899). Required next: quantitative flow/IHC B7-H3 surface density across ATRT-MYC/SHH/TYR primary tumours and PDX; CSF CAR persistence and cytokine kinetics in the ATRT subset; deliberate assessment of TME antigen sink and vascular on-target effect (contrast-enhancement/ADC imaging changes, endothelial injury markers); test whether differentiation-inducing epigenetic agents (corin, EZH2 degrader) raise B7-H3 density or instead reduce it. Resistance: low-density antigen escape, exhaustion, myeloid exclusion (PMID:41820710).","level":"LEAD","confidence":0.47,"citations":[{"kind":"PMID","id":"42503899","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04185038","verified":false,"isNew":false,"addedVisit":1},{"kind":"PMID","id":"41073827","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40801642","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":23,"lastVisit":2,"lastNote":"Two new independent reviews corroborate target attractiveness and low normal-tissue expression, but PMID:41073827 introduces a concrete TME antigen-sink/vascular liability. Not promoted to CANDIDATE: new citations are reviews, not ATRT-specific, and ATRT efficacy remains unreadable.","history":[{"visit":2,"cycle":78,"status":"STRENGTHENED","note":"Two new independent reviews corroborate target attractiveness and low normal-tissue expression, but PMID:41073827 introduces a concrete TME antigen-sink/vascular liability. Not promoted to CANDIDATE: new citations are reviews, not ATRT-specific, and ATRT efficacy remains unreadable."},{"visit":1,"cycle":23,"status":"NEW","note":"New this visit: first ATRT-inclusive CAR T safety dataset with a defined MTD regimen; graded LEAD not higher because ATRT-specific efficacy is not readable from the truncated abstract."}]},{"id":"L3","title":"PD-1 blockade (ONO-4538/nivolumab) in SMARCB1-deficient rhabdoid tumour","mechanism":"Proposed engageability of SWI/SNF-deficient tumours via ERV/interferon derepression remains [SPECULATIVE] and is unsupported by anything in this pack. Counter-evidence: low-TMB paediatric/adult CNS tumours are dominated by immunosuppressive myeloid microenvironments that block T-cell infiltration and drive adaptive resistance, producing scattered responses without population-level benefit (PMID:41820710, PMID:41460355).","approach":"Passive monitoring of NCT06622941 only. Do not propose ICI combinations for ATRT until ATRT-specific correlatives exist: MHC class I/B2M IHC, ERV/interferon transcriptional signature by subgroup, CD8 density and myeloid fraction. If a signature is absent, retire.","level":"LEAD","confidence":0.2,"citations":[{"kind":"NCT","id":"NCT06622941","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41289204","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41820710","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41460355","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":23,"lastVisit":2,"lastNote":"Weakened: fresh pack supplies the predicted failure mode (myeloid exclusion, low TMB) and no ATRT interferon/ERV derepression evidence. NCT06622941 remains empirical.","history":[{"visit":2,"cycle":78,"status":"WEAKENED","note":"Weakened: fresh pack supplies the predicted failure mode (myeloid exclusion, low TMB) and no ATRT interferon/ERV derepression evidence. NCT06622941 remains empirical."},{"visit":1,"cycle":23,"status":"NEW","note":"New this visit; deliberately low confidence — trial existence is the only evidence, no ATRT response data in the pack."}]},{"id":"L5","title":"DCAF5 degradation to restore residual SWI/SNF assembly in SMARCB1-deficient ATRT, with EZH2-degrader/MDM2/SINE combinations","mechanism":"DCAF5 is a DDB1-CUL4 substrate receptor performing quality control on incompletely assembled SWI/SNF; its removal permits SMARCB1-less complexes to persist and restore enhancer function [KNOWN]. Expert rhabdoid workshop ranks DCAF5 binders/degraders top priority and favours EZH2 degraders over catalytic inhibitors, with MDM2 (TP53-wild-type rhabdoid [KNOWN]) and SINE compounds as partners (PMID:41680284). New: an independent rhabdoid-kidney review reports EZH2 inhibition and CDK4/6 blockade give only proof-of-principle, modest single-agent activity with no predictive biomarkers (PMID:42358575), supporting degrader escalation and adding CDK4/6 (SMARCB1 loss derepresses cyclin D/represses p16 ","approach":"Genetic DCAF5 dependency across ATRT-MYC/SHH/TYR lines and orthotopic PDX with SWI/SNF re-assembly readouts (SMARCA4/ARID1A co-IP, ATAC at typical enhancers); benchmark EZH2 degrader vs tazemetostat in the same panel; matrices of EZH2 degrader with abemaciclib (CNS-penetrant CDK4/6i [KNOWN]) and with navtemadlin plus selinexor. Window: DCAF5 loss tolerated in murine tissue [KNOWN/INFERRED]; MDM2i limited by thrombocytopenia, selinexor by anorexia/hyponatraemia, CDK4/6i by neutropenia in infants. Resistance: RB1 loss or CCNE1 for CDK4/6, PRC2-independent silencing, EED mutation.","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"PMID","id":"41680284","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42098732","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41797932","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42358575","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":78,"lastVisit":3,"lastNote":"Second, independent rhabdoid-specific source (renal, PMID:42358575) confirms catalytic EZH2 inhibition is insufficient and adds CDK4/6 as a clinic-ready partner; DCAF5 itself still has no ATRT primary data or tool compound.","history":[{"visit":3,"cycle":157,"status":"STRENGTHENED","note":"Second, independent rhabdoid-specific source (renal, PMID:42358575) confirms catalytic EZH2 inhibition is insufficient and adds CDK4/6 as a clinic-ready partner; DCAF5 itself still has no ATRT primary data or tool compound."},{"visit":2,"cycle":78,"status":"NEW","note":"New this visit from an expert rhabdoid therapeutic-development workshop that sets a consensus target ranking; graded LEAD not higher because the pack contains no primary ATRT data for DCAF5 and no tool degrader exists. Also reframes open question 2: preferred partner is an EZH2 degrader, not tazemetostat."}]},{"id":"L6","title":"PHIP inhibition as SWI/SNF-loss synthetic lethality: weaponising NuRD-mediated promoter silencing in SMARCB1-null ATRT","mechanism":"PHIP is a selective dependency in SWI/SNF-disrupted lines, cooperating with SWI/SNF by ubiquitinating and suppressing NuRD subunits so that SWI/SNF loss plus PHIP loss causes lethal promoter silencing (PMID:41946722). Contradicting context this visit: PHIP is the obligate chromatin-loading partner of the repressor PHF6, and PHIP loss phenocopies PHF6 loss by derepressing a myeloid stemness network, converting Flt3-ITD CMML into AML (PMID:40721297). PHIP's polarity is therefore tissue-context-dependent, and systemic PHIP degradation carries a plausible leukaemogenic liability in infants on top of the Chung-Jansen haploinsufficiency floor [INFERRED].","approach":"Before any chemistry: degron PHIP depletion in SMARCB1-null ATRT vs SMARCB1-restored isogenic lines with catalytically dead rescue to test whether the ubiquitin-adaptor function is required; parallel murine HSPC assays for stemness-gene derepression and serial-replating transformation as a safety gate; measure NuRD occupancy and PHF6 target programmes in the same cells to determine which polarity dominates in ATRT.","level":"LEAD","confidence":0.34,"citations":[{"kind":"PMID","id":"41946722","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42098732","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41797932","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40721297","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":78,"lastVisit":3,"lastNote":"Weakened on new independent evidence that PHIP loss is transforming in myeloid lineage and that PHIP partners a repressor complex, contradicting the clean activator model; also directionally opposed by the CHD3 derepression-lethality result.","history":[{"visit":3,"cycle":157,"status":"WEAKENED","note":"Weakened on new independent evidence that PHIP loss is transforming in myeloid lineage and that PHIP partners a repressor complex, contradicting the clean activator model; also directionally opposed by the CHD3 derepression-lethality result."},{"visit":2,"cycle":78,"status":"NEW","note":"New this visit from a primary CRISPR screening paper; strongest fresh mechanistic match to the defining ATRT lesion, but evidence is pan-cancer SWI/SNF-disrupted lines with no ATRT model shown in the abstract, and no chemical probe exists."}]},{"id":"L7","title":"NuRD-ATPase (CHD3/CHD4) degradation as toxic-derepression synthetic lethality in SMARCB1-null ATRT","mechanism":"In SWI/SNF-deficient cancer cells, CHD3/NuRD functions as an essential epigenetic brake; CHD3 loss produces aberrant hyper-accessibility and toxic derepression of the polarity gene PARD3B, attenuation of MYC transcriptional output without MYC degradation, and tumour regression in dual SMARCA4/SMARCA2-null xenografts (PMID:42174139). Extrapolation to SMARCB1-null ATRT is [INFERRED]: ATRT retains SMARCA4 [SOMATIC anchor], so residual SWI/SNF may already buffer the brake; conversely ATRT's dependence on NuRD/CoREST-mediated repression of differentiation programmes (PMID:42479134) predicts the same gain-of-toxicity vulnerability, and MYC-output attenuation is especially attractive for ATRT-MYC.","approach":"Degron/CRISPR CHD3 and CHD4 knockdown across ATRT-MYC/SHH/TYR lines with SMARCB1-restored isogenic controls; readouts PARD3B induction, ATAC hyper-accessibility, MYC target signature, apoptosis; epistasis with corin (does CoREST inhibition phenocopy or add?) and with PHIP loss to settle the polarity question; then CHD4-directed degraders as the modality since no selective CHD3 chemical probe exists [KNOWN]. Window: CHD4/NuRD is required for haematopoiesis and neural development [KNOWN], so an infant CNS population needs intermittent-dosing and marrow/neurodevelopmental endpoints; CHD3-selective targeting may spare CHD4 functions. Resistance: PARD3B silencing by promoter methylation, CHD4 com","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42174139","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42479134","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":157,"lastVisit":3,"lastNote":"New from a primary paper with in vivo regression; graded LEAD only because the validating genotype is dual SMARCA4/SMARCA2 loss, not SMARCB1-null ATRT, and no ATRT model is shown.","history":[{"visit":3,"cycle":157,"status":"NEW","note":"New from a primary paper with in vivo regression; graded LEAD only because the validating genotype is dual SMARCA4/SMARCA2 loss, not SMARCB1-null ATRT, and no ATRT model is shown."}]}],"retired":[{"title":"Polyamine depletion (DFMO + AMXT 1501) targeting the MYC-driven ATRT subgroup","note":"Retired after two evidence-bearing visits with zero ATRT-specific preclinical support; also absent from the expert rhabdoid priority list (PMID:41680284). Recorded so the desk does not re-propose it without ODC1 dependency data.","cycle":78,"ts":"2026-08-19T18:37:35.249Z"}],"nextQueries":["(CHD4 OR CHD3 OR NuRD) AND (degrader OR PROTAC OR \"chemical probe\") AND PUB_YEAR:[2023 TO 2026] AND SRC:MED","(\"atypical teratoid\" OR rhabdoid) AND (EZH2 AND (degrader OR \"CDK4/6\" OR abemaciclib OR palbociclib)) AND PUB_YEAR:[2023 TO 2026] AND SRC:MED","(B7-H3 OR CD276) AND (\"atypical teratoid\" OR rhabdoid OR \"intracerebroventricular\") AND PUB_YEAR:[2024 TO 2026] AND SRC:MED"],"updatedAt":"2026-08-19T23:12:23.787Z"},{"key":"juvenile myelomonocytic leukemia","name":"juvenile myelomonocytic leukemia","mondo":{"id":"MONDO:0011908","name":"juvenile myelomonocytic leukemia"},"genes":[{"label":"CBL","kind":"causal"},{"label":"ARHGAP26","kind":"causal"},{"label":"PTPN11","kind":"causal"},{"label":"NF1","kind":"causal"},{"label":"NRAS","kind":"correlated"},{"label":"RRAS","kind":"correlated"},{"label":"KRAS","kind":"correlated"}],"visits":3,"openQuestions":["In JMML-only cohorts, does response to immunosuppression withdrawal or DLI differ by somatic genotype (PTPN11/NRAS/KRAS/NF1/CBL), and does pre- or post-HSCT azacitidine/decitabine or trametinib exposure change DLI response?","Does trametinib monotherapy in JMML reduce mutant VAF or only suppress counts, and what is the rebound risk on taper/discontinuation?","What is the quantified mucosal/airway toxicity rate of MEK inhibitors in RASopathy infants, and can MEK be staggered rather than combined with post-HSCT immunotherapy?","Which of the nine molecular CMML entities corresponds to the RAS-pathway/proliferative, JMML-like cluster, and is that the population enrolled in NCT07033598?","Which PTPN11 alleles beyond E76K carry the NLRP3/IL-1beta/PTGS2 signature, and do germline Noonan MPD alleles differ from somatic JMML alleles?","Is venetoclax resistance in JMML MCL-1/BCL-xL-driven, and does MEK or SHP2 pre-treatment re-prime BCL2 dependence in primary samples?"],"leads":[{"id":"L1","title":"IL-17A/NLRP3/PTGS2 inflammatory axis blockade combined with MEK inhibition in PTPN11-mutant JMML","mechanism":"Shp2E76K/+ macrophages drive IL-17A/NLRP3/caspase-1/IL-1beta maturation and PTGS2 induction, remodelling the marrow niche toward Treg expansion and T-cell exhaustion cooperatively with RAS/MAPK signalling in the clone [SOMATIC PTPN11]; MEK inhibition is independently cytoreductive in JMML (PMID:42077120), but MEK inhibitors cause severe mucosal injury in RASopathy infants (PMID:42503445), so blocking IL-17A-dependent mucosal defence on top of MEK is expected to compound airway/GI toxicity [INFERRED]","approach":"Re-specified doublet/triplet: trametinib + anakinra (short half-life, reversible IL-1beta blockade downstream of NLRP3) +/- celecoxib as the PTGS2 arm; reserve anti-IL-17A mAbs and clinical-stage NLRP3 inhibitors for non-MEK-containing arms or adult surrogates. Endpoints: GM-CSF-independent CFU output, marrow IL-1beta/IL-18, Treg fraction, CD8 cytotoxicity, plus serial NRAS/PTPN11 VAF on and off drug to test whether MEK response is suppressive with rebound (as suggested by fatal deterioration after trametinib tapering in RAF1 Noonan, PMID:42256976). Normal-tissue window: IL-1beta = innate host defence (infection risk, reversible with anakinra); PTGS2 = GI/renal prostaglandins; MEK = mucosa, ","level":"LEAD","confidence":0.58,"citations":[{"kind":"PMID","id":"42233403","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42077120","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42503445","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42256976","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":25,"lastVisit":2,"lastNote":"Backbone strengthened (first pack evidence of trametinib monotherapy response in JMML without HSCT) but the triplet as designed is weakened: airway mucosal sloughing/supraglottic scarring on trametinib in a Noonan infant makes IL-17A blockade the wrong partner; swapped to reversible IL-1beta blockade. Withdrawal-rebound risk newly flagged.","history":[{"visit":2,"cycle":79,"status":"WEAKENED","note":"Backbone strengthened (first pack evidence of trametinib monotherapy response in JMML without HSCT) but the triplet as designed is weakened: airway mucosal sloughing/supraglottic scarring on trametinib in a Noonan infant makes IL-17A blockade the wrong partner; swapped to reversible IL-1beta blockade. Withdrawal-rebound risk newly flagged."},{"visit":1,"cycle":25,"status":"NEW","note":"New this visit from P6; only JMML-specific paper in pack with both mouse survival benefit and primary-patient ex vivo activity, and every component has an approved or clinical-stage agent."}]},{"id":"L2","title":"Monocytic/RAS-driven BCL2-family rewiring predicts venetoclax failure in JMML; MCL-1/BCL-xL-directed priming plus MAPK blockade","mechanism":"RAS-mutant leukemia stem cells in granulocyte-monocyte progenitors shift apoptotic dependence from BCL2 to MCL-1/BCL2L1, conferring venetoclax resistance (PMID:42087923); JMML is definitionally RAS-driven and monocytic, so the same shift is predicted [INFERRED].","approach":"BH3 profiling and MCL1/BCL2L1/BCL2 protein in primary JMML by genotype, with MEK or SHP2 pre-treatment to test BCL2 re-priming before venetoclax; direct MCL-1 inhibition limited by cardiotoxicity [KNOWN]. Assay feasibility de-risked: a validated thaw protocol gives >80% post-thaw viability, 55.6% recovery and preserved CFU/immunophenotype in fragile monocyte-rich CMML/AML mononuclear cells (PMID:42305129) — adopt it for cryopreserved JMML biobank material. Watch NCT05600894 for venetoclax+ASTX727 in CMML.","level":"LEAD","confidence":0.44,"citations":[{"kind":"PMID","id":"42087923","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05600894","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42305129","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":25,"lastVisit":3,"lastNote":"Methodological only — no new biology. The rate-limiting step for this lead was viable primary monocyte-rich samples for BH3 profiling; that is now addressed. Confidence moved minimally and deliberately.","history":[{"visit":3,"cycle":158,"status":"STRENGTHENED","note":"Methodological only — no new biology. The rate-limiting step for this lead was viable primary monocyte-rich samples for BH3 profiling; that is now addressed. Confidence moved minimally and deliberately."},{"visit":1,"cycle":25,"status":"NEW","note":"New from P10; framed primarily as a de-risking/negative-prediction lead (naked venetoclax should fail in JMML) rather than a ready combination."}]},{"id":"L3","title":"Hypomethylating agent selection (decitabine vs azacitidine) as a modifiable pre-HSCT variable in JMML","mechanism":"HMAs debulk pre-transplant disease; agent choice may matter for CR, extramedullary coverage (azacitidine cleared bilateral testicular JMML infiltration, PMID:42568796) and now for immune priming — low-dose decitabine monotherapy raised NKT-like cells from 3.5% to 4.25% (p=0.035) with no Treg or CD8 change in chronic myeloid neoplasms (PMID:41908667), suggesting HMAs modulate innate-like effectors without correcting the Treg-dominated niche [INFERRED, n=12, 1 CMML].","approach":"Add an immune arm to the planned JMML-only registry extraction: for DAC vs AZA, record CR, extramedullary sites (testis/skin/CNS), post-HSCT relapse, and where samples exist, pre/post NKT-like, Treg and CD8 fractions; ask whether HMA-primed patients respond better to subsequent DLI/immunosuppression withdrawal (links to the new GvL lead). Pair HMA with venetoclax only where BH3 dependence is proven (PMID:41204420, L2).","level":"LEAD","confidence":0.38,"citations":[{"kind":"PMID","id":"42393761","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42568796","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41204420","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41908667","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":25,"lastVisit":3,"lastNote":"Small, orthogonal strengthening: decitabine now has a candidate immunologic mechanism (NKT-like expansion) that reframes agent choice as debulk-plus-prime; still no JMML-specific comparative data, so confidence rises only marginally.","history":[{"visit":3,"cycle":158,"status":"STRENGTHENED","note":"Small, orthogonal strengthening: decitabine now has a candidate immunologic mechanism (NKT-like expansion) that reframes agent choice as debulk-plus-prime; still no JMML-specific comparative data, so confidence rises only marginally."},{"visit":2,"cycle":79,"status":"WEAKENED","note":"Weakened: the decitabine-superiority framing loses ground because azacitidine bridged an NRAS JMML to molecular remission; reframed around agent choice plus a newly recognised sanctuary-site question."},{"visit":1,"cycle":25,"status":"NEW","note":"New from P4; abstract does not resolve the JMML-specific DAC/AZA split, so the lead is a data-extraction and biomarker question, not yet a therapeutic claim."}]},{"id":"L4","title":"Humanized NF1-LOF HSPC model enables synthetic-lethal screening for the undruggable 20% of JMML","mechanism":"CRISPR NF1 knockout (~89%) in human cord-blood HSPCs reproduces GM-CSF hypersensitivity and lethal myeloid expansion with RAS/MAPK/PI3K upregulation in NSG-SGM3 mice; independently, in vivo CRISPR screening shows Nf1 loss confers clonal dominance amplified by secondary transplantation, consistent with tumour-suppressor loss driving stem-cell-level maintenance [GERMLINE for predisposing NF1, SOMATIC second hit in JMML]","approach":"Use the humanized NF1-LOF model as the platform for vertical pathway blockade (MEK + PI3K/mTOR, or SHP2 + MEK) and for pooled CRISPR synthetic-lethal screens seeking NF1-LOF-selective dependencies; NF1 itself is not directly druggable, so the deliverable is a dependency list, not a drug.","level":"LEAD","confidence":0.38,"citations":[{"kind":"PMID","id":"41201956","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42220553","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":25,"lastVisit":1,"lastNote":"New from P2+P7; enabling-model lead with two independent citations but no therapeutic read-out yet.","history":[{"visit":1,"cycle":25,"status":"NEW","note":"New from P2+P7; enabling-model lead with two independent citations but no therapeutic read-out yet."}]},{"id":"L6","title":"Pacritinib as a dual GM-CSF/JAK2-STAT5 and IL-1R/IRAK1 node inhibitor in JMML","mechanism":"GM-CSF hypersensitivity signals through JAK2-STAT5; the L1 inflammasome arm signals IL-1beta -> IL-1R -> IRAK1 -> NF-kB. Pacritinib inhibits JAK2, IRAK1 and ACVR1 [KNOWN], potentially collapsing both arms without a second agent's mucosal toxicity [INFERRED]. Interpretability of the adult surrogate improved: CMML now resolves into nine genomic entities with distinct outcomes across 3,013 training and 516 validation patients (PMID:41894646), so the 'advanced proliferative CMML' population of NCT07033598 can be mapped onto a molecularly defined, RAS-enriched cluster before any read-across to JMML [INFERRED].","approach":"Determine which of the nine CMML entities the proliferative/pacritinib population occupies and whether it is RAS-pathway-enriched; only then treat T4 as a JMML surrogate. In parallel, pacritinib +/- trametinib on primary JMML mononuclear cells (thawed by the validated high-viability protocol, PMID:42305129) for GM-CSF-independent CFU suppression, pSTAT5, IL-1beta/IL-18 release, NLRP3 priming; then Shp2E76K/+ and NRAS-G12D mice. Normal tissue: JAK2 inhibition -> cytopenias (pacritinib comparatively platelet-sparing [KNOWN]); IRAK1/ACVR1 -> innate immunity, hepcidin. Resistance: STAT5-independent MAPK output.","level":"LEAD","confidence":0.42,"citations":[{"kind":"NCT","id":"NCT07033598","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42233403","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41894646","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42305129","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":79,"lastVisit":3,"lastNote":"Surrogate-selection logic and assay feasibility improved; mechanism unchanged. Explicitly noted: a targeted query for pacritinib/IRAK1/GM-CSF hypersensitivity in JMML/CMML returned no mechanistic paper, so this lead remains pharmacology-plus-trial only.","history":[{"visit":3,"cycle":158,"status":"STRENGTHENED","note":"Surrogate-selection logic and assay feasibility improved; mechanism unchanged. Explicitly noted: a targeted query for pacritinib/IRAK1/GM-CSF hypersensitivity in JMML/CMML returned no mechanistic paper, so this lead remains pharmacology-plus-trial only."},{"visit":2,"cycle":79,"status":"NEW","note":"New from the trial set this visit; chosen because it is the only agent in the pack that hits two independent arms of the existing programme (GM-CSF/JAK2 hypersensitivity and IL-1R/IRAK1) with a running phase 2 read-out in a monocytic surrogate disease."}]},{"id":"L7","title":"Allele-resolved PTPN11 variant-to-phenotype map as the stratifier for SHP2 vs MEK vs inflammasome-directed therapy","mechanism":"Multiplexed single-cell transcriptomics of clinically diverse SHP2 variants shows that catalytically dead variants do not phenocopy PTPN11 knockout, that mechanistically distinct mutations can converge, and that different substitutions at the same hotspot residue yield divergent cell states (PMID:42172315). My inflammatory-axis evidence derives from a single allele (E76K), so genotype-blind extrapolation across PTPN11-mutant JMML and germline Noonan MPD is unsafe [INFERRED]","approach":"Map JMML-recurrent somatic alleles (E76K/E76A/D61Y/A72V/E69K) and germline Noonan alleles (D61G, E139D, Y279C) onto the published variant-phenotype framework; ask which alleles carry the NLRP3/IL-1beta/PTGS2 inflammatory signature versus pure MAPK output, and whether allosteric SHP2 inhibitors (which require the closed autoinhibited conformation) are predicted to fail on specific alleles. Deliverable is a stratification rule, not a drug. Note germline PTPN11 alleles also cause non-haematologic disease including severe hearing loss (PMID:41862719), evidence that these alleles act pleiotropically in normal tissue and defining the systemic window.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42172315","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41862719","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":79,"lastVisit":2,"lastNote":"New this visit; directly addresses open question 1 (does the E76K inflammatory axis generalise) by providing the assay framework rather than the answer.","history":[{"visit":2,"cycle":79,"status":"NEW","note":"New this visit; directly addresses open question 1 (does the E76K inflammatory axis generalise) by providing the assay framework rather than the answer."}]},{"id":"L8","title":"RAS-genotype-blunted graft-versus-leukemia: pharmacologically augmented DLI/immunosuppression-withdrawal for post-HSCT JMML relapse","mechanism":"Post-HSCT relapse is the dominant failure mode in JMML and is conventionally salvaged by immunosuppression withdrawal or DLI [KNOWN]. In 62 myeloid-malignancy patients given DLI, therapeutic DLI produced CR/CRi in only 29% (median OS 6 months) and KRAS/NRAS/JAK2 mutations were associated with adverse outcome (PMID:42258587), implying RAS/MAPK-driven clones resist alloreactive T-cell pressure — plausibly via monocytic differentiation, IL-1beta/PTGS2-mediated Treg expansion and CD8 exhaustion described for Shp2E76K niches (PMID:42233403) [INFERRED]. Low-dose decitabine alone expands peripheral NKT-like cells without altering Tregs (PMID:41908667), offering an immune-priming rather than niche-c","approach":"JMML-only retrospective: response and OS after immunosuppression withdrawal vs DLI stratified by somatic genotype (PTPN11/NRAS/KRAS/NF1/CBL) and by pre-HSCT HMA exposure. Prospective concept: trametinib or azacitidine given with/before DLI or during targeted tacrolimus taper (NCT07302776) with serial VAF/chimerism, marrow Treg:CD8 ratio and NKT-like fraction as pharmacodynamic read-outs. Normal tissue/window: DLI risks GvHD; MEK inhibition risks mucosal and airway injury in RASopathy infants (PMID:42503445), which may be aggravated by concurrent GvHD — dose-staggering, not concurrency, is the safer design. Resistance routes: MAPK reactivation, clonal loss of HLA/antigen after DLI [KNOWN].","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"42258587","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41908667","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42233403","verified":true,"isNew":false,"addedVisit":3},{"kind":"PMID","id":"42503445","verified":true,"isNew":false,"addedVisit":3},{"kind":"NCT","id":"NCT07302776","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":158,"lastVisit":3,"lastNote":"New from P7+P2. First pack evidence that RAS-pathway genotype specifically predicts poor DLI outcome; caveat is a retrospective adult cohort with only 3 CMML patients and RAS not deconvoluted from TP53/complex karyotype.","history":[{"visit":3,"cycle":158,"status":"NEW","note":"New from P7+P2. First pack evidence that RAS-pathway genotype specifically predicts poor DLI outcome; caveat is a retrospective adult cohort with only 3 CMML patients and RAS not deconvoluted from TP53/complex karyotype."}]}],"retired":[{"title":"CD69 blockade to reverse Treg-dominated marrow niche in RAS-mutant myelomonocytic leukemia","note":"Retired per the rule set last visit: species- and disease-mismatched, and no corroborating JMML evidence this visit. Recorded so the desk does not re-propose anti-CD69 without human JMML marrow immunophenotyping first.","cycle":79,"ts":"2026-08-19T18:41:21.558Z"}],"nextQueries":["\"juvenile myelomonocytic leukemia\" AND (relapse OR \"donor lymphocyte\" OR \"immunosuppression withdrawal\" OR \"second transplant\" OR azacitidine maintenance) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(trametinib OR selumetinib) AND (\"juvenile myelomonocytic\" OR RASopathy) AND (\"variant allele frequency\" OR \"molecular response\" OR chimerism OR discontinuation) AND SRC:MED","PTPN11 AND (E76K OR D61Y OR allele OR variant) AND (NLRP3 OR \"IL-1\" OR inflammasome OR PTGS2 OR macrophage) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"updatedAt":"2026-08-19T23:15:51.746Z"},{"key":"uveal melanoma","name":"uveal melanoma","mondo":{"id":"MONDO:0006486","name":"uveal melanoma"},"genes":[{"label":"BAP1","kind":"correlated"},{"label":"CYSLTR2","kind":"correlated"},{"label":"GNAQ","kind":"correlated"},{"label":"GNA11","kind":"correlated"},{"label":"SF3B1","kind":"correlated"}],"visits":3,"openQuestions":["Does STREAM show any OS benefit or ITT (pre-randomisation) PFS advantage for sorafenib, and is the GNAQ/GNA11 ctDNA-poor-prognosis subgroup the one that benefits or the one that fails?","Is there any efficacy or ocular/pigmentary toxicity readout for DYP688 (PMEL17-FR900359 ADC) in humans, and does the short-half-life design translate into responses after darovasertib?","In paired pre/post-hepatic-perfusion biopsies, does melphalan raise MHC-I and gp100/PRAME expression and T-cell infiltration — i.e. is 'immunogenic debulking' real or just burden reduction?","Does any independent dataset beyond PMID:42322017 report ASS1 loss frequency or arginine-deprivation sensitivity in UM organoids or metastases (kill/keep decision for L5)?","In post-tebentafusp progression biopsies, what is the relative frequency of HLA-haplotype loss vs B2M/antigen-presentation defects vs gp100 downregulation, and does week-12 ctDNA non-clearance flag it prospectively?","Has the CoMpass phase 3 (NCT06007690) or its long-term follow-up (NCT07338968) reported any metastasis-free-survival signal for bel-sar primary ablation?"],"leads":[{"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","mechanism":"Gq->PLCbeta->DAG->PKC with RASGRP3/MAPK and Gq-independent YAP/TAZ output [SOMATIC; KNOWN]; proximal PKC blockade avoids the MEK bypass that sank distal inhibition (PMID:42108204, NCT01979523). DYP688 attacks the same node via PMEL17-directed delivery of the Gq inhibitor FR900359; QSP/PK modelling shows the payload is transiently inactivated on-antibody in plasma, so a SHORT antibody half-life is optimal and efficacy tracks AUC above a tumourostatic concentration, with interim clinical PK matching prediction (PMID:39690276) — developability supported, efficacy still unknown. Baseline GNAQ/GNA11-mutant ctDNA marks inferior outcome (PMID:41362626), giving a backbone-agnostic pharmacodynamic re","approach":"Organoid triage of darovasertib + TEAD palmitoylation inhibitor vs darovasertib + crizotinib (PMID:41798271) vs darovasertib + low-dose sorafenib (CRAF/VEGFR, PMID:41362626), stratified by sequencing-confirmed BAP1/chr3 status not IHC (PMID:42073538); serial GNAQ/GNA11 ctDNA as the shared pharmacodynamic endpoint; keep MEK+AKT permanently excluded (NCT01979523). For DYP688, demand ORR and ocular/pigmentary AE data before any combination design.","level":"CANDIDATE","confidence":0.7,"citations":[{"kind":"PMID","id":"42108204","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42290218","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT01979523","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41798271","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42073538","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42020098","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39690276","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41362626","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":26,"lastVisit":3,"lastNote":"PMID:39690276 [NEW] gives the first quantitative developability case for DYP688 (transient payload inactivation, short-half-life design, PK translation confirmed) but no efficacy; PMID:41362626 [NEW] adds a RAF/VEGFR partner candidate and validates GNAQ/GNA11 ctDNA as a backbone-agnostic stratifier. Held at CANDIDATE — the darovasertib backbone itself gained no new outcome data.","history":[{"visit":3,"cycle":159,"status":"STRENGTHENED","note":"PMID:39690276 [NEW] gives the first quantitative developability case for DYP688 (transient payload inactivation, short-half-life design, PK translation confirmed) but no efficacy; PMID:41362626 [NEW] adds a RAF/VEGFR partner candidate and validates GNAQ/GNA11 ctDNA as a backbone-agnostic stratifier. Held at CANDIDATE — the darovasertib backbone itself gained no new outcome data."},{"visit":2,"cycle":80,"status":"STRENGTHENED","note":"PMID:41798271 [NEW] independently corroborates the darovasertib backbone (NADOM neoadjuvant/adjuvant; darovasertib+crizotinib metastatic) and adds DYP688 as a second Gq-node modality; PMID:42073538 [NEW] forces replacement of BAP1 IHC with sequencing for stratification."},{"visit":1,"cycle":26,"status":"NEW","note":"New. PMID:42108204 [NEW] shows darovasertib alone retained activity as a clinical-signal-matched positive control while selumetinib, selumetinib+MK-2206, sotrastaurin+alpelisib and trametinib lost activity in patient-derived lines/organoids, mirroring their clinical failure; NCT01979523 (trametinib +/- uprosertib) recorded as a dead MEK/AKT branch."}]},{"id":"L2","title":"Next-generation ImmTAC/T-cell engagers plus innate priming for HLA-A*02:01-negative and post-tebentafusp metastatic UM","mechanism":"Tebentafusp redirects polyclonal T cells to gp100(280-288)/HLA-A*02:01; acquired resistance includes documented loss of the haplotype carrying the restriction element (PMID:42165161), so any pHLA engager (incl. PRAME/brenetefusp) is hostage to the same class I machinery [INFERRED]. Class ceiling ORR 5-12%, mOS 16.0->21.7 mo, benefit tracked by early rash and week-12 ctDNA clearance (PMID:41598579); tebentafusp remains the only approved systemic advance (PMID:40380030). The liver is a mechanistically distinct compartment — hepatic detoxification plus a tolerogenic innate/peripheral immune landscape and distinct LMUM growth patterns explain ICI/targeted failure there (PMID:41160198), arguing t","approach":"Serial ctDNA plus HLA/B2M genotyping at progression to classify escape (haplotype loss vs antigen downregulation vs exhaustion); haplotype-loss patients to non-pHLA modalities (TIL, oncolytic virus, PMEL17-ADC), antigen-loss patients to PRAME ImmTAC matched to the retained allele; prospectively test engager + hepatic melphalan sequencing and engager + TLR7 agonist (MBS8, NCT04855435) for cold liver lesions.","level":"CANDIDATE","confidence":0.7,"citations":[{"kind":"PMID","id":"42163062","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41700001","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41542910","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04855435","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42165161","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41598579","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41964902","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41798271","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41160198","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41795199","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":26,"lastVisit":3,"lastNote":"PMID:41160198 [NEW] supplies the hepatic-TME mechanism for the class ceiling; PMID:41795199 [NEW] shows concurrent chemosaturation + engager/ICI is tolerable with high hepatic control (n=10, retrospective). Deliberately NOT promoted to DOSSIER: this visit's additions are a review and a 10-patient series, not independent efficacy data.","history":[{"visit":3,"cycle":159,"status":"STRENGTHENED","note":"PMID:41160198 [NEW] supplies the hepatic-TME mechanism for the class ceiling; PMID:41795199 [NEW] shows concurrent chemosaturation + engager/ICI is tolerable with high hepatic control (n=10, retrospective). Deliberately NOT promoted to DOSSIER: this visit's additions are a review and a 10-patient series, not independent efficacy data."},{"visit":2,"cycle":80,"status":"STRENGTHENED","note":"PMID:42165161 [NEW] converts the predicted HLA-loss escape route from [INFERRED] to documented human genomic evidence; PMID:41598579 and PMID:41964902 [NEW] quantify the class ceiling and the engineering/combination menu. Promoted on new independent evidence."},{"visit":1,"cycle":26,"status":"NEW","note":"New. PMID:42163062 [NEW] product review confirms class validation and names brenetefusp; PMID:41700001 and PMID:41542910 [NEW] frame the format landscape and the unresolved solid-tumour activity bottleneck; NCT04855435 supplies a TLR7-agonist priming partner."}]},{"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","mechanism":"HSPG-avid virus-like particle carrying a phthalocyanine payload, activated by infrared laser after suprachoroidal injection, causing acute tumour-cell membrane disruption; such necrotic/immunogenic cell death could in principle prime systemic anti-melanoma immunity in addition to eradicating the primary [SPECULATIVE for the immune component]. Therapeutic window derives from selective HSPG binding by tumour cells and spatial confinement of laser activation, sparing retina/optic nerve.","approach":"Track the randomised phase 3 (bel-sar vs sham) readout for vision preservation and local control, and use the long-term follow-up cohort to ask whether metastasis-free survival differs — i.e. whether primary-tumour ablation with an immunogenic modality changes seeding rather than only local outcome.","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT06007690","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07338968","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":26,"lastVisit":1,"lastNote":"New. Both trials [NEW] this visit; a rare randomised, sham-controlled programme in early choroidal melanoma, so the readout is programme-relevant regardless of direction.","history":[{"visit":1,"cycle":26,"status":"NEW","note":"New. Both trials [NEW] this visit; a rare randomised, sham-controlled programme in early choroidal melanoma, so the readout is programme-relevant regardless of direction."}]},{"id":"L4","title":"MIAT/miR-4306/CXCR4 oxidative-stress survival axis as a repurposing handle (CXCR4 antagonism plus ROS induction)","mechanism":"lncRNA MIAT is upregulated in UM and sponges miR-4306, derepressing CXCR4, which protects cells from oxidative stress and apoptosis (PMID:42067178). CXCR4/CXCL12 also plausibly mediates hepatotropic homing [KNOWN, not shown here]. Normal tissue: CXCR4 is essential for HSC retention and B-lymphopoiesis, so antagonism is mobilising and time-limited rather than chronic.","approach":"Validate CXCR4 dependence in patient-derived UM organoids (not commercial lines) under ROS stress; test plerixafor/motixafortide combined with a ROS-inducing agent or with PKC inhibition; require in vivo hepatic-metastasis data before advancing.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42067178","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":26,"lastVisit":1,"lastNote":"New but deliberately low confidence: cell-line and bioinformatic evidence only, no animal data, and PMID:42108204 warns that commercial-line results in UM overestimate efficacy.","history":[{"visit":1,"cycle":26,"status":"NEW","note":"New but deliberately low confidence: cell-line and bioinformatic evidence only, no animal data, and PMID:42108204 warns that commercial-line results in UM overestimate efficacy."}]},{"id":"L5","title":"Arginine auxotrophy (ASS1 loss) as a liver-directed synthetic lethality: pegargiminase plus hepatic melphalan via Fanconi-anaemia pathway suppression","mechanism":"ASS1-deficient UM is arginine-auxotrophic [SOMATIC]; pegargiminase downregulates Fanconi-anaemia genes, impairing interstrand crosslink repair and synergising with melphalan for DSB accumulation in ASS1-null lines (PMID:42322017). The delivery route now looks combinable rather than prohibitive: PHP/chemosaturation cytopenias are the dominant toxicity but are transient, with ROTEM showing only ~11% loss of maximum clot firmness and no clinically relevant bleeding (PMID:41834299), and standardised peri-procedural protocols exist (PMID:42555789); systemic agents have already been co-administered within +/-40 days of chemosaturation (PMID:41795199). Resistance: ASS1 re-expression/promoter demeth","approach":"Confirm ASS1 loss by methylation/IHC in patient-derived organoids (not commercial 2D lines, PMID:42108204); gammaH2AX/RAD51 foci and FA-gene readouts with ADI-PEG20 + melphalan; hepatic-metastasis xenografts; only then a phase 1 with staggered dosing designed around documented PHP nadir kinetics, using a Bayesian hybrid control (PMID:42317800) for feasibility.","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"42322017","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42108204","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42020098","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41834299","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42555789","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41795199","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42317800","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":80,"lastVisit":3,"lastNote":"Delivery/haematologic feasibility strengthened by [NEW] PHP toxicity data; the BIOLOGY was not corroborated — a targeted ASS1/arginine-deprivation query returned zero independent papers. Kill rule set: if the next dedicated query is again empty, retire L5.","history":[{"visit":3,"cycle":159,"status":"STRENGTHENED","note":"Delivery/haematologic feasibility strengthened by [NEW] PHP toxicity data; the BIOLOGY was not corroborated — a targeted ASS1/arginine-deprivation query returned zero independent papers. Kill rule set: if the next dedicated query is again empty, retire L5."},{"visit":2,"cycle":80,"status":"NEW","note":"New from PMID:42322017 [NEW]; deliberately capped at 0.4 because evidence is 2D ASS1-deficient cell lines only and our own visit-1 finding (PMID:42108204) is that commercial UM lines overestimate efficacy."}]},{"id":"L6","title":"BAP1-loss nutrient-stress adaptation (mTORC1/p70S6K1 suppression, NF-kB-dependent immune coldness) as a metabolic and immunological vulnerability","mechanism":"BAP1 inactivation [SOMATIC] is reported to enforce a low-metabolic state by inhibiting mTORC1/p70S6K1, allowing survival under nutritional stress during hepatic seeding, and to reprogramme adhesion molecules while suppressing NF-kB, building an immunosuppressive microenvironment (PMID:41766295). Two testable consequences: (i) a quiescent, mTORC1-low cell may be either hypersensitive or refractory to antimetabolite stress such as arginine deprivation, and (ii) NF-kB restoration or innate agonism could reverse the cold niche [SPECULATIVE]. Normal tissue: BAP1 is a broadly expressed deubiquitinase and germline loss causes a tumour-predisposition syndrome [GERMLINE], so BAP1 itself is not the ta","approach":"In sequencing-confirmed BAP1-null vs BAP1-wildtype patient-derived organoids, measure survival under amino-acid/arginine withdrawal and glucose limitation, and profile mTORC1 (p-p70S6K1) and NF-kB target output; test whether TLR7 agonism (MBS8) or HDAC inhibition restores NF-kB-dependent antigen presentation. Do not use BAP1 IHC alone to assign genotype (PMID:42073538).","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"41766295","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42073538","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42322017","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT04855435","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":80,"lastVisit":2,"lastNote":"New, low confidence: derived from a review's secondary description (PMID:41766295 [NEW]) rather than primary data we can read; created mainly because it intersects testably with the new arginine-deprivation branch and with BAP1 stratification.","history":[{"visit":2,"cycle":80,"status":"NEW","note":"New, low confidence: derived from a review's secondary description (PMID:41766295 [NEW]) rather than primary data we can read; created mainly because it intersects testably with the new arginine-deprivation branch and with BAP1 stratification."}]},{"id":"L7","title":"Sorafenib (CRAF/VEGFR/PDGFR) as a repurposed maintenance backbone in mUM, with GNAQ/GNA11 ctDNA stratification","mechanism":"STREAM randomised 78 of 147 treatment-naive mUM patients with SD after a 56-day sorafenib run-in to blinded sorafenib vs placebo: mPFS 5.5 vs 1.9 months, HR 0.53, p=0.0083, well tolerated (PMID:41362626). Sorafenib inhibits CRAF/BRAF, VEGFR2/3, PDGFR-beta and KIT [KNOWN], plausibly acting both on the RAF node downstream of Gq->PKC->RASGRP3->MAPK [INFERRED] and on the hepatic angiogenic/stromal compartment that sustains LMUM (PMID:41160198). Baseline GNAQ/GNA11-mutant ctDNA predicted inferior outcome, identifying a high-risk stratum. Design caveats are decisive: randomised-discontinuation architecture enriches for run-in responders, PFS is measured from randomisation, and no OS benefit is rep","approach":"Reanalyse/request the full STREAM population for ITT PFS and OS from run-in start, and the GNAQ/GNA11 ctDNA-stratified subsets; preclinically test darovasertib + sorafenib (or a selective RAF/pan-RAF agent) in patient-derived UM organoids for ERK-rebound suppression and tolerability-relevant on-target overlap; if additive, design a Bayesian hybrid-controlled randomised phase 2 (PMID:42317800) of PKC inhibitor +/- antiangiogenic maintenance, excluding patients on concurrent hepatic perfusion until bleeding/wound-healing risk is bounded (PMID:41834299).","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"41362626","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41160198","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42317800","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41834299","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42108204","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":159,"lastVisit":3,"lastNote":"New from PMID:41362626 [NEW] — the only placebo-controlled positive randomised oral-agent signal in mUM in this programme. Capped at 0.45 because the discontinuation design measures maintenance benefit in a run-in-enriched population with no reported OS gain.","history":[{"visit":3,"cycle":159,"status":"NEW","note":"New from PMID:41362626 [NEW] — the only placebo-controlled positive randomised oral-agent signal in mUM in this programme. Capped at 0.45 because the discontinuation design measures maintenance benefit in a run-in-enriched population with no reported OS gain."}]},{"id":"L8","title":"Hepatic melphalan (PHP/chemosaturation) as immunogenic debulking combined with systemic immunotherapy, enabled by hybrid-Bayesian trial design","mechanism":"Liver-directed melphalan achieves high hepatic control but does not address extrahepatic seeding, while systemic ICI/engagers are blunted by the tolerogenic, detoxifying hepatic TME and distinct LMUM growth patterns (PMID:41160198, PMID:40380030). Concurrent delivery (systemic ICI or tebentafusp within +/-40 days of chemosaturation) gave hepatic control in 10/10 and PR in 7/10 with pancytopenia as the principal toxicity (PMID:41795199), consistent with tumour-burden reduction plus alkylator-induced immunogenic cell death releasing gp100/PRAME antigen for engager-redirected T cells [SPECULATIVE for the immunogenic component]. Haematologic risk is bounded: PHP thrombocytopenia is transient (na","approach":"Prospective sequencing study: PHP with tebentafusp or anti-PD-1 given at a defined interval, primary endpoints hepatic PFS and extrahepatic PFS separately, with paired pre/post-PHP biopsies for MHC-I, gp100/PRAME expression and T-cell infiltration, plus ctDNA kinetics (GNAQ/GNA11, PMID:41362626) as the early readout; power it as a Bayesian hybrid-controlled RCT borrowing best-alternative-care PFS priors (PMID:42317800, ~28% sample-size reduction); use viscoelastic assays rather than prophylactic platelet transfusion for safety monitoring.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"41795199","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41834299","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42555789","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41160198","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42317800","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40380030","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41362626","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":159,"lastVisit":3,"lastNote":"New this visit from four [NEW] locoregional papers that together convert 'melphalan + immunotherapy' from an assumed toxicity clash into a bounded, testable schedule; capped at 0.4 because the only efficacy data are 10 retrospective patients and the immunogenic-death mechanism is unmeasured.","history":[{"visit":3,"cycle":159,"status":"NEW","note":"New this visit from four [NEW] locoregional papers that together convert 'melphalan + immunotherapy' from an assumed toxicity clash into a bounded, testable schedule; capped at 0.4 because the only efficacy data are 10 retrospective patients and the immunogenic-death mechanism is unmeasured."}]}],"retired":[],"nextQueries":["\"uveal melanoma\" AND (sorafenib OR lenvatinib OR \"multikinase inhibitor\" OR antiangiogenic OR VEGFR) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"uveal melanoma\" OR \"ocular melanoma\") AND (\"percutaneous hepatic perfusion\" OR chemosaturation OR \"hepatic perfusion\") AND (tebentafusp OR immunotherapy OR \"checkpoint inhibitor\" OR \"immunogenic cell death\") AND SRC:ME","(\"uveal melanoma\" OR \"metastatic uveal melanoma\") AND (DYP688 OR \"FR900359\" OR PMEL17 OR ASS1 OR \"arginine deiminase\" OR pegargiminase) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-19T23:19:50.305Z"},{"key":"chordoma","name":"chordoma","mondo":{"id":"MONDO:0008978","name":"chordoma"},"genes":[{"label":"BRCA2","kind":"correlated"},{"label":"PALB2","kind":"correlated"},{"label":"TBXT","kind":"correlated"}],"visits":3,"openQuestions":["Which combination converts CDK4/6i cytostasis into cytoreduction in p16-null chordoma — CDK2/cyclin E co-inhibition, EPRS/ISR amplification, mTOR, or EGFR-TKI — and does cyclin E1/CDK2 activity rise in the palbociclib-treated biopsies from ","Does auceliciclib or another brain-penetrant CDK4/6i achieve clival tumour exposure sufficient for pRB suppression, and can a chordoma cohort be appended to its phase IIa framework?","Is the EPHA2-LYN-OGT-NICD1 axis druggable with an acceptable window in vivo — does dasatinib or intermittent OGT inhibition reduce post-resection recurrence in orthotopic chordoma models, and is the dependency confined to recurrent/stiff-ad","Do ERS-CAF-high chordomas show quantitatively reduced intratumoural CD8 density, and does IL-6R or TGF-beta/ITGB1 blockade increase T-cell penetration into fibrotic zones in chordoma explants?","Is the chordoma ATF4-DDIT3/EPRS dependency reproducible with a second chemotype and orthogonal knockdown, and what halofuginone dose is tolerable with particle radiotherapy?","Are BRCA2/PALB2 alterations in chordoma germline or somatic, with functional HR deficiency (RAD51 foci/HRDetect) exploitable under LETd-escalated particle therapy?"],"leads":[{"id":"L1","title":"TBXT (brachyury) lineage addiction: degraders, covalent binders, peptide-centric CAR-T","mechanism":"TBXT remains the pathognomonic notochordal TF sustaining chordoma identity with near-absent adult normal expression, approached by covalent ligands, targeted degradation and TCR-mimic CAR-T against HLA-presented TBXT epitopes. However, TBXT-directed clinical outcomes are described as underexplored or modest, and chordoma-lethal screening hits can act entirely independently of TBXT, indicating the addiction may be incomplete or bypassable.","approach":"Demand in vivo regression data before further investment: TBXT degrader chemistry (including oligonucleotide-based PROTAC designs exploiting the TF's DNA-binding surface) and peptide-centric CAR-T in TBXT-high PDX, with paired TBXT protein-degradation pharmacodynamics. Treat in silico-only ligands as non-evidence. Resistance readouts: TBXT-low mesenchymal drift, HLA-I loss, TBX2/4 compensation.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42571860","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42448412","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41319040","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41713321","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41419749","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":27,"lastVisit":2,"lastNote":"Weakened: new primary work states TBXT-directed clinical results are modest and finds TBXT-independent lethality; the only new TBXT chemistry in the pack is docking/MD with no cellular validation.","history":[{"visit":2,"cycle":81,"status":"WEAKENED","note":"Weakened: new primary work states TBXT-directed clinical results are modest and finds TBXT-independent lethality; the only new TBXT chemistry in the pack is docking/MD with no cellular validation."},{"visit":1,"cycle":27,"status":"NEW","note":"New programme. Two 2026 reviews converge on TBXT as the primary vulnerability and enumerate three modality classes; review-level only, no new primary efficacy data, hence LEAD not CANDIDATE."}]},{"id":"L2","title":"Copy-number cluster-directed therapy: CDK4/6 inhibition in chr9/CDKN2A-loss (C9), GLI/SHH blockade in chr2+chr7-gain (C2)","mechanism":"p16 loss (33% of chordoma) releases CDK4/6-cyclin D and predicts RB1-dependent CDK4/6i sensitivity [SOMATIC]. Prospective testing in the exact biomarker-selected population (p16/CDKN2A loss, CDK4/6 and RB1 retained) gave DCR 39% with zero objective responses and mPFS 5.6 months (PMID:40627883), showing Rb-pathway arrest is tolerated without apoptosis; a parallel survival input (CDK2/cyclin E, mTOR, ISR buffering) is implied [INFERRED].","approach":"Abandon single-agent CDK4/6i in chordoma. Test palbociclib/abemaciclib plus (i) SNS-032 or another CDK2/7/9 inhibitor (shared sarcoma sensitivity, PMID:42165630), (ii) EPRS inhibitor (halofuginone) to convert arrest to ISR-driven apoptosis, (iii) EGFR-TKI in EGFR-altered/CDKN2A-deleted tumours, (iv) particle RT. For clival/skull-base disease substitute auceliciclib, a brain-penetrant selective CDK4/6i with no DLTs and grade>=3 related TEAEs ~5% (PMID:41581338). Pharmacodynamics: pRB-S780, Ki-67, cyclin E1/CDK2 activity. Resistance: RB1 loss, CCNE1 gain, CDK6 amplification.","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"PMID","id":"42284679","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40802536","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42121852","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40627883","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41581338","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42165630","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":27,"lastVisit":3,"lastNote":"Prospective genotype-selected phase II answers open question 1: biology confirmed, monotherapy activity capped at stable disease with ORR 0. Re-specified as combination/CNS-penetrant only; monotherapy is now a closed avenue for the desk.","history":[{"visit":3,"cycle":160,"status":"WEAKENED","note":"Prospective genotype-selected phase II answers open question 1: biology confirmed, monotherapy activity capped at stable disease with ORR 0. Re-specified as combination/CNS-penetrant only; monotherapy is now a closed avenue for the desk."},{"visit":2,"cycle":81,"status":"STRENGTHENED","note":"Two independent NEW sources (86-tumour multi-centre NGS; 108-study synthesis) make CDKN2A/B loss prevalence-anchored rather than cluster-restricted; promoted to CANDIDATE and re-specified as genotype-selected."},{"visit":1,"cycle":27,"status":"NEW","note":"New, from the strongest primary dataset in the pack (n=32 + n=71, dual-platform, FISH-validated). Therapeutic mapping is [INFERRED] from the abstract's SHH and cell-cycle enrichment; drug sensitivity untested."}]},{"id":"L3","title":"SMARCB1/INI1-deficient (poorly differentiated) chordoma as a checkpoint-blockade subset","mechanism":"PDC is SMARCB1-deficient with a distinct methylation class, and PBRM1 is altered in 11% of conventional tumours, supporting SMARCA2/EZH2 paralogue dependency. New data reframe the immune arm: PD-L1 expression is consistently reported but immune exclusion in chordoma is spatially stromal (ERS-CAF, fibrotic zones) (PMID:41965872, PMID:41617967), so PD-1/PD-L1 expression is not a response predictor and single-agent checkpoint blockade remains unsupported by any chordoma-specific response.","approach":"Prioritise SMARCA2/BRM-selective degraders and EZH2 inhibition in SMARCB1- and PBRM1-altered, methylation-class-assigned models. Continue extracting chordoma-specific arm-level data from NCT05286801, NCT04416568, NCT02834013 purely to formally close the immunotherapy arm; do not open new chordoma checkpoint monotherapy arms.","level":"LEAD","confidence":0.32,"citations":[{"kind":"NCT","id":"NCT05286801","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04416568","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT02834013","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42571860","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42293322","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40802536","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42293462","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41965872","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41617967","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":27,"lastVisit":3,"lastNote":"Immunotherapy arm downgraded: stromal immune exclusion now has spatial/functional support and PD-L1 positivity is explicitly decoupled from response; the SWI/SNF paralogue arm carries the lead.","history":[{"visit":3,"cycle":160,"status":"WEAKENED","note":"Immunotherapy arm downgraded: stromal immune exclusion now has spatial/functional support and PD-L1 positivity is explicitly decoupled from response; the SWI/SNF paralogue arm carries the lead."},{"visit":2,"cycle":81,"status":"STRENGTHENED","note":"Subset biology sharpened by new paediatric PDC profiling and by PBRM1 at 11%; a non-immunological paralogue-dependency arm added. Still zero chordoma-specific checkpoint response data, so confidence stays low."},{"visit":1,"cycle":27,"status":"NEW","note":"New but deliberately low confidence: no chordoma-specific response data in the pack, only enrolling baskets. Will be retired if arm readouts show no chordoma responses."}]},{"id":"L4","title":"DDR/HR inhibition as radiosensitiser under LETd-optimised particle therapy","mechanism":"BRCA2 and PALB2 are the only non-TBXT KG anchors for chordoma (germline-vs-somatic unresolved; NCT01200680 is the susceptibility-gene ascertainment protocol), suggesting homologous-recombination fragility in a subset. High-LET carbon ions produce clustered DSBs whose repair is HR-dependent, so LETd escalation inside the GTV is now a deliverable delivery platform for combination with PARP or ATR inhibition [SPECULATIVE].","approach":"Genotype HR genes (BRCA2/PALB2, plus functional RAD51 foci assay) in resected chordoma; test olaparib or an ATR inhibitor with high- vs low-LET irradiation in chordoma lines/PDX. Any escalation hypothesis must respect the temporal-lobe-necrosis dose-LETd constraint derived from 61 skull-base chordomas.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42595265","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42499293","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT01200680","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT01346124","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":27,"lastVisit":1,"lastNote":"New and frankly speculative; the physics papers establish that LETd-escalated CIRT is clinically feasible (10 sacral patients) and that TLN risk is dose-LETd dependent, but nothing in the pack links HR status to chordoma radioresponse.","history":[{"visit":1,"cycle":27,"status":"NEW","note":"New and frankly speculative; the physics papers establish that LETd-escalated CIRT is clinically feasible (10 sacral patients) and that TLN risk is dose-LETd dependent, but nothing in the pack links HR status to chordoma radioresponse."}]},{"id":"L5","title":"EPRS/tRNA-synthetase inhibition (halofuginone) driving ATF4-DDIT3 integrated stress response apoptosis — TBXT-independent","mechanism":"Focused compound screening identified distinct chemotypes inhibiting human glutamyl-prolyl-tRNA synthetase (EPRS) that reduce chordoma cell viability through ATF4 up-regulation and downstream DDIT3(CHOP)-mediated pro-apoptotic signalling, explicitly not through TBXT regulation; halofuginone gave significant tumour growth inhibition in a chordoma PDX. Amino-acid-starvation-like ISR activation exploits a metabolic stress threshold rather than a lineage TF, so it is orthogonal to brachyury-directed failure modes.","approach":"Confirm on-target EPRS engagement (proline rescue, thermal shift) and ATF4/DDIT3 induction as pharmacodynamic biomarkers across TBXT-high and TBXT-low lines; repurpose halofuginone (existing clinical-stage antifibrotic [KNOWN]) at doses bounded by prior GI/thrombocytopenia limits; test combinations with CDK4/6i, ISR-amplifying agents (proteasome or GCN2 modulation) and radiotherapy. Resistance readouts: ATF4/DDIT3 loss, GADD34/eIF2alpha dephosphorylation, altered proline/glutamate supply.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"41319040","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":81,"lastVisit":2,"lastNote":"New this visit and the only pack item with in vivo chordoma tumour growth inhibition; single-group primary data, hence LEAD not CANDIDATE.","history":[{"visit":2,"cycle":81,"status":"NEW","note":"New this visit and the only pack item with in vivo chordoma tumour growth inhibition; single-group primary data, hence LEAD not CANDIDATE."}]},{"id":"L6","title":"Genotype-selected EGFR (and PDGFR) TKI arms in chordoma","mechanism":"EGFR alterations in 8/86 (9%) chordomas by NGS; an evidence-graded review of 30 chordoma studies now ranks EGF -> EGFR and PDGF -> PDGFR as the most consistently validated ligand-receptor circuits, with multi-modal experimental support but only limited clinical activity to date (PMID:41965872). Normal-tissue role: EGFR is essential in skin and gut epithelium, imposing the rash/diarrhoea ceiling [KNOWN].","approach":"Alteration-stratified retrospective analysis of afatinib/lapatinib series (mutation vs amplification vs ligand-high); prospective EGFR-TKI plus CDK4/6i in EGFR-altered, CDKN2A/B-deleted tumours, now the most defensible combination given the palbociclib monotherapy ceiling (PMID:40627883). Resistance: MET/HER3 bypass, PI3K activation, IL-6/STAT3-mediated stromal rescue.","level":"CANDIDATE","confidence":0.42,"citations":[{"kind":"PMID","id":"40802536","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41971904","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41965872","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40627883","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":81,"lastVisit":3,"lastNote":"Independent new evidence-graded review corroborates EGFR/PDGFR as the best-validated chordoma signalling axes, giving a second evidence-bearing visit and a concrete partner for the now-capped CDK4/6i arm.","history":[{"visit":3,"cycle":160,"status":"STRENGTHENED","note":"Independent new evidence-graded review corroborates EGFR/PDGFR as the best-validated chordoma signalling axes, giving a second evidence-bearing visit and a concrete partner for the now-capped CDK4/6i arm."},{"visit":2,"cycle":81,"status":"NEW","note":"New: prevalence figure for EGFR alterations plus systematic-review endorsement of EGFR/PDGFR inhibitors provides the first genotype-selection rationale in this programme."}]},{"id":"L7","title":"Stiffness-driven EPHA2-LYN-OGT-Notch1 mechanoadaptation as the recurrence-specific target","mechanism":"Recurrent chordoma arises from cells infiltrating stiffer bone/cartilage ECM; stiff substrate triggers ligand-independent EPHA2 phosphorylation, activating LYN, which phosphorylates OGT at Y989/Y418 to boost glycosyltransferase activity, driving NICD1 O-GlcNAcylation at T2063/T2090/S2162 and transcription of mechanical/stemness genes with MIR31 involvement (PMID:41632535). This is a post-surgical survival/stemness programme rather than a bulk-proliferation driver, orthogonal to TBXT and to the Rb axis [INFERRED].","approach":"In recurrent-derived chordoma lines on stiff hydrogels and in PDX after marginal resection, test dasatinib (LYN/SRC, approved [KNOWN]), OGT inhibition (OSMI-1 class), and gamma-secretase inhibition (nirogacestat-class, approved in desmoid [KNOWN]), alone and with CDK4/6i or RT. Pharmacodynamics: NICD1 O-GlcNAc site-specific mass spectrometry, EPHA2-pS897/OGT-pY989, stemness sphere assays. Normal-tissue caveat: OGT and Notch are broadly essential (gut goblet-cell metaplasia, hepatotoxicity), so the window must come from intermittent dosing or upstream LYN/EPHA2 selectivity, not chronic OGT blockade. Resistance: EPHA2-independent YAP/TAZ mechanotransduction, Notch-independent stemness.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"41632535","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":160,"lastVisit":3,"lastNote":"New primary mechanistic work with defined phospho/O-GlcNAc sites; first chordoma lead explicitly aimed at recurrence biology and populated entirely with approved or clinical-stage agents.","history":[{"visit":3,"cycle":160,"status":"NEW","note":"New primary mechanistic work with defined phospho/O-GlcNAc sites; first chordoma lead explicitly aimed at recurrence biology and populated entirely with approved or clinical-stage agents."}]},{"id":"L8","title":"Stromal-immune reprogramming: IL-6/STAT3 and ERS-CAF-ITGB1 blockade as the prerequisite for any immunotherapy in chordoma","mechanism":"Evidence-weighted mapping of 30 chordoma studies grades IL-6 -> IL-6R -> STAT3 as level A (causal/functional) linking CAF and macrophage activation to invasion, with TGF-beta -> TGFbetaR and a newly defined ER-stress CAF IER2 -> GMFG -> ITGB1 axis supported by single-cell/spatial data (PMID:41965872). In 126 chordoma cases, ERS-CAF programmes localise to fibrotic, immune-excluded regions and carry independent prognostic value (PMID:41617967). Immune exclusion is therefore stromal, which plausibly explains the absence of chordoma responses in checkpoint baskets [INFERRED].","approach":"Repurpose tocilizumab or siltuximab (IL-6/IL-6R, approved [KNOWN]) or a JAK1/2-STAT3 inhibitor as a stroma-normalising backbone; combine with anti-PD-1 only in tumours scored ERS-CAF-high by the transcriptomic/radiopathomic surrogate. Test ITGB1 or TGF-beta blockade for ECM softening in parallel with the mechanoadaptation lead (L7). Endpoints: paired-biopsy CD8 infiltration into fibrotic zones, pSTAT3, collagen/stiffness imaging. Resistance: IL-6-independent gp130 ligands (IL-11, OSM), CAF-state switching.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"41965872","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41617967","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":160,"lastVisit":3,"lastNote":"Two new independent sources define a functionally validated stromal axis and an image-based ERS-CAF readout; converts 'chordoma is immunotherapy-refractory' from an observation into a testable stromal hypothesis.","history":[{"visit":3,"cycle":160,"status":"NEW","note":"Two new independent sources define a functionally validated stromal axis and an image-based ERS-CAF readout; converts 'chordoma is immunotherapy-refractory' from an observation into a testable stromal hypothesis."}]}],"retired":[],"nextQueries":["\"chordoma\" AND (OGT OR \"O-GlcNAc\" OR NOTCH1 OR EPHA2 OR dasatinib OR stiffness OR mechanotransduction)","\"chordoma\" AND (IL-6 OR STAT3 OR tocilizumab OR \"cancer-associated fibroblast\" OR TGF-beta OR ITGB1) AND PUB_YEAR:[2023 TO 2026]","\"chordoma\" AND (CDK2 OR \"cyclin E\" OR abemaciclib OR combination OR resistance) AND (\"cell line\" OR xenograft OR trial)"],"updatedAt":"2026-08-19T23:23:29.056Z"},{"key":"chondrosarcoma","name":"chondrosarcoma","mondo":{"id":"MONDO:0008977","name":"chondrosarcoma"},"genes":[{"label":"EXT1","kind":"causal"}],"visits":3,"openQuestions":["Which specific chondrosarcoma subtype, line of therapy and TKI/ICI pairing produced the complete response reported in PMID:40927310, and what was its duration - can the individual patient-level data be recovered from the eight underlying ph","Is there ANY primary chondrosarcoma tissue evidence (IHC, phosphoproteomics, functional knockdown in endogenous CS lines) for AXL/GAS6 pathway activation? If a third targeted query fails, retire the AXL component of L5.","Do CRISPR-edited or endogenous IDH-MUT chondrosarcoma models respond to mutant-IDH inhibitors themselves, and does tumour D-2-HG concentration predict response in NCT04521686/NCT04340843?","Does the IDH-WT-2 high-CNV/high-grade methylome cluster (PMID:42575314) map onto CDKN2A-deleted, RB1-intact tumours suitable for abemaciclib selection in NCT04040205?","Is there any published readout for vismodegib in chondrosarcoma (NCT01267955, active-not-recruiting since years), and is EXT1/heparan-sulfate loss [GERMLINE] a maintenance dependency in secondary peripheral CS or purely predisposition?","Is T-cell priming (HPK1 inhibition, PMID:42097144; or other agonist backbones) worth testing in immune-cold chondrosarcoma, i.e. does any CS cohort show baseline CD8 infiltrate sufficient for a priming-plus-checkpoint strategy?"],"leads":[{"id":"L1","title":"Mutant IDH1/IDH2 inhibition plus hypomethylating/HDAC therapy in conventional central chondrosarcoma","mechanism":"IDH1 R132/IDH2 R172 [SOMATIC] neomorphic D-2-HG inhibits alpha-KG-dependent TET/KDM enzymes, giving a hypermethylator state. Fresh isogenic work shows this dependency is dose-dependent and model-dependent: vector-based IDH-MUT chondrosarcoma lines display the published synthetic-lethal sensitivities, CRISPR-edited and endogenous IDH-MUT lines do not, and sensitivity is restored by raising D-2-HG (PMID:42508370). Methylome profiling of 214 chondrogenic tumours places IDH-mutant cases in four clusters spanning enchondroma/ACT to dedifferentiated and skull-base CS, so the methylator signature behaves as a founder/lineage mark rather than a grade driver (PMID:42575314) [INFERRED]","approach":"Retain NCT04521686 (LY3410738 +/- gemcitabine/cisplatin/durvalumab) and NCT04340843 (belinostat + guadecitabine/ASTX727) but add mandatory pre-treatment tumour D-2-HG and mutant-IDH protein quantification as stratifiers; primary PD endpoints 5hmC restoration and differentiation markers; deprioritise engineered-model-derived synthetic lethal partners (PARP, NAD/NAMPT, glutaminase) until reproduced in CRISPR-edited or endogenous CS lines. Expected resistance: dimer-interface second-site IDH mutations, IDH1/IDH2 isoform switching, 2-HG-independent bypass [KNOWN]. Normal tissue: wild-type IDH spared by mutant-selective covalent binders; HMA/HDACi toxicity haematologic","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT04521686","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04340843","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42508370","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42575314","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":28,"lastVisit":2,"lastNote":"Weakened: the mechanistic premise (deep, exploitable 2-HG-driven epigenetic block) fails in endogenous and CRISPR-edited chondrosarcoma models, and methylome data show IDH-mutant clusters include benign enchondroma, arguing IDH mutation is an early founder event rather than a maintenance dependency. Not retired because two genotype-matched trials remain open and D-2-HG-high tumours may still be de","history":[{"visit":2,"cycle":82,"status":"WEAKENED","note":"Weakened: the mechanistic premise (deep, exploitable 2-HG-driven epigenetic block) fails in endogenous and CRISPR-edited chondrosarcoma models, and methylome data show IDH-mutant clusters include benign enchondroma, arguing IDH mutation is an early founder event rather than a maintenance dependency. Not retired because two genotype-matched trials remain open and D-2-HG-high tumours may still be de"},{"visit":1,"cycle":28,"status":"NEW","note":"Opening lead: two active NCI/industry trials in the pack give a genotype-matched route in the ~50% IDH-mutant conventional subset; no efficacy readout yet, so confidence capped."}]},{"id":"L2","title":"REGγ (PSME3) inhibition to release WDR6/STK11-AMPK-dependent ferroptosis and resensitise chondrosarcoma to cisplatin","mechanism":"REGγ-20S degrades WDR6 ubiquitin-independently, suppressing STK11/AMPK signalling and lipid peroxidation and conferring cisplatin resistance (PMID:42360152). No independent replication surfaced this visit; the returned ferroptosis literature is osteoarthritis-only, and chondrocyte ferroptosis via the p53/SLC7A11/GPX4 axis is the effector of cartilage matrix degradation in IL-1β-treated SW1353 and in rat OA (PMID:41287770; reviews PMID:39624950, PMID:39529997, PMID:40951445)","approach":"Hold. If pursued, RLY01 + cisplatin must be read out with articular cartilage histology, MMP13/Col II and subchondral bone endpoints in the same animals; drop the proposed GPX4 inhibitor/sulfasalazine co-treatment. Stratify REGγ-high/WDR6-low. Expected resistance: SLC7A11/GPX4 upregulation, ACSL4 loss, FSP1-CoQ10 bypass [KNOWN]. Normal tissue: broad REGγ expression plus a cartilage compartment that is intrinsically ferroptosis-vulnerable — window now argued against","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"42360152","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41287770","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":28,"lastVisit":2,"lastNote":"Weakened twice over: no independent chondrosarcoma replication after a targeted ferroptosis/PSME3 query, and new cartilage data make systemic ferroptosis induction a plausible chondrotoxic strategy. Notebook flag: do not re-propose GPX4/system-xc- inducers here without cartilage-toxicity data.","history":[{"visit":2,"cycle":82,"status":"WEAKENED","note":"Weakened twice over: no independent chondrosarcoma replication after a targeted ferroptosis/PSME3 query, and new cartilage data make systemic ferroptosis induction a plausible chondrotoxic strategy. Notebook flag: do not re-propose GPX4/system-xc- inducers here without cartilage-toxicity data."},{"visit":1,"cycle":28,"status":"NEW","note":"Single-paper mechanism with a tool inhibitor and in vivo chemosensitisation; needs independent replication and tolerability data before promotion."}]},{"id":"L3","title":"PI3K/AKT blockade to reverse Grb10-loss-driven platinum resistance (circHMGB2-IGF2BP1 axis)","mechanism":"circHMGB2 acts as a molecular decoy for IGF2BP1 rather than a miRNA sponge, destabilising Grb10 mRNA; loss of Grb10, a negative regulator of PI3K/AKT, yields constitutive AKT phosphorylation and cisplatin resistance, reversible by circHMGB2 silencing in vivo (PMID:42561431)","approach":"Repurposing-first: approved AKT (capivasertib) or PI3K inhibitors combined with cisplatin in Grb10-low/pAKT-high chondrosarcoma models; use Grb10 protein and circHMGB2 levels as candidate predictive biomarkers. Expected resistance: PIM/SGK-mediated bypass, mTORC1 reactivation, RTK feedback upregulation [KNOWN]. Normal tissue: AKT is central to insulin signalling — hyperglycaemia and rash are the dose-limiting window issues [KNOWN]","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42561431","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":28,"lastVisit":1,"lastNote":"New this visit; attractive because the downstream node is already drugged, but the axis rests on one report in SW1353/OUMS-27 and a low-profile journal.","history":[{"visit":1,"cycle":28,"status":"NEW","note":"New this visit; attractive because the downstream node is already drugged, but the axis rests on one report in SW1353/OUMS-27 and a low-profile journal."}]},{"id":"L4","title":"CDK4/6 inhibition in CDKN2A/B-deleted or CDK4-amplified high-grade and dedifferentiated chondrosarcoma","mechanism":"CDKN2A/B deletion [SOMATIC] removes p16 restraint on CDK4/6-cyclin D, driving RB1 phosphorylation and G1-S transit [KNOWN]. Methylome/CNV profiling of 214 chondrogenic tumours now shows CNV burden including CDKN2A loss increases with tumour grade, and that IDH-wildtype cluster 2 carries the highest grade and most extensive CNVs (PMID:42575314), identifying a grade-enriched, genotype-defined enrolment population","approach":"Genotype-selected enrolment into NCT04040205 (abemaciclib, CDK-pathway-altered bone/soft tissue sarcoma); require RB1 intact and CDKN2A deletion by CNV or methylation-array copy-number calling; use the IDH-WT-2/high-CNV methylome cluster as an enrichment strategy [INFERRED]. Expected resistance: RB1 loss, CCNE1/CDK2 activation, CDK6 amplification [KNOWN]. Normal tissue: proliferating marrow and gut — neutropenia and diarrhoea define the window","level":"LEAD","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT04040205","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42575314","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":28,"lastVisit":2,"lastNote":"Strengthened by new cohort-level evidence that CDKN2A loss tracks with grade in chondrogenic tumours and that a methylation/CNV classifier can prospectively select the altered population. Still no chondrosarcoma-specific efficacy readout, so it stays a LEAD.","history":[{"visit":2,"cycle":82,"status":"STRENGTHENED","note":"Strengthened by new cohort-level evidence that CDKN2A loss tracks with grade in chondrogenic tumours and that a methylation/CNV classifier can prospectively select the altered population. Still no chondrosarcoma-specific efficacy readout, so it stays a LEAD."},{"visit":1,"cycle":28,"status":"NEW","note":"Trial-anchored only; no chondrosarcoma-specific response data in this pack, so it stays a low-confidence LEAD pending the biomarker-selected readout."}]},{"id":"L5","title":"AXL/VEGFR multikinase inhibition combined with PD-(L)1 blockade in dedifferentiated and high-grade chondrosarcoma","mechanism":"VEGFR-directed antiangiogenic TKI normalises tumour vasculature and reduces VEGF-mediated myeloid suppression, increasing effector T-cell entry into an immune-cold, chemotherapy-refractory tumour (DDCS chemotherapy ceiling ORR ~20%, PFS 4-5 months; PMID:41895355). Pooled prospective data in advanced STS give ORR 33% and mPFS 7.1 months, but the effect is dominated by alveolar soft part sarcoma (ORR 73%) with grade >=3 AEs in 40% (PMID:41143677) [INFERRED: non-ASPS histologies fare worse]. Reviewing the same eight trials, complete responses were observed in DSRCT, angiosarcoma and chondrosarcoma, while bone sarcomas overall were called less responsive (PMID:40927310) - the first patient-level","approach":"Histology-specific arm: pembrolizumab/nivolumab or atezolizumab plus a VEGFR-TKI (axitinib, lenvatinib, apatinib or cabozantinib) restricted to DDCS and grade 3 conventional CS, using NCT04458922 as the ICI backbone anchor and NCT06239272 as precedent for maintenance antiangiogenic TKI dosing in sarcoma; power against the DDCS chemotherapy ceiling (PMID:41895355), not against ASPS-inflated pooled ORR. Mandatory correlatives: pre/post CD8 density and vessel maturation (CD31/alpha-SMA), PD-L1, TMB, methylome cluster assignment, plus pAXL/GAS6 IHC as exploratory only. Toxicity plan pre-specified for the 40% grade >=3 rate (hypothyroidism, diarrhoea, hepatic enzymes) (PMID:41143677). Expected re","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"42352463","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42525308","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41895355","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT04458922","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"40927310","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41143677","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42274206","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT06239272","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":82,"lastVisit":3,"lastNote":"First patient-level chondrosarcoma complete response documented in ICI+VEGFR-TKI series (PMID:40927310) and pooled ORR/PFS quantified (PMID:41143677) - hence strengthened to 0.55. Simultaneously narrowed: pooled ORR is ASPS-driven, bone sarcomas described as less responsive, and a second targeted AXL/GAS6 query again returned no primary chondrosarcoma data, so the mechanistic claim is now VEGFR/va","history":[{"visit":3,"cycle":161,"status":"STRENGTHENED","note":"First patient-level chondrosarcoma complete response documented in ICI+VEGFR-TKI series (PMID:40927310) and pooled ORR/PFS quantified (PMID:41143677) - hence strengthened to 0.55. Simultaneously narrowed: pooled ORR is ASPS-driven, bone sarcomas described as less responsive, and a second targeted AXL/GAS6 query again returned no primary chondrosarcoma data, so the mechanistic claim is now VEGFR/va"},{"visit":2,"cycle":82,"status":"NEW","note":"New this visit from three independent 2026 reviews: two DDCS reviews quantify the chemotherapy ceiling and report ICI+antiangiogenic TKI signals, and a dedicated review nominates AXL as a candidate node in conventional CS. All three are reviews, not primary data, so confidence is capped at 0.5 pending a primary series or trial readout."}]}],"retired":[],"nextQueries":["(\"chondrosarcoma\" AND (\"complete response\" OR \"case report\" OR \"objective response\") AND (pembrolizumab OR nivolumab OR atezolizumab OR camrelizumab) AND SRC:MED AND PUB_YEAR:[2019 TO 2026])","(\"chondrosarcoma\" AND (AXL OR GAS6 OR \"TAM receptor\" OR MERTK) AND (immunohistochemistry OR knockdown OR siRNA OR phosphoproteom*) AND SRC:MED)","(\"chondrosarcoma\" AND (vismodegib OR \"hedgehog\" OR GLI1 OR SMO OR EXT1 OR \"heparan sulfate\") AND SRC:MED AND PUB_YEAR:[2015 TO 2026])"],"updatedAt":"2026-08-19T23:26:38.421Z"},{"key":"synovial sarcoma","name":"synovial sarcoma","mondo":{"id":"MONDO:0010434","name":"synovial sarcoma"},"genes":[{"label":"SSX1","kind":"causal"},{"label":"SS18","kind":"correlated"},{"label":"SSX2","kind":"correlated"}],"visits":3,"openQuestions":["Do paired pre/post-relapse biopsies from afami-cel or lete-cel-treated SS show MAGE-A4/NY-ESO-1 downregulation, HLA-A*02 allelic LOH, TCR-T loss of persistence, or stromal exclusion — and is any mechanism dominant?","Does TAK-981 increase surface HLA-A*02 and MAGE-A4/NY-ESO-1 peptide density in SS18::SSX cells, and does a pulsed lead-in help or harm infused TCR-T fitness?","Is there any sarcoma-inclusive or SS-enrolling TAK-981/subasumstat trial, and what schedule and normal-tissue toxicity were reported in its dose-finding phases?","Does the PDAC TAK-981 + TIGIT design reproduce in an immunocompetent SS18::SSX GEMM, and is Treg depletion or MHC-I restoration the operative mechanism in SS?","Are SS18::SSX phase separation and PRC1 recruitment druggable with existing chemical matter, and do such agents phenocopy cBAF restoration and SMARCE1-SUMO loss?","Any prospective randomised data for anlotinib or pazopanib maintenance in lung-metastatic SS — if none appears next visit, retire L4."],"leads":[{"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","mechanism":"Fusion-driven BAF/PRC2 rewiring derepresses testis-restricted MAGE-A4 and CTAG1B/NY-ESO-1, giving HLA-I-presented targets in a checkpoint-cold histology; affinity-enhanced TCRs bypass absent endogenous priming. Ceiling set by HLA-A*02 restriction, TME exclusion (Treg/MDSC/TAM), limited persistence and possible antigen loss rather than antigen absence (PMID:39970827, PMID:41843290).","approach":"Continue afami-cel/lete-cel programmes (NCT05642455, NCT03967223, NCT06083883, NCT02650986). Priority unchanged and now overdue: paired pre/post-relapse biopsies scored for MAGE-A4 IHC intensity, HLA-A*02 allelic LOH, and CD8 exhaustion/persistence; add formal alanine-scan/off-target cross-reactivity panels as the window-defining assay emphasised by PMID:39970827. Normal tissue: MAGE-A4 restricted to testis and placenta, so on-target off-tumour risk is low and safety is governed by TCR cross-reactivity.","level":"CANDIDATE","confidence":0.8,"citations":[{"kind":"NCT","id":"NCT05642455","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03967223","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06083883","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT02650986","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42172443","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41472526","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42045541","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39970827","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41843290","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":29,"lastVisit":3,"lastNote":"Two NEW independent reviews corroborate target restriction, the ten-trial MAGE-A4 TCR-T landscape and the resistance quartet, but neither adds SS primary data or a relapse-biopsy series. Held at CANDIDATE deliberately: DOSSIER declined because the dominant SS relapse mechanism is still unpublished after two visits of targeted querying.","history":[{"visit":3,"cycle":162,"status":"STRENGTHENED","note":"Two NEW independent reviews corroborate target restriction, the ten-trial MAGE-A4 TCR-T landscape and the resistance quartet, but neither adds SS primary data or a relapse-biopsy series. Held at CANDIDATE deliberately: DOSSIER declined because the dominant SS relapse mechanism is still unpublished after two visits of targeted querying."},{"visit":2,"cycle":83,"status":"STRENGTHENED","note":"Promoted on NEW independent corroboration (PMID:41472526 quantifies SPEARHEAD-1 efficacy/safety and names HLA restriction + TME as resistance axes; PMID:42045541 places it in the approved-ACT solid-tumour class). Counterweight recorded: no published relapse-biopsy series yet, so the dominant resistance mechanism remains unknown."},{"visit":1,"cycle":29,"status":"NEW","note":"Created this visit; four independent NEW trials converge on the same antigen class, and the review confirms SS is otherwise checkpoint-cold."}]},{"id":"L2","title":"SPP1/OPN-PD-L1 axis as a combinable immune-evasion target in synovial sarcoma","mechanism":"OPN knockdown in SS cells reduces proliferation, invasion and migration and lowers PD-L1 protein; OPN-PD-L1 physical interaction (docking + Co-IP) and IHC correlation with CD8 infiltration suggest OPN stabilises PD-L1 to drive CD8+ T-cell exhaustion.","approach":"Test anti-SPP1 antibody or CD44/integrin-alphaVbeta3 receptor blockade plus anti-PD-1 in immunocompetent SS models (Sy18::SSX-driven GEMM or humanised PDX); ask whether SPP1 blockade raises TCR-T efficacy. Normal tissue: OPN is expressed in bone remodelling, kidney and activated macrophages, so expect on-target bone/immune effects - window needs explicit definition.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42399829","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42172443","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":29,"lastVisit":1,"lastNote":"Created from the single new mechanistic SS paper in the pack; abstract-only, no in vivo blockade experiment, so confidence held low.","history":[{"visit":1,"cycle":29,"status":"NEW","note":"Created from the single new mechanistic SS paper in the pack; abstract-only, no in vivo blockade experiment, so confidence held low."}]},{"id":"L4","title":"Anlotinib added to anthracycline/ifosfamide in lung-metastatic synovial sarcoma","mechanism":"Multi-target VEGFR/PDGFR/FGFR/c-Kit inhibition restrains the angiogenic, lung-tropic phenotype of SS and may improve chemotherapy delivery; VEGF biology is active in synovial-lineage tissue.","approach":"Retrospective 108-patient cohort: mPFS 8.1 vs 6.2 mo, mOS 14.8 vs 6.8 mo, mostly grade 1-2 AEs with hypertension/proteinuria. Requires prospective randomised confirmation; compare against pazopanib maintenance in NRSTS2021.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"41983866","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06239272","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":29,"lastVisit":1,"lastNote":"Registered at low confidence: single-centre retrospective 2007-2024 with an implausibly short 6.8-mo control OS, i.e. probable era/selection confounding.","history":[{"visit":1,"cycle":29,"status":"NEW","note":"Registered at low confidence: single-centre retrospective 2007-2024 with an implausibly short 6.8-mo control OS, i.e. probable era/selection confounding."}]},{"id":"L5","title":"TAK-981-mediated SUMOylation blockade to restore cBAF and collapse the SS18::SSX transcriptome, plus chemotherapy","mechanism":"SS18::SSX drives a SUMOylation program; TAK-981 de-SUMOylates SMARCE1, re-loading canonical BAF that outcompetes fusion-containing ncBAF, shutting down the SS transcriptome with DNA damage in human and mouse SS models (PMID:41193430, PMID:40849585). Newly corroborated second arm: SUMO E1 inhibition restores MHC-I antigen presentation and immunopeptidome diversity, activates type-I IFN, enhances CD8 cytotoxicity and reduces FoxP3+ Tregs via innate-cell-mediated clearance, and modulates PD-L1/TIGIT (PMID:42185884, PMID:42142669, PMID:41340481). Window argument: SUMOylation is broadly essential in normal tissue, but the fusion-conditional cBAF dependency plus existing human dose-finding limits ","approach":"Confirm SMARCE1-SUMO loss and cBAF re-occupancy as PD biomarkers in SS PDX/GEMM; test TAK-981 + doxorubicin/ifosfamide (NRSTS2021 backbone, NCT06239272) for DNA-damage synergy and TAK-981 + peposertib-class DDR blockade (NCT05711615). Import the PDAC design directly: TAK-981 + TIGIT blockade, and a perioperative/residual-disease arm, in immunocompetent SS18::SSX GEMMs (PMID:41340481). Resistance routes: SAE1/UBA2 mutation, SMARCE1/ARID1A loss, DDR upregulation, IFN-pathway silencing (JAK1/B2M).","level":"CANDIDATE","confidence":0.65,"citations":[{"kind":"PMID","id":"41193430","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40849585","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT06239272","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT05711615","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41340481","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42185884","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42142669","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":83,"lastVisit":3,"lastNote":"Promoted on NEW independent corroboration of the immunologic arm: PMID:41340481 gives in vivo survival benefit, Treg depletion and type-I IFN mechanism for TAK-981 + TIGIT in an orthotopic metastatic model; PMID:42185884 and PMID:42142669 independently document restored antigen presentation and ICB synergy. Counterweight recorded: all new evidence is non-sarcoma, the SS-specific cBAF mechanism sti","history":[{"visit":3,"cycle":162,"status":"STRENGTHENED","note":"Promoted on NEW independent corroboration of the immunologic arm: PMID:41340481 gives in vivo survival benefit, Treg depletion and type-I IFN mechanism for TAK-981 + TIGIT in an orthotopic metastatic model; PMID:42185884 and PMID:42142669 independently document restored antigen presentation and ICB synergy. Counterweight recorded: all new evidence is non-sarcoma, the SS-specific cBAF mechanism sti"},{"visit":2,"cycle":83,"status":"NEW","note":"Created from the only SS-specific mechanistic paper in the pack: in vivo tumour inhibition/regression in two model systems with a clinical-stage agent and a defined PD marker. Abstract-only; regression magnitude, schedule and normal-tissue toxicity in the combination are not visible."}]},{"id":"L6","title":"TAK-981 as an antigen-presentation priming lead-in before MAGE-A4/NY-ESO-1 TCR-T in synovial sarcoma","mechanism":"SUMOylation suppresses MHC-I antigen presentation and immunopeptidome diversity; SUMO E1 inhibition restores presentation, induces type-I IFN, expands CD8 cytotoxicity and depletes Tregs (PMID:42185884, PMID:42142669, PMID:41340481). In SS, where TCR-T efficacy is capped by HLA-restricted epitope density and a Treg/TAM-rich excluded TME rather than antigen absence (PMID:41472526, PMID:39970827), a short TAK-981 lead-in could raise peptide-MHC density per tumour cell and re-open the TME before infusion [SPECULATIVE until SS-model data exist].","approach":"In SS18::SSX cell lines and PDX: dose/schedule TAK-981, then quantify surface HLA-A*02 by flow, MAGE-A4/NY-ESO-1 peptide abundance by immunopeptidomics-MS, and killing by afami-cel-like TCR-T at fixed E:T. In immunocompetent GEMM, test lead-in vs concurrent vs post-infusion sequencing, reading Treg:CD8 ratio and TCR-T persistence; check that TAK-981 does not blunt infused T-cell fitness (SUMO inhibition affects T cells too) — that is the key falsification. Normal tissue: broad SUMO dependency; short pulsed lead-in is the window strategy.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42185884","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42142669","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41340481","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"39970827","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT03967223","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":162,"lastVisit":3,"lastNote":"Created because this visit converted the priming idea from speculation inside L5 into an independently evidenced, separately testable sequencing hypothesis; kept distinct from L5 so its failure mode (no gain in MAGE-A4 peptide density, or TAK-981 toxicity to infused T cells) can retire it without touching the cBAF-restoration mechanism.","history":[{"visit":3,"cycle":162,"status":"NEW","note":"Created because this visit converted the priming idea from speculation inside L5 into an independently evidenced, separately testable sequencing hypothesis; kept distinct from L5 so its failure mode (no gain in MAGE-A4 peptide density, or TAK-981 toxicity to infused T cells) can retire it without touching the cBAF-restoration mechanism."}]}],"retired":[{"title":"Degrader-based attack on SS18::SSX chromatin dependencies (BRD9, PRC2)","note":"Retired on evidence: the only new BRD9 paper (PMID:41797932) is a generic pan-cancer review that stresses context-dependent, sometimes tumour-suppressive BRD9 function and provides no SS18::SSX model data. The cBAF-restoration route (new lead) is the better-evidenced way to attack the same complex; do not re-propose bare BRD9 degradation for SS without SS-model data.","cycle":83,"ts":"2026-08-19T18:55:15.917Z"}],"nextQueries":["(\"synovial sarcoma\" OR \"SS18-SSX\" OR \"SS18::SSX\") AND (\"TAK-981\" OR subasumstat OR SUMOylation OR SMARCE1 OR \"canonical BAF\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(afamitresgene OR letetresgene OR \"MAGE-A4 TCR\" OR \"NY-ESO-1 TCR\") AND (relapse OR progression OR \"paired biopsy\" OR \"antigen loss\" OR \"HLA loss\" OR persistence) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(subasumstat OR \"TAK-981\") AND (\"phase 1\" OR \"dose escalation\" OR \"first-in-human\" OR sarcoma OR \"solid tumor\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T23:29:55.750Z"},{"key":"gastrointestinal stromal tumor","name":"gastrointestinal stromal tumor","mondo":{"id":"MONDO:0011719","name":"gastrointestinal stromal tumor"},"genes":[{"label":"SDHB","kind":"causal"},{"label":"SDHC","kind":"causal"},{"label":"KIT","kind":"causal"},{"label":"PDGFRA","kind":"correlated"},{"label":"SDHA","kind":"correlated"}],"visits":3,"openQuestions":["Has the rogaratinib SDH-deficient GIST cohort (NCT04595747) reported its serial-biopsy WES, and do acquired FGFR1 gatekeeper (V561M-class) mutations, FGF ligand switching, or RAS/MAPK reactivation dominate at progression?","Has the belzutifan GIST cohort of NCT04924075 reported, and is HIF-2alpha dependency real in SDH-deficient GIST after FGFR-inhibitor failure?","Which lipid-metabolic enzyme does olverembatinib modulate in SDH-null GIST, and is the effect kinase-independent (last chance before L6 retires)?","What is the measured prevalence of FGFR1/2/3 and NTRK fusions specifically in quadruple-wild-type, SDH-proficient GIST, and has any fusion-positive GIST responded to a pan-FGFR or TRK inhibitor?","Do ctDNA studies after ripretinib/avapritinib failure show new secondary KIT mutations versus KIT-independent bypass (FGFR/AXL/MAPK/cell-cycle), and does PDGFRA D842V resistance follow a distinct route warranting its own lead?","What fraction of early imatinib failure in GIST is attributable to sub-therapeutic trough concentration or CYP3A/acid-reducer interactions rather than clonal evolution?"],"leads":[{"id":"L2","title":"Pseudohypoxia-axis blockade in SDH-deficient (KIT/PDGFRA wild-type) GIST","mechanism":"Biallelic SDHA/SDHB/SDHC loss [GERMLINE first hit + somatic second hit] causes succinate accumulation, PHD/TET inhibition and genome-wide DNA hypermethylation; hypermethylation disrupts genomic insulators, de-repressing FGF3 and FGF4 and creating an autocrine FGFR1-dependent growth loop, alongside HIF-1/2alpha pseudohypoxia (PMID:42191879, PMID:41184234). The tumour suppressor itself is undruggable, so the downstream ligand-receptor node is the target. Matches 3 of 5 KG anchors.","approach":"Pan-FGFR inhibition (rogaratinib, NCT04595747) as the reference regimen for advanced SDH-deficient GIST; olverembatinib phase 3 (NCT06640361) as comparator; belzutifan (NCT04924075) tested at FGFR-inhibitor progression rather than upfront, since HIF-2alpha dependency is still unreported. Correlatives already generated by the trial: serial FGF3/FGF4/FGFR protein and serial-biopsy WES — mine for acquired FGFR1 gatekeeper (V561M-class) mutations, FGF ligand switching, and RAS/MAPK reactivation. Expected resistance: FGFR gatekeeper mutation, FGF ligand redundancy, MAPK/PI3K bypass, HIF-1alpha switch. Window: FGFR1-4 inhibition causes hyperphosphataemia, nail/mucosal toxicity, retinal risk; belzu","level":"CANDIDATE","confidence":0.8,"citations":[{"kind":"NCT","id":"NCT04924075","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04595747","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06640361","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42191879","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41184234","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":30,"lastVisit":2,"lastNote":"Promoted: NEW published phase 2 readout (PMID:42191879) gives both efficacy (ORR 41.7%, mPFS 31.0 mo) and the causal mechanism (insulator disruption -> FGF3/FGF4 -> FGFR1 autocrine loop), and a second NEW independent trial in the same subtype (PMID:41184234) confirms the genotype is drug-sensitive. Answers OQ2 in favour of FGFR over HIF-2alpha for now; belzutifan reframed as sequential, not combin","history":[{"visit":2,"cycle":85,"status":"STRENGTHENED","note":"Promoted: NEW published phase 2 readout (PMID:42191879) gives both efficacy (ORR 41.7%, mPFS 31.0 mo) and the causal mechanism (insulator disruption -> FGF3/FGF4 -> FGFR1 autocrine loop), and a second NEW independent trial in the same subtype (PMID:41184234) confirms the genotype is drug-sensitive. Answers OQ2 in favour of FGFR over HIF-2alpha for now; belzutifan reframed as sequential, not combin"},{"visit":1,"cycle":30,"status":"NEW","note":"New. Strongest structural lead of visit 1: independent sponsors converging on the same downstream axis for an imatinib-insensitive genotype that carries the germline KG anchors."}]},{"id":"L3","title":"Autophagy-dependent TKI-persister eradication (ULK1/2 + KIT inhibition)","mechanism":"KIT inhibition drives quiescent GIST cells into an autophagy-dependent tolerant state rather than apoptosis; ULK1/2 blockade (inlexisertib/DCC-3116) should convert cytostasis to cytotoxicity. Clinically supported by the observation that pathology-integrated response keeps deepening to 10-12 months while radiographic response plateaus at 4-6 months, i.e. viable tumour persists under imatinib.","approach":"Follow NCT05957367 (inlexisertib + ripretinib) for depth-of-response and residual viable-tumour endpoints; in the neoadjuvant setting use the PIRS framework (shrinkage + viable tumour % + necrosis) as the biological readout rather than RECIST. Expected resistance: non-canonical/ULK-independent autophagy, KIT-independent MAPK bypass. Window: basal autophagy matters in neurons, liver, heart - chronic dosing risk.","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT05957367","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42440135","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":30,"lastVisit":1,"lastNote":"New; pairs a clinical persistence observation (P3) with the only ULK1/2 clinical agent in GIST (T8).","history":[{"visit":1,"cycle":30,"status":"NEW","note":"New; pairs a clinical persistence observation (P3) with the only ULK1/2 clinical agent in GIST (T8)."}]},{"id":"L4","title":"Frontline broad-spectrum KIT coverage to pre-empt polyclonal secondary resistance","mechanism":"Imatinib selects heterogeneous secondary KIT mutations (exon 13/14 ATP-pocket, exon 17/18 activation-loop) across separate metastases [SOMATIC]. Two independent 2025 reviews document that each approved later line covers only a partial slice of that spectrum (sunitinib ATP-pocket-biased, regorafenib/ripretinib activation-loop-biased) and a GIST editorial frames kinase-inhibitor escape as the dominant failure mode (PMID:40368739, PMID:40733131, PMID:42169879), so sequential monotherapy is structurally reactive. A single agent covering exon 11 plus the secondary spectrum should suppress emergence rather than chase it.","approach":"Phase 3 velzatinib vs imatinib, treatment-naive metastatic/unresectable GIST (NCT07585266) with serial ctDNA clonal tracking as the mechanistic endpoint: is the secondary-KIT spectrum suppressed, or merely shifted to KIT amplification or KIT-independent FGFR/AXL/MAPK bypass? Ponatinib is explicitly excluded as the broad-coverage vehicle: its gatekeeper-agnostic potency is inseparable from >60-kinase promiscuity including FGFR1/SLK-linked cardiotoxicity (PMID:42313448). Window: on-target KIT inhibition hits mast cells, melanocytes, germ cells, haematopoiesis.","level":"CANDIDATE","confidence":0.6,"citations":[{"kind":"NCT","id":"NCT07585266","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42584765","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42136545","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40368739","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40733131","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42169879","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":30,"lastVisit":3,"lastNote":"Second evidence-bearing visit; three NEW independent 2025-2026 sources converge on the polyclonal-coverage rationale. Held at 0.6 because all new support is review/editorial level with zero velzatinib efficacy data.","history":[{"visit":3,"cycle":163,"status":"STRENGTHENED","note":"Second evidence-bearing visit; three NEW independent 2025-2026 sources converge on the polyclonal-coverage rationale. Held at 0.6 because all new support is review/editorial level with zero velzatinib efficacy data."},{"visit":1,"cycle":30,"status":"NEW","note":"New. Registrational-stage test of the field's central resistance hypothesis; graded LEAD only because no efficacy data are in the pack."}]},{"id":"L5","title":"Immune-adjuvant KIT inhibition: HPK1 blockade plus imatinib in first-line GIST","mechanism":"[KNOWN] Imatinib's antitumour effect in GIST is partly immune-mediated (intratumoural IDO downregulation, CD8+ T-cell activation, Treg reduction); HPK1 (MAP4K1) is a negative feedback brake on TCR/BCR signalling, so its inhibition could amplify that imatinib-induced T-cell response in an otherwise immune-cold sarcoma.","approach":"Phase 2 KQB198 + imatinib, first-line advanced GIST (NCT07406633); require paired biopsies for CD8 density, IDO1, Treg fraction. Expected failure mode: immune-cold baseline dominates (checkpoint blockade has been largely inactive across sarcoma histologies). Window: HPK1 expression is largely haematopoietic - relatively favourable, with autoimmunity as the main risk.","level":"LEAD","confidence":0.3,"citations":[{"kind":"NCT","id":"NCT07406633","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42172443","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":30,"lastVisit":1,"lastNote":"New and weakest of the five: the sarcoma immunotherapy review frames GIST/STS as predominantly immune-cold, so prior probability is low; logged so the desk tracks the readout rather than re-proposing generic checkpoint blockade.","history":[{"visit":1,"cycle":30,"status":"NEW","note":"New and weakest of the five: the sarcoma immunotherapy review frames GIST/STS as predominantly immune-cold, so prior probability is low; logged so the desk tracks the readout rather than re-proposing generic checkpoint blockade."}]},{"id":"L6","title":"Lipid-metabolic / reductive-stress vulnerability of Complex II-null GIST","mechanism":"SDH loss is a combined TCA/Complex II defect forcing succinate-independent rewiring (ubiquinone, NAD(P)+/NAD(P)H backpressure, acyl-CoA pools, ROS). Olverembatinib's translational arm attributes antitumour effect in SDH-deficient GIST to lipid-metabolic modulation rather than canonical kinase inhibition (PMID:41184234) [INFERRED, abstract truncated before the effector is named].","approach":"Unchanged: name the enzyme from the full text (SCD1/FASN/CPT1A/SREBP candidates [SPECULATIVE]), then test blockade in SDH-null GIST models with lipidomics and NAD(P)H readouts, and for additivity with FGFR inhibition. Window: FASN/SCD1 activity in liver, sebaceous gland, haematopoiesis.","level":"LEAD","confidence":0.32,"citations":[{"kind":"PMID","id":"41184234","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40285898","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40685935","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42150423","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40733131","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT06640361","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":85,"lastVisit":3,"lastNote":"Second visit without the effector enzyme; this pack mentions olverembatinib only as an investigational agent in a list (PMID:40733131), adding no mechanism. Confidence trimmed; retire if visit 4 again fails to identify the lipid node.","history":[{"visit":3,"cycle":163,"status":"WEAKENED","note":"Second visit without the effector enzyme; this pack mentions olverembatinib only as an investigational agent in a list (PMID:40733131), adding no mechanism. Confidence trimmed; retire if visit 4 again fails to identify the lipid node."},{"visit":2,"cycle":85,"status":"NEW","note":"New this visit. Split out of L2 deliberately: olverembatinib's benefit in SDHx-null GIST is ascribed to lipid-metabolic modulation, not kinase inhibition, which is a different hypothesis from the FGFR/pseudohypoxia axis and would fail or succeed independently. Held at LEAD because the effector enzyme is not named in the abstract and all supporting mechanism is review-level."}]},{"id":"L7","title":"FGFR-fusion-directed therapy in quadruple-wild-type, SDH-proficient GIST","mechanism":"A minority of KIT/PDGFRA-wild-type, SDH-proficient GISTs are driven by receptor-kinase fusions rather than pseudohypoxia [KNOWN, rare FGFR1 and NTRK fusions in quadruple-WT GIST]. New molecular-database work shows recurrent kinase-domain-retaining FGFR1/FGFR2/FGFR4 fusions define a previously unclassified high-grade spindle-cell sarcoma group (PMID:42185943), establishing that FGFR fusions recur as bona fide mesenchymal drivers independent of the SDH-deficient FGF3/FGF4 ligand mechanism of L2. Mechanistically distinct: constitutive fusion-kinase signalling, not autocrine ligand de-repression.","approach":"Mandate fusion-capable RNA sequencing (not panel DNA alone) in every KIT/PDGFRA-WT, SDH-proficient GIST; route FGFR-fusion cases to the FGFR-altered-sarcoma arm of rogaratinib NCT04595747 and BRAF V600E cases to plixorafenib NCT05503797. Expected resistance: FGFR gatekeeper V561M-class mutation, RAS/MAPK bypass. Window: pan-FGFR inhibition causes hyperphosphataemia, nail/mucosal toxicity, retinal risk. Caveat: PMID:42185943 contains no GIST cases, so GIST-specific fusion prevalence is unmeasured here [INFERRED].","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42185943","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT04595747","verified":true,"isNew":false,"addedVisit":3},{"kind":"NCT","id":"NCT05503797","verified":true,"isNew":false,"addedVisit":3},{"kind":"PMID","id":"40368739","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":163,"lastVisit":3,"lastNote":"Opened to answer OQ6 and to keep fusion-driven WT GIST separate from the SDH-deficient FGF ligand loop (L2), which would fail or succeed independently.","history":[{"visit":3,"cycle":163,"status":"NEW","note":"Opened to answer OQ6 and to keep fusion-driven WT GIST separate from the SDH-deficient FGF ligand loop (L2), which would fail or succeed independently."}]},{"id":"L8","title":"Pharmacokinetic pseudo-resistance: exposure verification before declaring imatinib failure","mechanism":"[KNOWN] Imatinib exposure-response is established in GIST and trough concentration predicts benefit. New EHR-plus-label analysis of 99 oral anticancer drugs finds 85.9% carry >=1 clinically relevant DDI mechanism (CYP3A substrates 55.6%, metabolic-inducer victims 71.7%, acid-reducer victims 17.2%), 17.4% of treated patients had a potential DDI, and 14 drugs have literature-documented mechanisms absent from their labels (PMID:41793262). A fraction of apparent primary or early secondary TKI failure in GIST is therefore predicted to be sub-therapeutic exposure, not clonal evolution [INFERRED].","approach":"In any GIST cohort progressing early, measure trough TKI concentration and reconcile the concomitant-medication list (CYP3A inducers, acid reducers) before assigning resistance; require paired ctDNA to distinguish exposure failure (no new KIT mutation) from clonal escape (new exon 13/14/17/18 mutation). Cheapest possible intervention: dose/interaction correction rather than a new drug. Window: none - no new pharmacology introduced; risk is over-exposure toxicity on de-inducing.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"41793262","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40733131","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":163,"lastVisit":3,"lastNote":"New this visit; a confounder-control lead that could reclassify part of the resistance denominator all other leads are built on.","history":[{"visit":3,"cycle":163,"status":"NEW","note":"New this visit; a confounder-control lead that could reclassify part of the resistance denominator all other leads are built on."}]}],"retired":[{"title":"PARP inhibition in the HRD-signature G4 (metabolic) GIST subtype","note":"Second consecutive visit with no independent cohort, no biallelic HR-gene lesion and no functional HR assay; the signature remains single-cohort and possibly purely transcriptional. Retired per the pre-committed stopping rule.","cycle":163,"ts":"2026-08-19T23:33:33.181Z"}],"nextQueries":["(GIST OR \"gastrointestinal stromal\") AND (\"SDH-deficient\" OR SDHA OR SDHB) AND (rogaratinib OR belzutifan OR olverembatinib OR \"HIF-2\" OR lipid OR FASN OR SCD1) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(GIST OR \"gastrointestinal stromal\") AND (\"wild-type\" OR quadruple-wildtype OR fusion) AND (FGFR1 OR NTRK OR BRAF OR NF1 OR plixorafenib OR larotrectinib) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(GIST OR \"gastrointestinal stromal\") AND (ctDNA OR \"circulating tumor DNA\" OR \"secondary mutation\") AND (ripretinib OR avapritinib OR velzatinib OR bezuclastinib OR IDRX-42) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-19T23:33:33.181Z"},{"key":"pheochromocytoma","name":"pheochromocytoma","mondo":{"id":"MONDO:0008233","name":"pheochromocytoma"},"genes":[{"label":"VHL","kind":"causal"},{"label":"RET","kind":"causal"},{"label":"TMEM127","kind":"correlated"},{"label":"MAX","kind":"correlated"}],"visits":3,"openQuestions":["Does a prospective selpercatinib/pralsetinib arm exist or can one be opened for RET-mutant/fusion metastatic PPGL, and are germline MEN2 and somatic/fusion RET cases equally responsive (PMID:41801283)?","What are the acquired-resistance genotypes on selective RET inhibitors in chromaffin tumours specifically - solvent-front/gatekeeper RET mutations versus MET/EGFR bypass - and does cabozantinib salvage them?","Still open: cluster-stratified belzutifan response rates in NCT04924075 (VHL vs SDHx vs EPAS1) and the acquired-resistance genotype (EPAS1 gatekeeper, HIF-1alpha switching, MYC/mTOR bypass); do EPO/CgA kinetics predict escape before RECIST?","In archival SDHx versus cluster-2 PPGL, what is the prevalence of MGMT promoter versus gene-body methylation, and does total gene methylation predict temozolomide response better than promoter status (PMID:40464417, PMID:41301064)?","Does UBE2F-dependent neddylation vulnerability replicate in human SDHB-deficient PPGL models with a marrow-sparing window for pevonedistat?","What is the optimal sequencing of belzutifan, VEGFR-axis TKI and SSTR2 radioligand therapy in cluster-1 disease, and does SSTR2 expression survive belzutifan-induced dedifferentiation?"],"leads":[{"id":"L1","title":"HIF-2α inhibition (belzutifan) in cluster-1 pseudohypoxic PPGL","mechanism":"VHL [GERMLINE, Monarch causal anchor] loss, SDHx loss and EPAS1 gain-of-function (usually SOMATIC/mosaic [KNOWN]) converge on constitutive HIF-2alpha-ARNT transcription (VEGF, PDGF, GLUT1, EPO); belzutifan blocks HIF-2alpha-ARNT dimerisation (PMID:41569310). Real-world EPAS1-related PPGL shows shrinkage with EPO -97% and CgA -69% (PMID:41043588). Two independent 2025 reviews now record the 2025 approval as the first oral targeted therapy for advanced/metastatic PPGL and frame it as biomarker-guided, particularly for pseudohypoxic cluster 1 (PMID:41301064, PMID:41300999).","approach":"Unchanged: cluster-stratified analysis of NCT04924075 (EPAS1 vs VHL vs SDHx vs RET/NF1/HRAS) with plasma EPO, CgA, metanephrines and Hb as PD; ctDNA/biopsy at progression for EPAS1 gatekeeper variants, HIF-1alpha isoform switching or MYC/mTOR bypass [SPECULATIVE]. Added this visit: prespecify post-belzutifan sequencing to a VEGFR-axis TKI (L10) versus SSTR2 radioligand therapy (L2). Window: HIF-2alpha governs EPO and duodenal iron handling - anaemia and hypoxia-mimicry are dose-limiting (PMID:41569310).","level":"CANDIDATE","confidence":0.8,"citations":[{"kind":"NCT","id":"NCT04924075","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT00001238","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41043588","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41569310","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41301064","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41300999","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":31,"lastVisit":3,"lastNote":"Strengthened only modestly and deliberately not promoted to DOSSIER: the two NEW sources are secondary reviews confirming regulatory approval and cluster-1 framing (PMID:41301064, PMID:41300999), not new primary response data. The core unanswered question - response rate in VHL and SDHx versus EPAS1 - is untouched, so the kill test has not yet been run.","history":[{"visit":3,"cycle":164,"status":"STRENGTHENED","note":"Strengthened only modestly and deliberately not promoted to DOSSIER: the two NEW sources are secondary reviews confirming regulatory approval and cluster-1 framing (PMID:41301064, PMID:41300999), not new primary response data. The core unanswered question - response rate in VHL and SDHx versus EPAS1 - is untouched, so the kill test has not yet been run."},{"visit":2,"cycle":86,"status":"STRENGTHENED","note":"Promoted: two NEW independent 2026 sources — a real-world series with 4/5 PR, 1 SD, mean −36.8% summed diameters and EPO/CgA collapse (PMID:41043588), and a review documenting approval in advanced PPGL ≥12 years (PMID:41569310). Caveats retained: n=5, retrospective, and responders were EPAS1-lesion patients, so VHL/SDHx response is still unproven — hence CANDIDATE, not DOSSIER."},{"visit":1,"cycle":31,"status":"NEW","note":"New lead founded on the fresh trial pack; NCT04924075 gives a recruiting phase 2 with PPGL explicitly enrolled, and NCT00001238 anchors the VHL natural-history/germline cohort from which cluster-1 patients would be drawn. No response data in the pack — confidence capped."}]},{"id":"L2","title":"Sequenced SSTR2 radioligand therapy: β-emitter first, α-emitter [²¹²Pb]VMT-alpha-NET on failure","mechanism":"PPGL cells express SSTR2 (highest in SDHx/cluster-1 disease [KNOWN]), permitting receptor-mediated internalisation of DOTATATE-class chelates. ¹⁷⁷Lu β-particles give sparse, repair-dependent damage; ²¹²Pb/²¹²Bi α-particles give dense, largely repair-independent double-strand breaks over a few cell diameters, so α-RLT should retain activity where β-RLT failed for dosimetric rather than antigenic reasons [INFERRED].","approach":"Test the sequence explicitly: ¹⁷⁷Lu-DOTATATE (NCT03206060) as first-line RLT, then [²¹²Pb]VMT-alpha-NET in prior-RLT-treated patients (NCT06427798) or RLT-naïve (NCT06479811), using paired ⁶⁸Ga-DOTATATE and [²⁰³Pb]VMT-alpha-NET imaging to separate SSTR2-antigen loss from insufficient absorbed dose. Normal tissue at risk: SSTR2-expressing kidney tubule/pituitary and marrow — α-emitter renal and haematologic dosimetry is the window argument. Resistance routes: SSTR2 downregulation/heterogeneous uptake, DNA-repair upregulation, marrow dose ceiling.","level":"LEAD","confidence":0.6,"citations":[{"kind":"NCT","id":"NCT03206060","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06427798","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06479811","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":31,"lastVisit":1,"lastNote":"New lead; three recruiting NCI trials in this pack collectively define a β→α escalation ladder, with NCT06427798 uniquely enrolling prior-RLT PPGL — the cleanest test of the antigenic-vs-dosimetric failure question. No efficacy data yet.","history":[{"visit":1,"cycle":31,"status":"NEW","note":"New lead; three recruiting NCI trials in this pack collectively define a β→α escalation ladder, with NCT06427798 uniquely enrolling prior-RLT PPGL — the cleanest test of the antigenic-vs-dosimetric failure question. No efficacy data yet."}]},{"id":"L3","title":"Intratumoral innate-immune agonist cocktail (MBTA) for injectable PPGL metastases","mechanism":"Mannan-BAM anchors a phagocytosis-promoting opsonin to the tumour cell membrane; combined with TLR7/8 (resiquimod), TLR3 (poly(I:C)), TLR2 (LTA) agonists and anti-CD40, this converts a lesion into an in-situ vaccine driving neutrophil/macrophage phagocytosis and downstream T-cell priming. P4 shows efficacy is opsonisation- and schedule-dependent (optimised 5×2 dosing, 87.5% survival in Panc02; confirmed in MC38) and controls local recurrence.","approach":"Port the optimised schedule to cutaneous/nodal/hepatic PPGL metastases as intratumoral therapy with abscopal readout; pair with plasma metanephrines and ⁶⁸Ga-DOTATATE for non-injected lesion response. Caveat: catecholamine release during intratumoral inflammation is a real hazard in a secretory tumour, so α/β-blockade pre-treatment would be mandatory [INFERRED]. Window: agonists are locally administered, limiting systemic cytokine exposure.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42318705","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":31,"lastVisit":1,"lastNote":"New but deliberately low-confidence: the pack paper is pancreatic/colon adenocarcinoma, not PPGL. MBTA originated in PPGL models [KNOWN] but this visit supplies no PPGL data — must be corroborated with a PPGL-specific report before it advances.","history":[{"visit":1,"cycle":31,"status":"NEW","note":"New but deliberately low-confidence: the pack paper is pancreatic/colon adenocarcinoma, not PPGL. MBTA originated in PPGL models [KNOWN] but this visit supplies no PPGL data — must be corroborated with a PPGL-specific report before it advances."}]},{"id":"L4","title":"β-adrenoceptor blockade as skeletal-protective and immune-modulatory adjunct in metastatic PPGL","mechanism":"Catecholamine excess acts through β-adrenoceptors on osteoblast/osteoclast axes to increase bone resorption; PPGL patients show lower BMD and trabecular bone score with elevated CTX, partially reversible after resection (PMID:41715942). Since bone is a dominant metastatic site in SDHB-driven PPGL [KNOWN], β-blockade may reduce the osteolytic 'vicious cycle' substrate rather than only controlling hypertension. Independently, propranolol suppresses IFN-I/JAK-STAT signalling (PMID:41866332), suggesting an adjuvant role with oncolytic or innate-agonist therapy.","approach":"Retrospective then prospective testing of β-blocker exposure (after adequate α-blockade — unopposed β-blockade is hazardous in secretory pheo [KNOWN]) against skeletal-event-free survival and CTX/BMD trajectories in bone-metastatic PPGL; separately, propranolol + oncolytic virus or MBTA as an IFN-I-dampening combination, in vitro first. Window: β-blockers are approved, cheap, already standard peri-operatively — repurposing-first.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"41715942","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41866332","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":31,"lastVisit":1,"lastNote":"New; two independent fresh papers, but PMID:41715942 is a review of retrospective BMD series (no oncologic endpoint) and PMID:41866332 is canine mammary tumour — cross-species and cross-indication, so this stays a hypothesis-generating lead, not a therapeutic claim.","history":[{"visit":1,"cycle":31,"status":"NEW","note":"New; two independent fresh papers, but PMID:41715942 is a review of retrospective BMD series (no oncologic endpoint) and PMID:41866332 is canine mammary tumour — cross-species and cross-indication, so this stays a hypothesis-generating lead, not a therapeutic claim."}]},{"id":"L5","title":"UBE2F-dependent neddylation as a synthetic-lethal vulnerability in SDHB-deficient PPGL (pevonedistat repurposing)","mechanism":"Unbiased CRISPR-Cas9 screening in immortalised mouse chromaffin cells ± Sdhb loss showed asymmetric neddylation dependency: UBE2F loss selectively suppressed growth of Sdhb-deficient cells whereas UBE2M loss increased it, and mediator-complex subunits behaved as tumour suppressors in the SDH-deficient state (PMID:42181244). [INFERRED] the dependency is on UBE2F-charged CUL5-type cullin-RING ligase substrate turnover rather than global CRL inhibition — a specific node downstream of succinate accumulation, distinct from HIF-2α.","approach":"Validate in human SDHB-mutant material (hPheo1 SDHB-knockout, patient-derived SDHB PPGL organoids/xenografts) with pevonedistat (MLN4924) and HA-9104; confirm target engagement by loss of CUL5 neddylation and UBE2F-specific rescue; test combination with belzutifan and with temozolomide. Enrichment cohort: germline SDHB carriers at high metastatic risk, e.g. the p.R90* founder population (PMID:42164133). Normal tissue: neddylation is ubiquitous; pevonedistat's clinical dose-limiting toxicities are myelosuppression and transaminitis [KNOWN], so the window rests on the SDHB-selective differential seen in vitro. Resistance: UBE2M compensation, NAE1 mutation, CUL5 substrate bypass [SPECULATIVE].","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"42181244","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42164133","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":86,"lastVisit":2,"lastNote":"New lead from the fresh pack; first unbiased functional genomics answer to open question 3. Notably the screen did NOT nominate PARP or glutamine dependency — recorded so the desk stops re-proposing those without new evidence. Murine chromaffin model only, single laboratory, pharmacology shown in vitro.","history":[{"visit":2,"cycle":86,"status":"NEW","note":"New lead from the fresh pack; first unbiased functional genomics answer to open question 3. Notably the screen did NOT nominate PARP or glutamine dependency — recorded so the desk stops re-proposing those without new evidence. Murine chromaffin model only, single laboratory, pharmacology shown in vitro."}]},{"id":"L6","title":"BUB1 kinase inhibition (BAY1816032) as non-oncogene addiction in metastatic PPGL","mechanism":"Integrative TCGA/COMETE transcriptomics identified BUB1, a mitotic-checkpoint kinase, as upregulated specifically in metastatic PPGL; RT-qPCR confirmed overexpression in primary tumours. Genetic silencing or BAY1816032 reduced hPheo1 viability, colony formation, migration and invasion, with loss of pH2A-T120 confirming on-target kinase inhibition and reduced N-cadherin/vimentin implying an EMT-linked motility function (PMID:42014906).","approach":"Replicate in additional human PPGL models (SDHB-null hPheo1 derivatives, PDX) using pH2A-T120 as pharmacodynamic assay; test whether BUB1 dependency tracks with metastatic/SDHx genotype rather than proliferation index alone; explore combination with SSTR2 radioligand therapy since checkpoint-kinase inhibition should impair repair of radiation-induced damage [SPECULATIVE]. Window: BUB1 is required for faithful chromosome segregation in all dividing cells — marrow and gut crypt toxicity expected [KNOWN]; the argument must be a metastatic-vs-normal expression differential. Resistance: aneuploidy tolerance, SAC rewiring via MPS1/BUBR1.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42014906","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":86,"lastVisit":2,"lastNote":"New lead from NEW 2026 paper. Deliberately capped: one cell line, one tool compound, biomarker not yet shown to be metastasis-specific rather than proliferation-correlated; explicitly framed by the authors as requiring multi-institutional validation.","history":[{"visit":2,"cycle":86,"status":"NEW","note":"New lead from NEW 2026 paper. Deliberately capped: one cell line, one tool compound, biomarker not yet shown to be metastasis-specific rather than proliferation-correlated; explicitly framed by the authors as requiring multi-institutional validation."}]},{"id":"L7","title":"Succinate-driven hypermethylation as a temozolomide-sensitivity rationale in SDHx PPGL (MGMT-guided)","mechanism":"Succinate accumulation inhibits alpha-KG-dependent TET/KDM dioxygenases producing global hypermethylation (PMID:41637165); in PPGL specifically, SDHB-mutated tumours are now reported to show heightened temozolomide sensitivity associated with MGMT promoter hypermethylation and reduced MGMT expression (PMID:41301064), with MGMT flagged as a promising but cautiously interpreted tissue biomarker in neuroendocrine neoplasms (PMID:41300999). Assay caveat that changes the design: MGMT gene-body methylation correlates positively with MGMT transcript and anticorrelates with promoter methylation in non-glioma and IDH-wild-type cohorts, and alkylator sensitivity tracks total gene methylation rather th","approach":"Archival SDHx versus cluster-2 PPGL with documented temozolomide exposure profiled by 850k-class methylation array reporting both MGMT promoter and body methylation plus MGMT protein by IHC, correlated with RECIST response and PFS; enrich with high-metastatic-risk germline SDHB founder cohorts (PMID:42164133). If total-methylation status outperforms promoter status, run a biomarker-selected temozolomide arm and test combination with pevonedistat (L5) or PARP inhibition. Window: temozolomide is oral and approved; myelosuppression is dose-limiting [KNOWN]. Resistance: MGMT re-expression, MMR loss with hypermutant progression.","level":"CANDIDATE","confidence":0.5,"citations":[{"kind":"PMID","id":"41637165","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42316325","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42164133","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41301064","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41300999","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40464417","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":86,"lastVisit":3,"lastNote":"Promoted: first PPGL-specific (not glioma-extrapolated) statement linking SDHB genotype, MGMT hypermethylation/low expression and temozolomide sensitivity (PMID:41301064), independently echoed by PMID:41300999. PMID:40464417 is a methodological correction that reshapes the assay - promoter-only methylation is insufficient. Still no primary PPGL cohort with paired MGMT status and response, so not D","history":[{"visit":3,"cycle":164,"status":"STRENGTHENED","note":"Promoted: first PPGL-specific (not glioma-extrapolated) statement linking SDHB genotype, MGMT hypermethylation/low expression and temozolomide sensitivity (PMID:41301064), independently echoed by PMID:41300999. PMID:40464417 is a methodological correction that reshapes the assay - promoter-only methylation is insufficient. Still no primary PPGL cohort with paired MGMT status and response, so not D"},{"visit":2,"cycle":86,"status":"NEW","note":"New but low confidence and honestly so: the mechanistic paper is glioma, not PPGL, and the clinical support is a single case report with mixed outcome (intracranial control, extracranial progression). No MGMT status was reported in either. Kept because it is cheap to falsify with archival tissue."}]},{"id":"L8","title":"SRS/SBRT as local-control backbone for oligometastatic/oligoprogressive non-head-and-neck PGL and pheochromocytoma","mechanism":"PPGL has historically been considered radioresistant; a 74-patient/129-lesion single-institution series plus PRISMA systematic review reports 5-year local control of 95.3% for non-HNPGL lesions (100% for HNPGL) with 78% symptomatic control, median BED10 50.8 Gy (PMID:42122265). Distant PFS of 37.6 months against OS of 131 months indicates local ablation does not control systemic disease — i.e. EBRT is a consolidation, not a systemic, modality [INFERRED].","approach":"Use SRS/SBRT as the comparator any new systemic lead must beat for a solitary or oligoprogressive lesion, and test it prospectively as consolidation after belzutifan or SSTR2 radioligand therapy to address the dominant-lesion failure pattern. Catecholamine-crisis risk during irradiation of a secretory lesion mandates α- then β-blockade [INFERRED; unopposed β-blockade is hazardous, KNOWN]. Window: highly conformal, spinal-cord/kidney/bowel dose constraints are the limits.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42122265","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":86,"lastVisit":2,"lastNote":"New lead from NEW 2026 evidence. Retrospective, single institution, heterogeneous dose/fractionation and no genotype stratification, so it is recorded as a backbone/comparator hypothesis rather than a novel mechanism.","history":[{"visit":2,"cycle":86,"status":"NEW","note":"New lead from NEW 2026 evidence. Retrospective, single institution, heterogeneous dose/fractionation and no genotype stratification, so it is recorded as a backbone/comparator hypothesis rather than a novel mechanism."}]},{"id":"L9","title":"Selective RET inhibition (selpercatinib/pralsetinib) in RET-mutant/fusion pheochromocytoma","mechanism":"RET [Monarch causal anchor; GERMLINE in MEN2, also SOMATIC mutation/fusion cases] encodes a receptor tyrosine kinase whose activating mutations drive constitutive RAS-MAPK, PI3K-AKT and JAK-STAT signalling in chromaffin/parafollicular lineages (PMID:41977363, PMID:41930492). This is a directly druggable activated oncogene rather than a tumour-suppressor loss, so ATP-competitive selective inhibition applies. Pooled clinical data in advanced RET-mutant pheochromocytoma: 9 patients (8 selpercatinib, 1 pralsetinib), 2 CR, 5 PR, 2 durable SD, PFS 5.5-56.3 months, urinary catecholamine/metanephrine improvement or normalisation in 7 (PMID:41801283) - i.e. biochemical PD tracks radiological response","approach":"Prospective single-arm trial of selpercatinib in RET-mutant/fusion metastatic PPGL with RECIST plus plasma/urinary metanephrines as co-primary PD endpoints; leverage existing MEN2 natural-history infrastructure for genotype ascertainment (NCT01660984) and RET testing frameworks from MTC practice (PMID:42116529). At progression, sequence tumour/ctDNA for secondary RET solvent-front or gatekeeper mutations and for MET/EGFR-amplification bypass (PMID:41977363), which dictate next-generation RET inhibitor versus RET+MET combination arms. Mandatory alpha- then beta-blockade before initiating therapy in a secretory tumour given tumour-lysis-associated catecholamine release [INFERRED; unopposed bet","level":"LEAD","confidence":0.68,"citations":[{"kind":"PMID","id":"41801283","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41977363","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41930492","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42116529","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41968620","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT01660984","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":164,"lastVisit":3,"lastNote":"NEW lead answering open question 6 affirmatively: RET-inhibitor activity in PPGL is no longer confined to MTC inference. Capped at LEAD despite a striking response fraction because the evidence is a pooled retrospective case series (n=9, publication-biased, no prospective arm, heterogeneous prior lines).","history":[{"visit":3,"cycle":164,"status":"NEW","note":"NEW lead answering open question 6 affirmatively: RET-inhibitor activity in PPGL is no longer confined to MTC inference. Capped at LEAD despite a striking response fraction because the evidence is a pooled retrospective case series (n=9, publication-biased, no prospective arm, heterogeneous prior lines)."}]},{"id":"L10","title":"VEGFR-axis multikinase inhibition (cabozantinib/sunitinib/anlotinib) as sequencing partner and comparator for cluster-1 PPGL","mechanism":"Cluster-1 pseudohypoxic PPGL is transcriptionally angiogenic (HIF-2alpha-driven VEGF/PDGF output), so VEGFR2/PDGFR/MET blockade attacks the same axis one step downstream of the ligand rather than at the transcription factor [INFERRED]. Cabozantinib improves PFS after prior therapy in neuroendocrine neoplasms (PMID:41300999) and sunitinib, anlotinib and cabozantinib all show meaningful activity in metastatic/unresectable PPGL (PMID:41301064). Cabozantinib additionally inhibits RET and MET, making it a mechanistic bridge to L-RET: MET-mediated bypass is a documented escape route from selective RET inhibitors (PMID:41977363). Normal tissue: VEGFR blockade impairs endothelial homeostasis - hyper","approach":"Retrospective comparison of belzutifan-then-TKI versus TKI-then-belzutifan sequences in cluster-1 PPGL using time-to-next-treatment; prospectively, a randomised sequencing question against SRS/SBRT consolidation for oligoprogression (L8). Mechanistically, test whether MET/RET co-inhibition by cabozantinib salvages selective-RET-inhibitor progression in RET-mutant PPGL models. Record as the efficacy floor any novel systemic lead must beat.","level":"LEAD","confidence":0.48,"citations":[{"kind":"PMID","id":"41301064","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41300999","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41977363","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":164,"lastVisit":3,"lastNote":"NEW lead built from two NEW 2025 reviews; deliberately low confidence because the underlying PPGL TKI data are small single-arm studies summarised at review level, with no head-to-head against belzutifan and no genotype stratification. Also recorded here as a notebook negative: checkpoint-inhibitor monotherapy gives only modest responses in PPGL (PMID:41301064) - do not re-propose single-agent PD-","history":[{"visit":3,"cycle":164,"status":"NEW","note":"NEW lead built from two NEW 2025 reviews; deliberately low confidence because the underlying PPGL TKI data are small single-arm studies summarised at review level, with no head-to-head against belzutifan and no genotype stratification. Also recorded here as a notebook negative: checkpoint-inhibitor monotherapy gives only modest responses in PPGL (PMID:41301064) - do not re-propose single-agent PD-"}]}],"retired":[],"nextQueries":["(\"pheochromocytoma\" OR \"paraganglioma\") AND (cabozantinib OR sunitinib OR anlotinib OR lenvatinib) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\") AND (belzutifan OR \"HIF-2\") AND (resistance OR progression OR \"cluster 1\" OR SDHB) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\" OR \"chromaffin\") AND (neddylation OR UBE2F OR pevonedistat OR MLN4924 OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T23:37:02.992Z"},{"key":"paraganglioma","name":"paraganglioma","mondo":{"id":"MONDO:0000448","name":"paraganglioma"},"genes":[{"label":"SDHAF2","kind":"causal"},{"label":"SLC25A11","kind":"causal"},{"label":"DLST","kind":"causal"},{"label":"SDHB","kind":"causal"},{"label":"SDHC","kind":"causal"},{"label":"SDHD","kind":"causal"},{"label":"SDHA","kind":"causal"},{"label":"EPAS1","kind":"correlated"},{"label":"VHL","kind":"correlated"},{"label":"RET","kind":"correlated"},{"label":"DNMT3A","kind":"correlated"}],"visits":3,"openQuestions":["Does pan-NAE inhibition (pevonedistat) actually promote rather than suppress growth of SDHB-deficient chromaffin cells, as the succinate→p-UBC12 model predicts, and is UBE2F-selective inhibition separable from it?","Is p-UBC12/UBE2M phosphorylation and reduced CRL1/2 neddylation demonstrable in human SDHx-mutant PPGL tissue, and is CRL5-NOXA the effector of the UBE2F dependency?","Have LITESPARK-015 genomic correlates or any on-treatment post-belzutifan PPGL biopsies been published showing PAS-B mutation, HIF1α switching, or HIF-independent pVHL-driven escape?","Do any patient-derived PPGL models (PDX, organoid, allograft) with defined SDHB/SDHD/EPAS1 genotypes now exist, given P7 names their absence as the field's rate-limiting gap?","Is post-177Lu-DOTATATE progression in SDHB-mutant PGL driven by SSTR2 loss versus uptake heterogeneity, and has NCT06427798 reported any 212Pb-VMT-alpha-NET PPGL response or dosimetry data?","Can plasma or tumour succinate be pharmacologically lowered in SDH-deficient models, and does it restore sensitivity to cabozantinib or alkylators?"],"leads":[{"id":"L1","title":"HIF2α antagonism in pseudohypoxic (cluster 1) paraganglioma","mechanism":"SDHx loss [GERMLINE] → succinate accumulation → inhibition of α-KG-dependent prolyl hydroxylases → HIF2α stabilisation; VHL loss and EPAS1 gain-of-function [SOMATIC] converge on HIF2α-ARNT-driven VEGF/EPO/GLUT1. Belzutifan blocks HIF2α PAS-B dimerisation. New this visit: pVHL also has HIF-independent tumour-suppressor functions (PMID:42313274), predicting a subset of VHL-driven lesions with HIF2α-blockade-insensitive drivers.","approach":"Axis is established (FDA-approved oral therapy for metastatic PPGL; durable responses, hypertension and QoL benefit — PMID:42025325, PMID:42503916, NCT04924075). Remaining work is entirely correlative/combinatorial: (i) genotype-resolved ORR/PFS (SDHB vs SDHD vs EPAS1 vs VHL) and plasma succinate:fumarate as PD biomarker; (ii) on-progression biopsies for PAS-B mutation, HIF1α/MYC switching, and HIF-independent VHL escape; (iii) belzutifan + cabozantinib or sunitinib to close VEGF-mediated angiogenic escape given the ORR-DCR gap; (iv) enrich with high-risk SDHB founder alleles. Expected resistance: PAS-B pocket mutation, HIF1α switching, VEGF-independent escape, HIF-independent pVHL loss.","level":"DOSSIER","confidence":0.8,"citations":[{"kind":"PMID","id":"42050152","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04924075","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42573142","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42481355","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42164133","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42025325","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42503916","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42313274","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":32,"lastVisit":3,"lastNote":"Third evidence-bearing visit; three independent NEW 2026 reviews (P7, P9, P10) confirm approval, durability, BP/QoL benefit and cluster-based positioning. P10 adds a previously unlogged resistance route (HIF-independent pVHL functions). Tier reflects a settled therapeutic axis; the correlative programme is still unanswered — genotype-resolved LITESPARK-015 data absent for a third visit, and P7 sta","history":[{"visit":3,"cycle":165,"status":"STRENGTHENED","note":"Third evidence-bearing visit; three independent NEW 2026 reviews (P7, P9, P10) confirm approval, durability, BP/QoL benefit and cluster-based positioning. P10 adds a previously unlogged resistance route (HIF-independent pVHL functions). Tier reflects a settled therapeutic axis; the correlative programme is still unanswered — genotype-resolved LITESPARK-015 data absent for a third visit, and P7 sta"},{"visit":2,"cycle":87,"status":"STRENGTHENED","note":"Second evidence-bearing visit with new independent citations. P9 [NEW] gives the efficacy numbers I demanded (ORR 26%, DCR 85%, FDA approval, BP/QoL benefit). P10 [NEW] confirms genotype correlates are absent from the public record, so stratification remains open, not refuted. P6 [NEW] supplies a high-metastatic-risk SDHB founder population for enrichment. Resistance routes (PAS-B mutation, HIF1α "},{"visit":1,"cycle":32,"status":"NEW","note":"New lead. P10 (Nat Rev Clin Oncol review) states belzutifan has shown substantial efficacy in pheochromocytoma/paraganglioma and treats HIF2α as a validated oncology target; NCT04924075 is the recruiting phase 2 PPGL arm. Mechanistic link succinate→PHD inhibition→HIF2α is [KNOWN]. Named resistance routes: PAS-B pocket mutation abolishing drug binding (analogous to ccRCC belzutifan resistance [KNOW"}]},{"id":"L2","title":"SSTR2-directed radioligand therapy with β→α emitter escalation in metastatic paraganglioma","mechanism":"SSTR2 is highly and homogeneously expressed on metastatic PPGL, particularly SDHB-mutant disease [KNOWN], permitting receptor-mediated internalisation of radiolabelled octreotate analogues. 177Lu delivers long-range β crossfire; 212Pb delivers short-range, high-LET α particles causing clustered double-strand breaks less dependent on oxygenation or DNA-repair capacity — relevant because pseudohypoxic PGL is hypoxia-adapted [INFERRED].","approach":"Sequence 68Ga-DOTATATE selection → 177Lu-DOTATATE (NCT03206060) → on progression, 212Pb-VMT-alpha-NET with 203Pb dosimetry imaging (NCT06427798, NCT06479811). Prospectively capture SDHx genotype, tumour SSTR2 SUVmax, and paired pre/post biopsies to test whether radioligand failure is SSTR2 loss or uptake heterogeneity.","level":"LEAD","confidence":0.62,"citations":[{"kind":"NCT","id":"NCT03206060","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06427798","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06479811","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":32,"lastVisit":1,"lastNote":"New lead. Three recruiting NCI trials in the pack, and critically NCT06427798 enrols specifically after prior systemic radioligand therapy — the field has already constructed the resistance-sequencing experiment. Normal-tissue window: SSTR2 on pituitary, pancreatic islets, GI tract; dose-limiting organs are marrow and kidney. Expected resistance: SSTR2 downregulation/dedifferentiation, heterogeneo","history":[{"visit":1,"cycle":32,"status":"NEW","note":"New lead. Three recruiting NCI trials in the pack, and critically NCT06427798 enrols specifically after prior systemic radioligand therapy — the field has already constructed the resistance-sequencing experiment. Normal-tissue window: SSTR2 on pituitary, pancreatic islets, GI tract; dose-limiting organs are marrow and kidney. Expected resistance: SSTR2 downregulation/dedifferentiation, heterogeneo"}]},{"id":"L3","title":"DLK1 as a cell-surface target for ADC or antibody therapy in paraganglioma","mechanism":"DLK1 is a cleavable transmembrane non-canonical Notch ligand, silenced in most adult tissues but persisting in endocrine stem/progenitor compartments, and re-expressed at high prevalence in PPGL where it is linked to a de-differentiated, stem-like, treatment-resistant phenotype.","approach":"Establish PPGL-specific DLK1 prevalence and staining intensity by IHC across SDHx-mutant vs cluster-2 tumours and metastatic vs indolent lesions; then test afucosylated anti-DLK1 mAb and DLK1 ADC in SDHB-deficient PGL models. Assess soluble ectodomain shedding as a confound for ADC delivery and as a possible circulating biomarker.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42023826","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":32,"lastVisit":1,"lastNote":"New lead, deliberately low confidence: evidence is a single 2026 review (abstract only) asserting high DLK1 prevalence in PPGL and multiple DLK1-directed agents in preclinical/early clinical development. No PPGL-specific quantitative data, no genotype correlation, no in vivo PGL efficacy in the pack. Window argument rests on developmentally restricted adult expression — but endocrine progenitor an","history":[{"visit":1,"cycle":32,"status":"NEW","note":"New lead, deliberately low confidence: evidence is a single 2026 review (abstract only) asserting high DLK1 prevalence in PPGL and multiple DLK1-directed agents in preclinical/early clinical development. No PPGL-specific quantitative data, no genotype correlation, no in vivo PGL efficacy in the pack. Window argument rests on developmentally restricted adult expression — but endocrine progenitor an"}]},{"id":"L5","title":"Neddylation / UBE2F-CRL5 as a synthetic-lethal vulnerability of SDHB-deficient paraganglioma","mechanism":"CRISPR screen in isogenic Sdhb-null mouse chromaffin cells: Ube2f loss suppresses growth, Ube2m loss increases proliferation (PMID:42181244). P2 [NEW] shows succinate itself phosphorylates UBC12/UBE2M and impairs its E2 function in cullin neddylation, stabilising oncoproteins and conferring multi-drug resistance in SDH-deficient AML (PMID:39537588). [INFERRED] Together these define an E2-switch: succinate disables the UBE2M-CRL1/2 arm, leaving SDH-deficient cells reliant on UBE2F-SAG/RBX2-CRL5, whose substrates include NOXA and p27. Normal tissue: neddylation is ubiquitous; NAE inhibition perturbs hepatocyte cardiolipin synthesis via TAM41 (PMID:39019009) and granulosa-cell CPT1A/FAO (PMID:4","approach":"Priority experiment is a kill test, not a confirmation: dose pevonedistat across isogenic human SDHB-proficient/deficient chromaffin models and ask whether pan-NAE inhibition is neutral or growth-PROMOTING, as P2 predicts. In parallel, test UBE2F/SAG-selective tools (HA-9104, UBE2F degradation) with PD readouts of UBE2F charging, CRL5 substrate accumulation (NOXA, p27) and both UBE2M- and UBE2F-arm substrates; establish NOXA dependence by knockout and BH3-mimetic combination; test succinate rescue (dimethyl-succinate) and SDHA/SDHC/SDHD isogenic generality. Expected resistance: NEDD8/UBA3 site mutation, NAE1 amplification, loss of apoptotic effector, compensatory UBE2M rephosphorylation.","level":"CANDIDATE","confidence":0.5,"citations":[{"kind":"PMID","id":"42181244","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39537588","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"39019009","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41939244","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":87,"lastVisit":3,"lastNote":"Second evidence-bearing visit with independent NEW mechanism (P2) linking succinate directly to cullin neddylation via UBC12/UBE2M phosphorylation — explains the paradoxical Ube2m-suppressor result in the PPGL screen. Confidence raised only modestly because the same paper argues AGAINST the original clinical handle: pan-NAE inhibitors would phenocopy the pro-tumour UBE2M-off state. Approach rewrit","history":[{"visit":3,"cycle":165,"status":"STRENGTHENED","note":"Second evidence-bearing visit with independent NEW mechanism (P2) linking succinate directly to cullin neddylation via UBC12/UBE2M phosphorylation — explains the paradoxical Ube2m-suppressor result in the PPGL screen. Confidence raised only modestly because the same paper argues AGAINST the original clinical handle: pan-NAE inhibitors would phenocopy the pro-tumour UBE2M-off state. Approach rewrit"},{"visit":2,"cycle":87,"status":"NEW","note":"First citable synthetic-lethality axis for SDHx loss in the programme, partially answering open question 2 — and notably it is NOT PARP, NAMPT or glutamine. Held at LEAD: single 2026 paper, mouse imCC monoculture, no in vivo efficacy, no human PPGL tissue, and clinical-stage NAE inhibitors have a weak track record in unselected solid tumours [KNOWN]."}]},{"id":"L7","title":"Succinate lowering as a resensitising strategy in SDHx-mutant metastatic paraganglioma","mechanism":"Succinate is not only a HIF2α stabiliser but an autonomous drug-resistance effector: in SDH-deficient AML, cumulative succinate confers resistance to multiple anti-cancer agents via p-UBC12/cullin dysregulation, and pharmacological succinate reduction with fludarabine restores sensitivity (PMID:39537588). PMID:40285898 formalises succinate-dependent vs succinate-independent mechanisms in SDH-defective cancers. [INFERRED] In SDHx PPGL, where succinate concentrations are among the highest measured in human tumours, the same axis could underlie the low objective-response rates of cabozantinib, CVD chemotherapy and radioligand therapy.","approach":"Measure intracellular succinate and p-UBC12 in SDHB-knockdown hPheo1 and SDHB-mutant allografts; screen succinate-lowering interventions (fludarabine, glutaminase/anaplerosis blockade, malonate-free complex-II bypass) for restoration of sensitivity to cabozantinib, temozolomide/dacarbazine and radiation surrogates; use plasma succinate:fumarate ratio as the clinical PD readout, shared with L1. Deliberately low confidence: zero PPGL data, and fludarabine's succinate effect may be lineage-specific to haematopoietic cells. Expected resistance: re-accumulation of succinate via residual SDH loss, succinate-independent HIF2α or kinase-cluster drivers.","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"39537588","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40285898","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":165,"lastVisit":3,"lastNote":"New lead extracted from P2 to separate a distinct therapeutic logic — normalise the oncometabolite rather than block one downstream effector — from L1 and L5, so the desk tests it rather than re-deriving it. Opened low; retire next visit unless PPGL-model succinate-depletion data appear.","history":[{"visit":3,"cycle":165,"status":"NEW","note":"New lead extracted from P2 to separate a distinct therapeutic logic — normalise the oncometabolite rather than block one downstream effector — from L1 and L5, so the desk tests it rather than re-deriving it. Opened low; retire next visit unless PPGL-model succinate-depletion data appear."}]}],"retired":[{"title":"Alkylator/MGMT axis in metastatic SDHx paraganglioma (low-confidence placeholder)","note":"Pre-committed retirement executed. Third pack, still no PPGL-specific MGMT methylation or protein data and no PARP+TMZ in vivo chromaffin data; P9's contemporary systemic-therapy review discusses CVD chemotherapy with no methylation stratification whatsoever. Logged so the desk does not re-open MGMT-guided temozolomide in PPGL without primary methylation data from SDHx-genotyped tumours.","cycle":165,"ts":"2026-08-19T23:40:38.551Z"},{"title":"MBTA intratumoral innate-immune agonist cocktail for locally accessible or recurrent paraganglioma","note":"Pre-committed retirement executed. Two evidence packs, zero paraganglioma-model data; the only citable efficacy remains pancreatic/colon adenocarcinoma allografts, and PGL extrapolation rested on uncitable recollection. Logged so the desk does not re-propose intratumoral MBTA for PPGL without primary chromaffin-model evidence.","cycle":87,"ts":"2026-08-19T19:09:23.823Z"}],"nextQueries":["(UBE2F OR UBE2M OR UBC12 OR \"SAG\" OR RBX2 OR \"cullin-RING\") AND (SDHB OR \"succinate dehydrogenase\" OR succinate) AND SRC:MED AND PUB_YEAR:[2024 TO 2027]","(pheochromocytoma OR paraganglioma) AND (\"patient-derived xenograft\" OR organoid OR \"cell line\" OR allograft OR hPheo1) AND SRC:MED AND PUB_YEAR:[2023 TO 2027]","(pheochromocytoma OR paraganglioma) AND (\"DOTATATE\" OR \"radioligand\" OR SSTR2) AND (resistance OR progression OR heterogeneity OR \"alpha emitter\" OR 212Pb) AND SRC:MED AND PUB_YEAR:[2024 TO 2027]"],"updatedAt":"2026-08-19T23:40:38.551Z"},{"key":"medullary thyroid carcinoma","name":"medullary thyroid carcinoma","mondo":{"id":"MONDO:0015277","name":"medullary thyroid gland carcinoma"},"genes":[{"label":"RET","kind":"causal"},{"label":"ESR2","kind":"correlated"},{"label":"NTRK1","kind":"correlated"}],"visits":3,"openQuestions":["What is the MTC-specific frequency of acquired MET amplification at selpercatinib/pralsetinib progression, and is any human dosing precedent available for selective RET plus selective MET TKI co-administration?","Does the standardized DLL3 assay (PMID:39558076) concord with SP347 >=50% on MTC blocks, and what density threshold separates tarlatamab responders from non-responders?","Do calcitonin and CEA kinetics under T-cell engagement track radiographic response tightly enough to serve as a co-primary endpoint, given engager-induced tumour lysis and inflammation?","Is DLL3-low MTC enriched for SSTR2 or FAP positivity, permitting single-biopsy triage between engager, radioligand and MET/MEK arms?","What drives RET-wildtype MTC (RAS-mutant and quadruple-negative), and is there any supported somatic role for NTRK1 or ESR2 there?","Can ERK hyperactivation-induced toxicity be exploited in RET-driven MTC as an alternative to MAPK suppression?"],"leads":[{"id":"L1","title":"RET + MEK dual blockade for MAPK-bypass resistance in RET-mutant MTC","mechanism":"NF1 [SOMATIC] loss or RAS/MAPK reactivation without RET-site mutation restores ERK output on selective RET inhibition; CRISPR NF1 knockout was sufficient and selpercatinib+trametinib restored control in vivo (PMID:42258786). Clinical resistance landscape now shows KRAS acquired in 7.1% of post-SRI biopsies but no reported NF1 events, so the addressable fraction is smaller than the preclinical model implied (PMID:41537704).","approach":"Retain as a biomarker-gated, second-priority combination: phase 1b of selpercatinib + intermittent trametinib restricted to progression biopsies with absent secondary RET mutation, absent MET amplification, and a positive MAPK-output signature (pERK/DUSP6 IHC or KRAS/NF1 alteration). Normal-tissue window: MEK1/2 sustains epidermal, retinal and cardiac homeostasis, RET sustains enteric/renal tissue [KNOWN]; intermittent dosing plus serial LVEF/ocular/hepatic monitoring given fatal hepatic failure on long-term selpercatinib (PMID:42606612). Resistance: RET G810S, MEK1 mutation, ERK reactivation.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42258786","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42525389","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42520863","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41537704","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41977363","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":33,"lastVisit":2,"lastNote":"Weakened: the first clinical resistance landscape in RET-altered tumours reports no NF1 events and only 7.1% KRAS, while MET amplification dominates; hypothesis survives only as a MAPK-output-gated niche.","history":[{"visit":2,"cycle":88,"status":"WEAKENED","note":"Weakened: the first clinical resistance landscape in RET-altered tumours reports no NF1 events and only 7.1% KRAS, while MET amplification dominates; hypothesis survives only as a MAPK-output-gated niche."},{"visit":1,"cycle":33,"status":"NEW","note":"New this visit; built on the CRISPR + xenograft evidence in P9, with two independent 2026 reviews corroborating MAPK bypass as a distinct resistance class."}]},{"id":"L2","title":"Next-generation RET inhibitors for on-target gatekeeper/solvent-front resistance","mechanism":"Secondary RET kinase-domain mutations (e.g. p.G810S solvent front) sterically exclude selpercatinib/pralsetinib while RET dependency persists (PMID:42258786, PMID:42520863, PMID:41977363).","approach":"Allele-specific ctDNA-selected cohorts of zeteletinib/SYHA1815/BOS172738/SY-5007-class agents; do not enrol bypass-resistant patients. Enrolment feasibility must assume only ~20-23% of progressing thyroid tumours carry a secondary RET mutation (PMID:41537704), implying multi-tumour, ctDNA-screened basket design rather than an MTC-only trial. Resistance: compound RET mutations, then loss of RET dependency.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42520863","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42525389","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04280081","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41537704","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41977363","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":33,"lastVisit":2,"lastNote":"Weakened on prevalence, not on mechanism: RETgistry quantifies the eligible fraction as small (14% overall, 22.7% thyroid biopsies), making histology-based trials underpowered.","history":[{"visit":2,"cycle":88,"status":"WEAKENED","note":"Weakened on prevalence, not on mechanism: RETgistry quantifies the eligible fraction as small (14% overall, 22.7% thyroid biopsies), making histology-based trials underpowered."},{"visit":1,"cycle":33,"status":"NEW","note":"New; supported only by narrative reviews plus the preclinical G810S observation — no MTC-specific efficacy data for the next-gen agents in this pack."}]},{"id":"L3","title":"FAP as a selection/imaging biomarker in SSTR-poor MTC, with FAP radioligand therapy currently unsupported as monotherapy","mechanism":"MTC stroma expresses FAP; 68Ga-FAPI PET/CT detected hepatic and extensive skeletal metastases missed by 68Ga-DOTATATE and 99mTc-octreotide, including a low-secretory phenotype, indicating SSTR2 expression is an unreliable target in advanced MTC (PMID:41984869, PMID:41950235).","approach":"Use FAPI PET as the staging/eligibility modality for advanced MTC trials rather than SSTR imaging. Therapeutic use deferred: 177Lu-FAPI-2286 produced no biochemical response in the reported case (PMID:41984869) — NEGATIVE result logged; revisit only with long-residence FAP ligands (dimeric/albumin-binder scaffolds) or combination with DNA-damage-response inhibition. Window caveat: FAP is expressed in wound-healing fibroblasts and some bone marrow stroma [KNOWN].","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"41984869","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41950235","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":33,"lastVisit":1,"lastNote":"New; deliberately entered as a biomarker lead, not a therapy lead, because the only therapeutic datapoint in the pack is a failure.","history":[{"visit":1,"cycle":33,"status":"NEW","note":"New; deliberately entered as a biomarker lead, not a therapy lead, because the only therapeutic datapoint in the pack is a failure."}]},{"id":"L4","title":"MET-directed rescue at selective RET inhibitor progression: cabozantinib re-sequencing or selpercatinib + selective MET TKI, gated on MET amplification","mechanism":"MET alterations were the most frequent acquired off-target event in post-selective-RET-inhibitor progression biopsies (18.2%; amplification 15%), restoring RAS-MAPK and PI3K-AKT flux downstream of a still-inhibited RET (PMID:41537704, PMID:41977363) [INFERRED]. Cabozantinib, already approved in MTC, inhibits MET, RET and VEGFR2 [KNOWN].","approach":"ctDNA/tissue triage at selpercatinib progression; MET-amplified patients to cabozantinib re-sequencing or selpercatinib + capmatinib/tepotinib at staggered, de-escalated doses with MET copy number and HGF as PD covariates. Safety scaffold must assume class-effect hepatic enzyme elevation, hypertension and neutropenia on selective RET-TKIs independent of tumour type (PMID:42161875), overlapping MET-TKI hepatotoxicity and cabozantinib VEGFR2 toxicity, and prior fatal hepatic failure on long-term selpercatinib (PMID:42606612). RET normal-tissue dependencies: enteric/autonomic/sensory neurons, renal development, spermatogenesis (PMID:42107510). Escape: MET kinase-domain mutation, HGF autocrine l","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"41537704","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41977363","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42606612","verified":false,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT04280081","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42161875","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42107510","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":88,"lastVisit":3,"lastNote":"Weakened on feasibility: a targeted search for MTC-specific MET amplification/capmatinib/tepotinib/crizotinib resistance data returned no MTC datapoints, so the 18.2% figure remains extrapolated from a mixed-histology cohort with only 15 thyroid primaries. New AE consensus (PMID:42161875) documents overlapping hepatic/hypertensive class toxicity, tightening the dosing constraint on any doublet.","history":[{"visit":3,"cycle":166,"status":"WEAKENED","note":"Weakened on feasibility: a targeted search for MTC-specific MET amplification/capmatinib/tepotinib/crizotinib resistance data returned no MTC datapoints, so the 18.2% figure remains extrapolated from a mixed-histology cohort with only 15 thyroid primaries. New AE consensus (PMID:42161875) documents overlapping hepatic/hypertensive class toxicity, tightening the dosing constraint on any doublet."},{"visit":2,"cycle":88,"status":"NEW","note":"New this visit; created directly by the RETgistry landscape, which displaces NF1/MEK as the leading bypass hypothesis and points at an already-approved MTC drug with MET activity."}]},{"id":"L5","title":"DLL3-directed T-cell engagement (tarlatamab) in DLL3-high MTC after RET inhibitor failure","mechanism":"MTC is a neuroendocrine neoplasm expressing DLL3 in 89.1% of resected cases (35.3% high), with DLL3-high tracking high-grade histology and markedly shorter DFS/OS (PMID:41345358). Standardized-assay profiling confirms DLL3 is expressed across high-grade extrapulmonary NEN over a wide dynamic range (PMID:39558076), so MTC sits in a druggable-target class where density/heterogeneity, not absence, limits engager activity [INFERRED]. Tarlatamab (DLL3xCD3 BiTE) redirects T cells to DLL3+ cells; one post-selpercatinib RET-altered MTC patient achieved ongoing biochemical and radiographic CR with only grade 2 CRS/ICANS under an intensified step-up (PMID:42134278).","approach":"MTC-specific phase 2 in DLL3-high tumours progressing on selective RET inhibitor, using a single centrally read standardized DLL3 IHC assay (PMID:39558076) alongside SP347, mandatory paired pre/post-progression biopsies, three-step step-up dosing with intensified CRS/ICANS management, and co-primary RECIST plus prospectively defined calcitonin/CEA kinetics. Power against a realistic prior: pooled DLL3-inhibitor ORR 21%, DCR 57%, mPFS 3.54 months, with combination immunotherapy arms showing longer PFS (4.2 vs 3.36 mo) (PMID:40110579), justifying a checkpoint-combination arm. Prespecify CRS (49%) and thrombocytopenia (23%) monitoring (PMID:40110579). Window: DLL3 near-absent in adult normal ti","level":"CANDIDATE","confidence":0.56,"citations":[{"kind":"PMID","id":"41345358","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42117355","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42134278","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41992056","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT07016230","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"39558076","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40110579","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40496850","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40284515","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":88,"lastVisit":3,"lastNote":"Second evidence-bearing visit with new independent literature: standardized-assay EP-NEN landscape (PMID:39558076) and a 21-trial/2452-patient meta-analysis (PMID:40110579) that both corroborates the modality and caps expected ORR at ~21% with CRS 49%. Promoted to CANDIDATE; confidence raised only slightly because efficacy remains n=1 in MTC and the pooled data mix ADC with engager platforms.","history":[{"visit":3,"cycle":166,"status":"STRENGTHENED","note":"Second evidence-bearing visit with new independent literature: standardized-assay EP-NEN landscape (PMID:39558076) and a 21-trial/2452-patient meta-analysis (PMID:40110579) that both corroborates the modality and caps expected ORR at ~21% with CRS 49%. Promoted to CANDIDATE; confidence raised only slightly because efficacy remains n=1 in MTC and the pooled data mix ADC with engager platforms."},{"visit":2,"cycle":88,"status":"NEW","note":"New this visit; answers the DLL3 arm of open question 3 with a 119-case multicentre prevalence/prognosis dataset plus a single deep clinical response under a de-risked step-up protocol. n=1 efficacy, so LEAD not higher."}]},{"id":"L6","title":"Modality-matching for DLL3-low/heterogeneous MTC: next-payload ADCs, trispecific engagers, CAR-T/NK and DLL3 radioligands","mechanism":"Roughly half of MTC is DLL3-low (53.8% low vs 35.3% high; PMID:41345358) and DLL3 expression in extrapulmonary high-grade NEN is graded rather than binary (PMID:39558076). Engager-mediated killing scales steeply with surface antigen density, so DLL3-low/heterogeneous tumours are predicted to escape tarlatamab while retaining enough target for higher-payload or signal-amplifying platforms (next-generation ADCs, trispecific BiTEs such as HPN328, engineered CAR-T/NK, DLL3 radiopharmaceuticals) (PMID:40284515, PMID:40496850) [INFERRED/SPECULATIVE].","approach":"Stage 1: quantify DLL3 by standardized IHC plus mRNA on the same MTC blocks to define a density continuum and its concordance with WHO 2022 grade; test whether DLL3-low tumours cluster with SSTR2- or FAP-positive phenotypes to enable one-biopsy triage. Stage 2: modality assignment by density tier — engager for high, radioligand or crosslinking/next-payload ADC for intermediate/low. Explicit prior negative: pyrrolobenzodiazepine ADC (rovalpituzumab tesirine) failed on toxicity in SCLC [KNOWN], so ADC re-entry requires a new payload class (e.g. FZ-AD005-type) (PMID:40496850). Window: DLL3 near-absent in adult normal tissue, but radioligand marrow dose and ADC payload toxicity dominate risk [KN","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"41345358","verified":true,"isNew":false,"addedVisit":3},{"kind":"PMID","id":"39558076","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40284515","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40496850","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":166,"lastVisit":3,"lastNote":"New this visit; created because the standardized-assay landscape reframes DLL3 in extrapulmonary NEN as a density continuum, making the DLL3-low majority of MTC an explicit, separately addressable problem rather than an exclusion criterion.","history":[{"visit":3,"cycle":166,"status":"NEW","note":"New this visit; created because the standardized-assay landscape reframes DLL3 in extrapulmonary NEN as a density continuum, making the DLL3-low majority of MTC an explicit, separately addressable problem rather than an exclusion criterion."}]}],"retired":[],"nextQueries":["(RET AND (selpercatinib OR pralsetinib) AND resistance AND (\"MET amplification\" OR \"acquired alteration\" OR bypass)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"medullary thyroid\" AND (\"RET wild-type\" OR \"RAS mutant\" OR quadruple-negative OR HRAS OR KRAS) AND (sequencing OR genomic OR transcriptomic)) AND SRC:MED","(DLL3 AND immunohistochemistry AND (threshold OR \"H-score\" OR heterogeneity) AND (\"neuroendocrine\" OR \"medullary thyroid\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T23:44:04.847Z"},{"key":"papillary renal cell carcinoma","name":"papillary renal cell carcinoma","mondo":{"id":"MONDO:0017884","name":"papillary renal cell carcinoma"},"genes":[{"label":"PRCC","kind":"causal"},{"label":"MET","kind":"causal"},{"label":"MITF","kind":"correlated"}],"visits":3,"openQuestions":["Does fumarate-driven RPA1 succination translate into measurable PARPi/WEE1i/platinum sensitivity in FH-deficient RCC models, and is ATR inhibition redundant or synergistic given the pre-existing ATR-CHK1 defect?","Is there any centrally-reviewed, pRCC-restricted (or molecularly classified per WHO 2022) OS analysis of SUNNIFORECAST, and what biomarker subset would power a confirmatory ipi/nivo trial?","What are the primary readouts of PAPMET2 (NCT05411081) and SAMETA (savolitinib+durvalumab), and does benefit track with MET alteration versus inflamed/PD-L1 signature?","What is the primary evidence base for sintilimab+axitinib in FH-deficient RCC, and how does it compare with bevacizumab+erlotinib response rates?","How frequent is SMARCB1/INI-1 co-loss in FH-deficient RCC, and does it redirect therapy toward platinum or EZH2 inhibition?","Has XmAb819 (NCT05433142) cleared dose escalation without dose-limiting AKI, and what does that imply for membrane-epitope-selected KIM-1 constructs?"],"leads":[{"id":"L1","title":"MET-axis inhibition in type 1/MET-altered pRCC (cabozantinib backbone, savolitinib in MET-driven subset)","mechanism":"Germline [GERMLINE] MET kinase-domain mutations cause hereditary papillary RCC type 1; sporadic type 1 pRCC carries somatic [SOMATIC] MET mutation/trisomy 7 amplification driving HGF-independent MET signalling to ERK/PI3K. Cabozantinib inhibits MET plus VEGFR2/AXL, covering both the driver and the angiogenic dependency; savolitinib is MET-selective.","approach":"Prospective MET-stratified arms: cabozantinib +/- atezolizumab (PAPMET2) with mandatory central pathology and MET NGS/FISH; savolitinib + durvalumab restricted to MET-driven pRCC. Resistance surveillance by ctDNA for MET second-site mutations and EGFR/ERBB3 or NF2 bypass.","level":"LEAD","confidence":0.6,"citations":[{"kind":"NCT","id":"NCT05411081","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41934036","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT02819596","verified":false,"isNew":false,"addedVisit":1},{"kind":"NCT","id":"NCT03866382","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":34,"lastVisit":1,"lastNote":"Opened visit 1 from the KG MET anchor; supported by active PAPMET2 and the CALYPSO savolitinib arm reported in PMID:41934036 [NEW]. No new efficacy data this visit, so confidence capped.","history":[{"visit":1,"cycle":34,"status":"NEW","note":"Opened visit 1 from the KG MET anchor; supported by active PAPMET2 and the CALYPSO savolitinib arm reported in PMID:41934036 [NEW]. No new efficacy data this visit, so confidence capped."}]},{"id":"L2","title":"Ipilimumab/nivolumab as first-line systemic therapy in advanced pRCC","mechanism":"CTLA-4 + PD-1 co-blockade expands intratumoural effector T cells in a histology often TKI-refractory; PD-L1 CPS>1 frequency rises with IMDC risk, indicating inflamed high-risk subsets. Randomised nccRCC evidence now supports the regimen at histology-agnostic level (PMID:41874435), with pembrolizumab+lenvatinib as the ICI/TKI comparator benchmark from KEYNOTE-B61/ARON-1.","approach":"pRCC-restricted confirmatory randomisation vs cabozantinib-based SOC with central pathology per WHO 2022 molecular classes (MET-driven, FH-deficient, unclassified papillary), powered on OS; stratify PD-L1 CPS; banked-tissue reanalysis of SUNNIFORECAST pRCC cases for MET alteration, FH/2SC status and LOY. Resistance routes: primary PD-L1-low/immune-desert tumours, LAG-3/TIM-3 upregulation, IMDC-poor rapid progression.","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"PMID","id":"42235464","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03866382","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41874435","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":34,"lastVisit":3,"lastNote":"P6 [NEW] reports SUNNIFORECAST as a positive randomised trial for ipi/nivo in nccRCC with OS benefit, plus consistent pembro+lenvatinib nccRCC activity. Promoted to CANDIDATE, but confidence held at 0.55: the pRCC-specific subgroup remains exploratory and non-significant (p=0.085), and P6 is a review of the same parent trial, not independent primary data.","history":[{"visit":3,"cycle":167,"status":"STRENGTHENED","note":"P6 [NEW] reports SUNNIFORECAST as a positive randomised trial for ipi/nivo in nccRCC with OS benefit, plus consistent pembro+lenvatinib nccRCC activity. Promoted to CANDIDATE, but confidence held at 0.55: the pRCC-specific subgroup remains exploratory and non-significant (p=0.085), and P6 is a review of the same parent trial, not independent primary data."},{"visit":1,"cycle":34,"status":"NEW","note":"New this visit: SUNNIFORECAST pRCC exploratory subgroup, 12-mo OS 74.8% vs 63.4% (p=0.085), mOS 24.9 vs 18.9 mo. Signal only, not significant, exploratory subgroup — deliberately not called a candidate."}]},{"id":"L3","title":"Proximal-tubule lineage as the therapeutic window: KIM-1/HAVCR1-directed agents and tubule-selective toxins","mechanism":"pRCC retains proximal-tubule differentiation and KIM-1 (HAVCR1) is elevated in advanced pRCC above ccRCC (PMID:41934036). However KIM-1 is an injury-inducible antigen: it is upregulated on normal proximal tubule cells during cisplatin AKI and shed into urine/plasma (PMID:42157797), and PT injury programmes (KLF15 loss, PMID:42238184) drive exactly this state. Antigen is therefore not tumour-restricted whenever tubular injury occurs, and a soluble decoy pool exists.","approach":"Quantify membrane-retained vs shed KIM-1 ectodomain on pRCC tissue and primary cells; select epitopes proximal to the membrane that survive shedding; explicitly exclude nephrotoxic combination partners (platinum, aminoglycosides) from any KIM-1 ADC/CAR design; do not use plasma KIM-1 as an unconfounded PD marker. Continue watching NCT05433142 (XmAb819/ENPP3xCD3) DLT and renal-toxicity profile as the falsification hook, plus orellanine (NCT05287945) renal safety.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"41934036","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05287945","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05433142","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42157797","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42238184","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":34,"lastVisit":3,"lastNote":"Weakened by P10 and P2 [NEW]: KIM-1 is induced on injured normal proximal tubule and heavily shed, creating on-target off-tumour risk and an antigen sink. Still no XmAb819 safety readout and no KIM-1 immunoconjugate literature retrieved, so the window remains unfalsified but the design constraints are now tighter.","history":[{"visit":3,"cycle":167,"status":"WEAKENED","note":"Weakened by P10 and P2 [NEW]: KIM-1 is induced on injured normal proximal tubule and heavily shed, creating on-target off-tumour risk and an antigen sink. Still no XmAb819 safety readout and no KIM-1 immunoconjugate literature retrieved, so the window remains unfalsified but the design constraints are now tighter."},{"visit":2,"cycle":89,"status":"STRENGTHENED","note":"Modest strengthening from NCT05433142 [NEW]: an ENPP3xCD3 bispecific in ccRCC provides an adjacent clinical test of the proximal-tubule antigen window. Held below 0.5 because the trial excludes pRCC and the KIM-1 shedding/decoy question remains unresolved (no immunoconjugate literature retrieved this visit)."},{"visit":1,"cycle":34,"status":"NEW","note":"New this visit from PMID:41934036 [NEW] (KIM-1 higher in pRCC, 7835 vs 5470 pg/ml; lower baseline in responders) converging with the recruiting orellanine trial. Main risk: on-target AKI and soluble-KIM-1 decoy effect."}]},{"id":"L4","title":"MTHFD2 / one-carbon metabolism dependency in the LOY-associated pRCC transcriptional programme","mechanism":"Loss of chromosome Y in male pRCC is paradoxically favourable and accompanied by de-repression of immunosuppressive programmes; the derived prognostic trio WASF1/MTHFD2/CHMP1A contains MTHFD2, a mitochondrial folate-cycle enzyme re-expressed in tumours but minimal in adult normal tissue, giving a plausible metabolic window.","approach":"Validate MTHFD2 protein by IHC in LOY-stratified pRCC; test MTHFD2 knockdown/inhibition +/- purine-synthesis or ICI combination in pRCC lines and organoids; ask whether LOY status predicts ICI benefit in banked SUNNIFORECAST/PAPMET2 specimens.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42259100","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":34,"lastVisit":1,"lastNote":"New, purely computational (TCGA KIRP bulk + scRNAseq, LASSO signature) with no functional validation — entered at low confidence as a hypothesis-generating lead only.","history":[{"visit":1,"cycle":34,"status":"NEW","note":"New, purely computational (TCGA KIRP bulk + scRNAseq, LASSO signature) with no functional validation — entered at low confidence as a hypothesis-generating lead only."}]},{"id":"L5","title":"Cohesion/mitotic stress vulnerability in SGO1/SGO2-high pRCC","mechanism":"SGO1 and SGO2 protect centromeric cohesin; both are overexpressed in KIRP, correlate with stage/poor OS, and knockdown reduces proliferation, migration and invasion, with an associated immunosuppressive microenvironment. Shugoshin overexpression implies tolerance of chromosome-segregation stress, a classic setting for spindle-assembly-checkpoint or kinase-directed synthetic lethality.","approach":"Shugoshins are not directly druggable; test MPS1/TTK, AURKB and PLK1 inhibitors for selective killing in SGO1/2-high pRCC lines and PDX, with micronucleus/cGAS-STING readouts to ask whether induced missegregation converts the immunosuppressed phenotype into ICI sensitivity.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42287003","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":34,"lastVisit":1,"lastNote":"New this visit; has knockdown functional data and patient IHC but the drug hypothesis (mitotic kinase inhibition) is my inference [INFERRED], untested in pRCC.","history":[{"visit":1,"cycle":34,"status":"NEW","note":"New this visit; has knockdown functional data and patient IHC but the drug hypothesis (mitotic kinase inhibition) is my inference [INFERRED], untested in pRCC."}]},{"id":"L6","title":"Dual VEGF/EGFR blockade plus PD-L1 inhibition in FH-deficient/HLRCC-associated and type 2 papillary RCC","mechanism":"[KNOWN/GERMLINE in HLRCC, SOMATIC in sporadic] FH loss accumulates fumarate, inhibits PHDs, stabilises HIF and drives glycolytic rewiring plus EGFR-pathway dependence; bevacizumab strips HIF-driven VEGF output, erlotinib blocks the EGFR arm, atezolizumab tests checkpoint tractability of succination-associated phenotypes. Fumarate-driven CpG island methylator phenotype can secondarily silence SMARCB1/INI-1 (PMID:42084236), defining a distinct high-grade subset. [INFERRED] EGFR/ERBB3 is also a predicted MET-inhibitor bypass, so this doubles as post-cabozantinib salvage.","approach":"Follow NCT04981509 with mandatory FH IHC/2SC, germline FH sequencing and added INI-1 IHC; stratify FH-deficient vs FH-intact papillary; correlate with EGFR/ERBB copy number, NRF2/KEAP1 activation, PD-L1 CPS. Benchmark against sintilimab+axitinib in FH-deficient RCC (PMID:41874435). [SPECULATIVE] INI-1-co-deficient cases diverted to platinum +/- EZH2 inhibition rather than VEGF/EGFR blockade. Resistance: NRF2 activation, ERBB2/3 switching, VEGF-independent angiogenesis. Window: EGFR (rash/diarrhoea) and VEGF (hypertension/proteinuria) toxicities are familiar and manageable.","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"NCT","id":"NCT04981509","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT05411081","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41874435","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42084236","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":89,"lastVisit":3,"lastNote":"Two [NEW] sources converge: P6 reports high response rates for bevacizumab+erlotinib and for sintilimab+axitinib in FH-deficient RCC; P3 independently names bev+erlo as the principal systemic consideration and adds the FH/SMARCB1 CIMP co-loss subset. Promoted to CANDIDATE; still no randomised comparison, hence 0.55.","history":[{"visit":3,"cycle":167,"status":"STRENGTHENED","note":"Two [NEW] sources converge: P6 reports high response rates for bevacizumab+erlotinib and for sintilimab+axitinib in FH-deficient RCC; P3 independently names bev+erlo as the principal systemic consideration and adds the FH/SMARCB1 CIMP co-loss subset. Promoted to CANDIDATE; still no randomised comparison, hence 0.55."},{"visit":2,"cycle":89,"status":"NEW","note":"New this visit from trial NCT04981509 [NEW]; fills the FH/type-2 gap in a programme that was MET/type-1 heavy and gives L1 a pre-specified bypass-resistance arm. No efficacy data in pack, so entered as LEAD only."}]},{"id":"L7","title":"Fumarate-induced BRCAness in FH-deficient papillary RCC: RPA1 succination as an exploitable replication-stress defect","mechanism":"Fumarate succinates RPA1 at Cys481/486, reducing ssDNA binding, blocking TOPBP1 recruitment and attenuating ATR-CHK1 activation, with measurably reduced homologous recombination in FH-mutant cells (PMID:42050641). [INFERRED] This is a chemically defined, non-genetic BRCAness: cells cannot mount a proper intra-S/G2 checkpoint or high-fidelity HR repair, so they should be selectively killed by agents that raise replication-fork burden or remove the residual G2 brake. [SPECULATIVE] Mitochondrial reductive stress/ETC limitation (PMID:42150423) may modulate the succination burden and therefore the depth of the defect, giving a spatial-heterogeneity caveat.","approach":"In UOK262/UOK268 and FH-null isogenic pairs: dose-response to olaparib, WEE1 inhibition (adavosertib), cisplatin/gemcitabine, POLQ inhibition, and ATR inhibition (test whether ATRi is redundant or synergistic given the pre-existing pathway defect); readouts RAD51 foci, gH2AX, micronuclei, CHK1-pS345. Validate 2SC/FH IHC and an RPA1-succination or RAD51-foci functional HRD assay as patient-selection biomarkers on banked NCT04981509 tissue. Normal-tissue window: PARP/WEE1 toxicity is haematological and reversible [KNOWN]; the argument is that succination is tumour-restricted to FH-null cells. Resistance routes: FH-independent restoration of RPA1 function, loss of succination via glutathione/NR","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42050641","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42150423","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT04981509","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":167,"lastVisit":3,"lastNote":"New this visit from P8 [NEW], a mechanistic paper with LC-MS/MS-mapped succination sites, EMSA and HR assays in FH-mutant cells. Entered as LEAD only: the drug hypothesis (PARPi/WEE1i/platinum) is my inference, untested in any pRCC model or patient in the pack.","history":[{"visit":3,"cycle":167,"status":"NEW","note":"New this visit from P8 [NEW], a mechanistic paper with LC-MS/MS-mapped succination sites, EMSA and HR assays in FH-mutant cells. Entered as LEAD only: the drug hypothesis (PARPi/WEE1i/platinum) is my inference, untested in any pRCC model or patient in the pack."}]}],"retired":[],"nextQueries":["(\"FH-deficient\" OR HLRCC OR \"fumarate hydratase\") AND (\"renal cell\") AND (PARP OR olaparib OR WEE1 OR adavosertib OR ATR OR \"replication stress\" OR \"homologous recombination\") AND SRC:MED AND PUB_YEAR:[2019 TO 2026]","(papillary OR \"non-clear cell\") AND (\"renal cell carcinoma\") AND (savolitinib OR SAMETA OR PAPMET2 OR \"sintilimab\" OR \"ipilimumab nivolumab\") AND (\"overall survival\" OR \"progression-free\") AND SRC:MED AND PUB_YEAR:[2024 ","(SMARCB1 OR \"INI-1\") AND (\"renal cell carcinoma\") AND (EZH2 OR tazemetostat OR platinum) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"updatedAt":"2026-08-19T23:47:46.011Z"},{"key":"renal cell carcinoma","name":"renal cell carcinoma","mondo":{"id":"MONDO:0005086","name":"renal cell carcinoma"},"genes":[{"label":"FLCN","kind":"causal"},{"label":"PRCC","kind":"causal"},{"label":"PAX6","kind":"causal"},{"label":"HNF1A","kind":"causal"},{"label":"RNF139","kind":"causal"},{"label":"OGG1","kind":"causal"},{"label":"TRIM44","kind":"causal"},{"label":"ELP4","kind":"causal"},{"label":"PBRM1","kind":"causal"},{"label":"TFE3","kind":"causal"},{"label":"MET","kind":"causal"},{"label":"VHL","kind":"causal"}],"visits":3,"openQuestions":["Does bempedoic acid (with confirmed ACSVL1/SLC27A2 expression) or a direct ACLY inhibitor reduce growth of VHL-null ccRCC lines/PDX, and is the effect non-additive with ACLY knockdown and additive with belzutifan?","Is the CDK13→METTL16(S329)→m6A→YTHDC2→ACLY axis reproducible with selective CDK12/13 inhibitors or degraders rather than an analog-sensitive allele, and does CDK13 inhibition create a PARP-inhibitor-sensitising HR-deficient state in ccRCC?","Does ATF4 loss suppress established VHL-null ccRCC tumours (not just pre-cancerous lesions in a HIF1α transgenic), and is GCN2/PERK modulation a usable surrogate?","Does ACLY or LPCAT1 loss sensitise ccRCC to RSL3/IKE (predicting lipid-composition control of ferroptosis threshold) or protect against it, and what is adult renal ACLY dependence?","Does zileuton or FLAP inhibition restore sunitinib/axitinib sensitivity in ALOX5-high resistant RCC in vivo, epistatic with CPT1A/etomoxir — still unanswered after a targeted query returned only reviews?","Do OPTIC RCC (NCT05361720) or NCT03866382 report subtype-resolved responses for MET-altered papillary vs FH-deficient vs TFE3-fusion nccRCC?"],"leads":[{"id":"L2","title":"Sequence-defined axitinib priming → survivin peptide vaccine + PD-1 blockade (vaccine AFTER, not during, VEGFR TKI)","mechanism":"Short-term VEGFR inhibition transiently normalises tumour vasculature, relieves hypoxia and depletes suppressive myeloid subsets, creating an immune-permissive window; survivin long-peptide vaccination in that window primes Th1 CD4+ and polyfunctional CD8+ responses, and concomitant PD-1 blockade converts an immune-excluded tumour into a cytotoxic niche. Efficacy is schedule-dependent, with vaccine+anti-PD-1 given after axitinib superior to concurrent dosing.","approach":"Confirm sequence dependence in a second RCC model (immune-humanised or Vhl-null GEMM) and in human tumour-fragment/organoid systems; define the duration of the permissive window by serial myeloid/hypoxia profiling. Clinically, a schedule-randomised phase 1b: axitinib lead-in → survivin (or defined neoantigen) peptide vaccine + pembrolizumab vs concurrent dosing. [KNOWN] prior RCC vaccine phase 3 failures (IMA901+sunitinib, TroVax/5T4) all used concurrent TKI — the untested variable is timing. Resistance: survivin antigen loss/HLA downregulation, Treg re-accumulation after TKI washout.","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"42343214","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":35,"lastVisit":1,"lastNote":"New from P3; single orthotopic RENCA study, murine only, no human antigen validation — confidence capped.","history":[{"visit":1,"cycle":35,"status":"NEW","note":"New from P3; single orthotopic RENCA study, murine only, no human antigen validation — confidence capped."}]},{"id":"L3","title":"Histology/genotype-stratified cabozantinib + nivolumab in non-clear-cell RCC, anchored on MET and TFE3-rearranged biology","mechanism":"nccRCC subtypes converge on MET/AXL/VEGFR2 signalling (papillary MET [GERMLINE and SOMATIC], FH-deficient pseudohypoxic HIF activation, TFE3 fusions [SOMATIC] driving lysosomal/mTOR-linked transcription); cabozantinib inhibits MET/AXL/VEGFR2 while nivolumab releases PD-1, giving cross-subtype activity.","approach":"Retrospective ORR 45.2%/DCR 93.6% with responses in papillary (48%), FH-deficient (50%) and TFE3-rearranged (50%) tumours needs prospective, genotype-selected confirmation via NCT03866382 (nivo/ipi/cabo, rare GU) and NCT05361720 (OPTIC RCC, sequencing-directed arm assignment). Prespecify MET exon-14/kinase-domain mutation, FH loss (2SC IHC), TFE3 fusion partner (ASPSCR1 vs PRCC — both KG anchors) as stratifiers; correlate with resistance routes: MET Y1230/D1228 secondary mutations, AXL/GAS6 bypass, HGF-independent RAS reactivation.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42366526","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03866382","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05361720","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":35,"lastVisit":1,"lastNote":"New from P2; retrospective, 62 patients, subtype n's tiny (chromophobe/collecting duct n=4 each) and P=0.876 for subtype difference is underpowered, not evidence of equivalence.","history":[{"visit":1,"cycle":35,"status":"NEW","note":"New from P2; retrospective, 62 patients, subtype n's tiny (chromophobe/collecting duct n=4 each) and P=0.876 for subtype difference is underpowered, not evidence of equivalence."}]},{"id":"L5","title":"ALOX5 inhibition (zileuton) to reverse VEGFR-TKI resistance in RCC by blocking p38/ERK/PPARα/CPT1A fatty-acid oxidation","mechanism":"ALOX5 [SOMATIC, overexpressed] is upregulated in TKI-resistant RCC tissues and in sunitinib-resistant 786-O-R cells, correlates with poor prognosis, and enhances proliferation, migration, invasion and sunitinib resistance by reprogramming lipid metabolism through p38/ERK→PPARα→CPT1A, i.e. driving fatty-acid oxidation (PMID:42287957). [INFERRED] Diverting PUFAs into β-oxidation depletes peroxidisable phospholipid pools, which would also raise the ferroptosis threshold — linking this node to the L1 axis and to ACLY/LPCAT1 phospholipid remodelling (PMID:41958067). Normal-tissue role: ALOX5 generates leukotrienes in myeloid cells; 5-LOX blockade is tolerated chronically in asthma [KNOWN], giving","approach":"In 786-O-R and additional TKI-resistant RCC lines/PDX: zileuton or MK-886 (FLAP) ± sunitinib/axitinib, with genetic ALOX5 knockdown as on-target control; readouts CPT1A flux (etomoxir epistasis), Seahorse FAO, PPARα target transcripts, C11-BODIPY peroxidation, and ferroptosis-sensitisation with RSL3/IKE. Test whether ALOX5-high resistant tumours become ferroptosis-sensitive (predicted) or ferroptosis-resistant. IHC/RNA of ALOX5 in paired pre/post-TKI human RCC. Resistance routes: ALOX15/ALOX12 or COX-2 substitution, PPARα-independent CPT1A upregulation, LTB4/BLT1 paracrine myeloid signalling.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42287957","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41958067","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":90,"lastVisit":2,"lastNote":"New from P7. First RCC-specific, functionally validated (in vitro + in vivo) evidence in this programme for a lipid-metabolic resistance node with an approved inhibitor; also answers Open Question 5 by re-casting ALOX5 as a pro-FAO rather than pro-ferroptotic actor in RCC.","history":[{"visit":2,"cycle":90,"status":"NEW","note":"New from P7. First RCC-specific, functionally validated (in vitro + in vivo) evidence in this programme for a lipid-metabolic resistance node with an approved inhibitor; also answers Open Question 5 by re-casting ALOX5 as a pro-FAO rather than pro-ferroptotic actor in RCC."}]},{"id":"L6","title":"Iron efflux/chelation (deferiprone) as an anti-metastatic, TAM-reprogramming strategy in RCC — distinct from ferroptosis induction","mechanism":"Tumours and tumour-associated macrophages accumulate iron to support DNA synthesis/repair, oxidative phosphorylation, iron-sulfur cluster and heme enzymes, and immune-evasive myeloid polarisation (PMID:41513613, PMID:42122232). Deferiprone is reported capable of removing excess iron from iron-loaded renal cancer cells with potential to limit metastasis in renal carcinoma (PMID:42122232). Mechanism here is iron restriction (ribonucleotide reductase, Fe-S cluster biogenesis, HIF-prolyl-hydroxylase cofactor supply) and TAM repolarisation, NOT lipid peroxidation. Normal tissue: systemic chelation risks agranulocytosis (deferiprone) and renal/hepatic toxicity (deferasirox) [KNOWN], so the window ","approach":"Orthotopic/metastatic RCC models: deferiprone vs deferasirox vs deferoxamine, scoring lung metastasis, tumour labile iron, TAM iron content (MRI/R2* per PMID:42122232) and M1/M2 markers; explicitly test ferrostatin insensitivity to confirm non-ferroptotic mechanism. Test whether chelation antagonises RSL3/IKE-induced ferroptosis (a direct falsification test of L1's premise) and whether it synergises with anti-PD-1 via myeloid reprogramming. Biomarker: pretreatment tumour iron by MRI.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42122232","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41513613","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":90,"lastVisit":2,"lastNote":"New; carved out of L1 so that any chelator activity in RCC is not misattributed to ferroptosis. Both citations are reviews — no primary RCC dataset yet, hence low confidence.","history":[{"visit":2,"cycle":90,"status":"NEW","note":"New; carved out of L1 so that any chelator activity in RCC is not misattributed to ferroptosis. Both citations are reviews — no primary RCC dataset yet, hence low confidence."}]},{"id":"L7","title":"ACLY/LPCAT1 lipogenic axis downstream of HIF-2alpha and VHL/PPARgamma as a ccRCC metabolic vulnerability","mechanism":"HIF-2α binds the LPCAT1 promoter and drives its transcription; LPCAT1 loss activates NF-κB→FBXW7, which ubiquitinates and degrades ACLY, cutting acetyl-CoA supply, de novo fatty-acid synthesis and triglyceride/lipid-droplet accumulation (PMID:39781455). ACLY abundance is independently raised by CDK13-METTL16-YTHDC2 m6A stabilisation of ACLY mRNA (PMID:41680470) and by ATF4-driven fatty-acid metabolism transcripts in a proximal-tubule HIF1α ccRCC model (PMID:40472739). [INFERRED] LPCAT1-dependent lysophospholipid re-acylation sets membrane PUFA/MUFA ratio and hence ferroptosis threshold, consistent with lipid-reprogramming/ferroptosis crosstalk in ccRCC (PMID:41039547). Normal tissue: ACLY is","approach":"ACLY and LPCAT1 knockout plus bempedoic acid (verify ACSVL1/SLC27A2 expression) in VHL-null vs VHL-restored ccRCC lines and PDX; lipidomics for PUFA-phospholipid content; belzutifan epistasis to test HIF-2α→LPCAT1→FBXW7→ACLY wiring; FBXW7-mutant subsets as predicted resistance; test whether ACLY/LPCAT1 loss sensitises to RSL3/IKE and to sunitinib/axitinib. Resistance: acetate/ACSS2 bypass, SREBP2 feedback, CD36-mediated exogenous lipid uptake, FBXW7 loss.","level":"CANDIDATE","confidence":0.58,"citations":[{"kind":"PMID","id":"41958067","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39781455","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41680470","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40472739","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41039547","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":90,"lastVisit":3,"lastNote":"Promoted: the review-level claim from visit 2 is now backed by the primary HIF-2α/LPCAT1/FBXW7-ACLY study plus two independent studies converging on ACLY (m6A stabilisation; ATF4-dependent FAO programme with reduced pre-cancerous lesions). Still no pharmacological ACLY inhibition data in ccRCC — that gap caps confidence.","history":[{"visit":3,"cycle":169,"status":"STRENGTHENED","note":"Promoted: the review-level claim from visit 2 is now backed by the primary HIF-2α/LPCAT1/FBXW7-ACLY study plus two independent studies converging on ACLY (m6A stabilisation; ATF4-dependent FAO programme with reduced pre-cancerous lesions). Still no pharmacological ACLY inhibition data in ccRCC — that gap caps confidence."},{"visit":2,"cycle":90,"status":"NEW","note":"New from P6, a kidney-disease review with a ccRCC section; single review-level citation, mechanism plausible and convergent with L1/L5 but untested as an intervention in RCC. Deliberately low confidence."}]},{"id":"L8","title":"CDK13–METTL16–YTHDC2 epitranscriptomic control of ACLY: a kinase entry point to ccRCC lipogenesis","mechanism":"CDK13 [SOMATIC, overexpressed] correlates with advanced stage, poor prognosis and lipid accumulation in ccRCC tissue; it phosphorylates METTL16 at Ser329, boosting m6A deposition on ACLY mRNA, which YTHDC2 reads to stabilise the transcript, raising acetyl-CoA and sustaining growth and metastasis. Genetic or pharmacological disruption of the axis suppresses lipid deposition, tumour growth and metastasis in vitro and in vivo (PMID:41680470). [KNOWN] CDK12/13 are transcription-CDKs whose loss impairs expression of long DNA-damage-response genes.","approach":"Confirm on-target-ness with selective CDK12/13 inhibitors (e.g. THZ531-class) and CDK13 degraders in VHL-null ccRCC lines/PDX, with METTL16 S329A knock-in as the specificity control; MeRIP-seq for ACLY m6A, YTHDC2 CLIP, ACLY protein/acetyl-CoA and lipid-droplet readouts; epistasis with ACLY knockdown (should be non-additive) and with belzutifan (should be additive if the HIF-2α route is parallel). [SPECULATIVE] Test PARP-inhibitor combination for CDK12/13-loss-induced HR deficiency. Caveat: P8's '1NM-PP1' most plausibly indicates an analog-sensitive CDK13 allele, not a clinical agent [INFERRED]. Normal tissue: CDK13 is broadly expressed and germline CDK13 variants cause developmental syndrom","level":"LEAD","confidence":0.32,"citations":[{"kind":"PMID","id":"41680470","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"39781455","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":169,"lastVisit":3,"lastNote":"New from P8. Single primary study, but it is RCC-specific with in vitro and in vivo validation and converges on the same ACLY node as L7 from an orthogonal regulatory layer; kept separate because its druggable handle is a kinase, not a lipogenic enzyme.","history":[{"visit":3,"cycle":169,"status":"NEW","note":"New from P8. Single primary study, but it is RCC-specific with in vitro and in vivo validation and converges on the same ACLY node as L7 from an orthogonal regulatory layer; kept separate because its druggable handle is a kinase, not a lipogenic enzyme."}]},{"id":"L9","title":"ATF4/integrated-stress-response dependence for lipid-droplet accumulation and early tumourigenesis in HIF-driven ccRCC","mechanism":"In TRACK mice expressing a degradation-resistant HIF1α in proximal tubule cells, ATF4 and its targets are high (as in human ccRCC); proximal-tubule ATF4 deletion alters ~20% of the mRNA/protein landscape, downregulates the fatty-acid metabolism programme including ATP-citrate lyase, reverses ccRCC-elevated transcripts and reduces cystic pre-cancerous lesions (PMID:40472739). [INFERRED] ATF4 therefore sits upstream of the ACLY lipogenic node (L7) as a stress-responsive transcriptional amplifier, potentially reachable via GCN2/PERK/eIF2α-phosphatase modulation rather than direct ATF4 inhibition.","approach":"Test ATF4 knockout/knockdown in VHL-null (not just HIF1α-transgenic) human ccRCC lines and PDX for lipid droplet content, ACLY levels and growth; GCN2 inhibitors and ISRIB-type agents versus ATF4 genetic loss to check pharmacological tractability and direction of effect; asparaginase/amino-acid-restriction stress as a sensitiser; establish whether ATF4 loss sensitises to RSL3/IKE. Normal tissue: ATF4 is required for proximal tubule stress adaptation and erythroid/skeletal homeostasis [KNOWN] — a real window concern.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"40472739","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"39781455","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":169,"lastVisit":3,"lastNote":"New from P5. Genetic in vivo support, but the model is HIF1α-driven rather than VHL-null and the phenotype is pre-cancerous lesion reduction, not established-tumour regression; ATF4 itself is not directly druggable, so confidence deliberately low.","history":[{"visit":3,"cycle":169,"status":"NEW","note":"New from P5. Genetic in vivo support, but the model is HIF1α-driven rather than VHL-null and the phenotype is pre-cancerous lesion reduction, not established-tumour regression; ATF4 itself is not directly druggable, so confidence deliberately low."}]}],"retired":[{"title":"Wnt/β-catenin reactivation as a targetable node in sunitinib-resistant RCC (ZC3H13/m6A–sFRP-4 axis)","note":"Retired on schedule: no independent corroboration across three visits, no patient-level Wnt-implicating RCC resistance cohort in this pack, and systemic Wnt blockade carries prohibitive crypt/bone toxicity [KNOWN]. Note that m6A biology in ccRCC did appear this visit, but via METTL16/YTHDC2 on ACLY, not ZC3H13/sFRP-4.","cycle":169,"ts":"2026-08-19T23:54:42.459Z"},{"title":"Deferasirox-mediated disruption of the ITPRIP(DANGER)/NRF2/FTH1 axis to force ferroptosis in VHL-null ccRCC","note":"Retired: three evidence-bearing visits with zero independent support for ITPRIP/DANGER as an RCC target, and a competing, better-supported iron-depletion mechanism already carved into L6. Do not re-propose deferasirox as a ferroptosis inducer in RCC without primary ITPRIP loss-of-function data.","cycle":169,"ts":"2026-08-19T23:54:42.459Z"}],"nextQueries":["(\"renal cell carcinoma\" OR ccRCC) AND (\"ATP citrate lyase\" OR ACLY OR bempedoic OR SLC27A2 OR ACSS2) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"renal cell carcinoma\" OR ccRCC) AND (CDK12 OR CDK13 OR METTL16 OR YTHDC2 OR \"m6A\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"renal cell carcinoma\" OR ccRCC) AND (zileuton OR ALOX5 OR CPT1A OR etomoxir OR \"fatty acid oxidation\") AND (sunitinib OR axitinib OR cabozantinib OR resistance) AND SRC:MED"],"updatedAt":"2026-08-19T23:54:42.459Z"},{"key":"acute myeloid leukemia","name":"acute myeloid leukemia","mondo":{"id":"MONDO:0018874","name":"acute myeloid leukemia"},"genes":[{"label":"CEBPA","kind":"causal"},{"label":"FLT3","kind":"causal"},{"label":"NUP214","kind":"causal"},{"label":"MLLT10","kind":"causal"},{"label":"RUNX1","kind":"causal"},{"label":"ETV6","kind":"causal"},{"label":"RARA","kind":"causal"},{"label":"JAK2","kind":"causal"},{"label":"DNMT3A","kind":"causal"},{"label":"LPP","kind":"causal"},{"label":"KIT","kind":"causal"},{"label":"KRAS","kind":"causal"}],"visits":3,"openQuestions":["Does bortezomib+venetoclax synergy survive in primary venetoclax-refractory and monocytic AML blasts and PDX, is it PMAIP1/NOXA-dependent there, and does it spare normal CD34+ colony formation?","Does an anti-CD16 x anti-TIM3 construct cause NK self-targeting/fratricide or CD16 shedding, given that TIM3 is expressed on NK cells (PMID:42599272), and does VINCENT beat an untargeted venetoclax-LNP?","What is the clinical prevalence of BAX/BAK and other post-mitochondrial executioner lesions at venetoclax relapse, and do they abolish benefit from MCL1-directed strategies (L2, bortezomib) as well?","Is the WNK1 dependency genotype-restricted (FLT3-ITD) and on-target, and can any schedule separate leukaemic apoptosis from WNK1-SPAK electrolyte/blood-pressure toxicity?","Which biomarker segregates ATRA benefit on the DAC+VEN backbone in DECIDER-2, and does ATRA-driven monocytic differentiation antagonise venetoclax in a subset?","What is the composition and mechanism of QTX-2101 (NCT07504458), and can it displace IV arsenic trioxide in APL?"],"leads":[{"id":"L1","title":"FLT3 inhibition plus BCL2/HMA triplet in FLT3-mutant AML unfit for intensive therapy","mechanism":"FLT3-ITD/TKD [SOMATIC] signalling via STAT5/PIM sustains MCL1 and BCL-xL; gilteritinib collapses this buffer and shifts apoptotic dependence onto BCL2, occupied by venetoclax, with azacitidine lowering MCL1 and priming BAX/BAK [KNOWN]. PMID:42575085 independently codifies compensatory MCL-1/BCL-xL switching, oncogenic signalling activation and differentiation state as the principal venetoclax-resistance axes, which is exactly this triplet's rationale.","approach":"Follow NCT06317649 (MyeloMATCH). Demand correlatives: serial FLT3 allelic ratio, emergent RAS/MAPK and F691L clones, BH3 profiling for MCL1/BCL-xL shift, monocytic differentiation state at relapse, and now BAX sequencing plus integrated-stress-response markers per PMID:42575085. Kill criterion: triplet CR/CRi not exceeding FLT3i+HMA doublet at equal early-mortality, or relapse dominated by BAX/RAS lesions insensitive to all three drugs.","level":"CANDIDATE","confidence":0.66,"citations":[{"kind":"NCT","id":"NCT06317649","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05554393","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42575085","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":37,"lastVisit":2,"lastNote":"Promoted on second evidence-bearing visit via independent mechanistic corroboration (Cancer Cell review) of the MCL-1/BCL-xL switch; flagged that no trial readout yet exists, so this is mechanism-level, not outcome-level, promotion.","history":[{"visit":2,"cycle":91,"status":"STRENGTHENED","note":"Promoted on second evidence-bearing visit via independent mechanistic corroboration (Cancer Cell review) of the MCL-1/BCL-xL switch; flagged that no trial readout yet exists, so this is mechanism-level, not outcome-level, promotion."},{"visit":1,"cycle":37,"status":"NEW","note":"New lead from fresh trial pack; strongest mechanism-to-clinic chain available in AML this visit. Window argument: FLT3 required for normal HSPC/cDC development, so toxicity is cytopenic not organ-toxic."}]},{"id":"L2","title":"XPO1 inhibition (eltanexor) to resensitise R/R AML/MDS to venetoclax","mechanism":"XPO1 blockade retains p53, FOXO and IkB in the nucleus and lowers MCL1 output, restoring BCL-2 dependence [KNOWN/INFERRED]. TP53-mutant-specific review now enumerates the same escape architecture — shift away from BCL-2 dependence, BCL-2-family mutations, post-mitochondrial executioner defects, monocytic lineage plasticity and fatty-acid metabolism (PMID:41929632) — implying XPO1i benefit should be confined to patients whose resistance is MCL1-mediated and whose executioner apparatus is intact.","approach":"Track NCT06399640 for dose-limiting anorexia/thrombocytopenia and response segregation by TP53 status and baseline MCL1:BCL2 ratio; add BAX/BAK genotyping and BH3 profiling. Direct comparison now warranted: is proteasome-mediated NOXA stabilisation (PMID:41883151) a better-tolerated way to hit the same node than global nuclear-export blockade, which has no tumour-selective window? Kill criterion unchanged: no responses in TP53-wildtype, MCL1-high patients.","level":"LEAD","confidence":0.48,"citations":[{"kind":"NCT","id":"NCT06399640","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42575085","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41929632","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41883151","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":37,"lastVisit":3,"lastNote":"Mechanistic premise reinforced by the TP53-mutant resistance review, but L2 now has a cheaper, approved competitor at the same node (bortezomib); kept at LEAD with confidence essentially flat pending any clinical response data.","history":[{"visit":3,"cycle":170,"status":"STRENGTHENED","note":"Mechanistic premise reinforced by the TP53-mutant resistance review, but L2 now has a cheaper, approved competitor at the same node (bortezomib); kept at LEAD with confidence essentially flat pending any clinical response data."},{"visit":2,"cycle":91,"status":"STRENGTHENED","note":"Mechanistic premise independently supported this visit; kept at LEAD because no clinical response data exist and XPO1 has no tumour-selective window."},{"visit":1,"cycle":37,"status":"NEW","note":"New lead. XPO1 is ubiquitously expressed in normal tissue, so the therapeutic window rests entirely on tumour BCL2 addiction, not on target selectivity."}]},{"id":"L3","title":"Cystine-import/ferroptosis vulnerability in AML via the OTUD5-SLC7A11 axis","mechanism":"OTUD5 deubiquitinates and stabilises SLC7A11, sustaining cystine import and GSH synthesis and suppressing ferroptosis; OTUD5 knockdown raises labile Fe2+/ROS and shrinks xenografts, rescued by SLC7A11 re-expression or GSH (PMID:42333513).","approach":"Do not chase the DUB (no selective OTUD5 chemistry). Test pharmacological SLC7A11/system xc- blockade (sulfasalazine, imidazole ketone erastin-class) or cyst(e)ine depletion combined with venetoclax/azacitidine, prioritising monocytic/venetoclax-refractory AML which is GSH/GPX4-dependent [KNOWN, to verify]. Resistance: NRF2/KEAP1 pathway activation, transsulfuration flux via CBS, MUFA/ACSL3 rewiring.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42333513","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":37,"lastVisit":1,"lastNote":"New lead from P2. Epistasis (SLC7A11/GSH rescue) is clean but all in THP-1/HL-60 plus xenograft; no primary-AML or normal-HSPC toxicity data in the abstract. SLC7A11 is needed by normal activated lymphocytes and some epithelia, so window is unproven.","history":[{"visit":1,"cycle":37,"status":"NEW","note":"New lead from P2. Epistasis (SLC7A11/GSH rescue) is clean but all in THP-1/HL-60 plus xenograft; no primary-AML or normal-HSPC toxicity data in the abstract. SLC7A11 is needed by normal activated lymphocytes and some epithelia, so window is unproven."}]},{"id":"L5","title":"CD69 blockade to remodel the marrow immune niche and delay RAS-mutant myeloid transformation to AML","mechanism":"Nras-G12D CMML marrow accumulates CD69+ T cells and Tregs; anti-CD69 mAb reduced GMP output, cut Treg accumulation and prolonged survival, implicating CD69 as a marrow-restricted immunosuppression node (PMID:42330053).","approach":"Prevention-of-transformation framing, not established AML: test anti-CD69 in NRAS/KRAS-mutant CMML and secondary-AML models, alone and with azacitidine; measure GMP compartment, marrow Treg:CD8 ratio, and whether CD69 blockade impairs normal tissue-resident memory T cell function (the main window risk).","level":"LEAD","confidence":0.2,"citations":[{"kind":"PMID","id":"42330053","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":37,"lastVisit":1,"lastNote":"New, exploratory. Single mouse model, CMML not AML, antibody effect could be Treg-depletion rather than niche restoration; peripheral vs marrow CD69 gradient is the one testable biomarker claim.","history":[{"visit":1,"cycle":37,"status":"NEW","note":"New, exploratory. Single mouse model, CMML not AML, antibody effect could be Treg-depletion rather than niche restoration; peripheral vs marrow CD69 gradient is the one testable biomarker claim."}]},{"id":"L6","title":"TIM3-directed nanoformulated venetoclax with NK engagement (VINCENT) for venetoclax-resistant AML","mechanism":"Anti-CD16 x anti-TIM3 construct concentrates nanoformulated venetoclax on TIM3+ blasts while cross-linking CD16 on NK cells (PMID:42587178). Human correlatives from sabatolimab+decitabine now show TIM3 is expressed broadly across NK, myeloid and T cells, and that TIM3 blockade with HMA expands cytotoxic NK subsets, raises type I interferon signalling and expands cytotoxic CD4+/small CD8+ clones in responders (PMID:42599272) — i.e. the NK/innate arm is the real effector axis, not exhaustion release.","approach":"Falsification order now: (1) does anti-TIM3 x CD16 cross-link NK cells against each other, given TIM3 on NK (PMID:42599272)? Assay NK viability, CD16 shedding and degranulation in autologous NK-alone cultures; (2) benchmark against untargeted venetoclax-LNP (PMID:42529898) to prove the TIM3 arm adds beyond pharmacokinetics; (3) normal CD34+ colony formation; (4) activity in MCL-1/BCL-xL-switched and monocytic blasts (PMID:42575085). Drop the 'depletes exhausted T cells' rationale — <1% of marrow CD8+ T cells are canonically exhausted (PMID:42599272). Prospective biomarker: NK:TIM3+ blast ratio plus type I IFN signature. Resistance: TIM3 antigen loss, BAX mutation, NK exhaustion/fratricide.","level":"CANDIDATE","confidence":0.47,"citations":[{"kind":"PMID","id":"42587178","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42529898","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42575085","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42599272","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT03066648","verified":false,"isNew":false,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":91,"lastVisit":3,"lastNote":"Promoted on independent human single-cell/TCR data confirming NK-cell and cytotoxic CD4 activation as the TIM3 mechanism; confidence held flat because the same paper shows TIM3 on NK cells (fratricide risk) and refutes the exhausted-T-cell-depletion rationale.","history":[{"visit":3,"cycle":170,"status":"STRENGTHENED","note":"Promoted on independent human single-cell/TCR data confirming NK-cell and cytotoxic CD4 activation as the TIM3 mechanism; confidence held flat because the same paper shows TIM3 on NK cells (fratricide risk) and refutes the exhausted-T-cell-depletion rationale."},{"visit":2,"cycle":91,"status":"NEW","note":"New from P7; strongest primary-data entry in this pack (Nature Cancer, PDX plus primary samples). Deliberately not higher because the formulation confound from P10 is unresolved and TIM3 blockade has a poor clinical track record."}]},{"id":"L7","title":"ATRA add-on to decitabine plus venetoclax in non-fit AML (DECIDER-2)","mechanism":"Hypomethylating agents prime AML blasts to retinoid-driven differentiation, plausibly by restoring RARA-pathway responsiveness at methylated loci [INFERRED]; RARA is a KG causal anchor. Randomised phase II (DECIDER) showed ATRA added to decitabine improved median OS 8.2 vs 5.1 months (HR 0.65, P=0.006) without added toxicity and including adverse-genetics patients; DECIDER-2 is the double-blind phase III adding ATRA to the approved DAC+VEN backbone (PMID:42563153).","approach":"Track DECIDER-2 OS/response and, critically, its translational programme for the marker that predicts ATRA benefit — candidate hypotheses to test: RARA-locus/enhancer methylation, differentiation-stage or monocytic phenotype, NPM1/IDH genotype. Mechanistic corollary worth testing preclinically: does ATRA-driven differentiation push blasts toward the monocytic, MCL-1-dependent state that confers venetoclax resistance (PMID:42575085), which would predict antagonism rather than synergy in a subset. Window: ATRA toxicity is well characterised and non-cumulative [KNOWN]; differentiation syndrome risk in non-APL AML must be monitored.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42563153","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42575085","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":91,"lastVisit":2,"lastNote":"New from P9. Highest-value repurposing bet in the dossier: all three agents approved, randomised phase II signal already positive, phase III running. Confidence capped because the phase II backbone was decitabine alone, not DAC+VEN.","history":[{"visit":2,"cycle":91,"status":"NEW","note":"New from P9. Highest-value repurposing bet in the dossier: all three agents approved, randomised phase II signal already positive, phase III running. Confidence capped because the phase II backbone was decitabine alone, not DAC+VEN."}]},{"id":"L8","title":"Bortezomib as a NOXA-dependent venetoclax resensitiser in intrinsically and acquired-resistant AML","mechanism":"Proteasome inhibition stabilises the short-lived BH3-only protein NOXA [KNOWN] plus BIM/PUMA, which neutralise MCL1 and restore BCL-2 dependence; bortezomib synergised with venetoclax across AML lines including venetoclax-adapted derivatives, irrespective of RAS or TP53 mutation, with NOXA upregulation required for the effect (PMID:41883151). This is the same MCL-1 compensation node identified as a principal escape route (PMID:42575085) and reiterated for TP53-mutant AML (PMID:41929632).","approach":"Test bortezomib (or carfilzomib/ixazomib for schedule flexibility) + venetoclax in primary venetoclax-refractory blasts, monocytic-phenotype samples and PDX, with paired normal CD34+ colony assays; confirm NOXA-dependence by PMAIP1 knockout epistasis and BH3 profiling shift; position strictly as resensitisation on a VEN/HMA backbone, NOT as an addition to intensive induction (proteasome inhibitors added to 7+3 have not delivered) [KNOWN]. Kill criteria: synergy lost in primary samples, requirement of supra-clinical bortezomib exposure, or equal killing of normal HSPCs. Expected resistance: BAX/executioner-phase loss, PMAIP1 silencing, PSMB5 mutation, BCL-xL dominance; peripheral neuropathy a","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"41883151","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42575085","verified":true,"isNew":false,"addedVisit":3},{"kind":"PMID","id":"41929632","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":170,"lastVisit":3,"lastNote":"New from P8: mechanistically clean (NOXA-required epistasis), genotype-agnostic including TP53-mutant, and both drugs are approved — the fastest-to-clinic entry in the dossier. Capped at 0.4 because the abstract reports cell lines only, no primary/PDX or normal-marrow toxicity data.","history":[{"visit":3,"cycle":170,"status":"NEW","note":"New from P8: mechanistically clean (NOXA-required epistasis), genotype-agnostic including TP53-mutant, and both drugs are approved — the fastest-to-clinic entry in the dossier. Capped at 0.4 because the abstract reports cell lines only, no primary/PDX or normal-marrow toxicity data."}]},{"id":"L9","title":"WNK1 kinase as a FLT3-ITD-enriched dependency that primes AML for venetoclax","mechanism":"WNK1 (not other WNK family members) is overexpressed in AML, highest in adverse subtypes including FLT3-ITD [SOMATIC], and scores as essential in CRISPR dependency data; WNK463/WNK11 inhibition suppressed proliferation of lines and primary blasts, induced BIM/PUMA-mediated apoptosis, downregulated DNA-replication genes (MCM5, CHAF1B, GINS2) and slowed xenografts without gross toxicity, with WNK1-high expression associated with venetoclax resistance and WNK463+venetoclax synergy (PMID:42326325).","approach":"Define whether the dependency is genotype-restricted (FLT3-ITD/adverse vs favourable) in isogenic and primary panels; determine whether the pro-apoptotic effect is on-target by WNK1 rescue/degron rather than WNK463 polypharmacology; measure normal CD34+ and T-cell colony/proliferation effects. Window is the central problem: WNK1-SPAK/OSR1 controls NCC/NKCC electrolyte transport and vascular tone in normal tissue [KNOWN], predicting hyperkalaemia, acid-base and blood-pressure toxicity — a leukaemia-selective degrader or dose-fractionated schedule would be required. Combination logic to test: WNK1i + venetoclax vs WNK1i + gilteritinib in FLT3-ITD models (relates to L1).","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"42326325","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":170,"lastVisit":3,"lastNote":"New from P9. Single-paper, tool-compound target with a genuinely worrying normal-tissue role; retained because the FLT3-ITD enrichment and venetoclax-resistance association are directly testable and intersect L1.","history":[{"visit":3,"cycle":170,"status":"NEW","note":"New from P9. Single-paper, tool-compound target with a genuinely worrying normal-tissue role; retained because the FLT3-ITD enrichment and venetoclax-resistance association are directly testable and intersect L1."}]}],"retired":[{"title":"Raloxifene repurposing against the ANP32B-MYC super-enhancer axis in pediatric AML","note":"Retired per the falsification criterion set at visit 1: no independent target-engagement or epistasis data appeared in this pack; single-agent docking plus MYC downregulation is not a target assignment.","cycle":91,"ts":"2026-08-19T19:23:43.990Z"}],"nextQueries":["(\"acute myeloid leukemia\") AND (bortezomib OR carfilzomib OR proteasome) AND (venetoclax OR NOXA OR PMAIP1) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"acute myeloid leukemia\") AND (BAX OR BAK1 OR \"executioner\") AND (mutation OR loss) AND (venetoclax OR relapse) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"acute myeloid leukemia\" OR \"myelodysplastic\") AND (CD16 OR \"NK cell engager\") AND (fratricide OR \"antigen sink\" OR HAVCR2) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T23:58:15.137Z"},{"key":"acute lymphoblastic leukemia","name":"acute lymphoblastic leukemia","mondo":{"id":"MONDO:0004967","name":"acute lymphoblastic leukemia"},"genes":[{"label":"TAL1","kind":"correlated"},{"label":"TLX3","kind":"correlated"},{"label":"NUP214","kind":"correlated"},{"label":"ABL1","kind":"correlated"},{"label":"AUTS2","kind":"correlated"},{"label":"PAX5","kind":"correlated"},{"label":"TLX1","kind":"correlated"},{"label":"MYB","kind":"correlated"},{"label":"STIL","kind":"correlated"},{"label":"BCR","kind":"correlated"},{"label":"PICALM","kind":"correlated"},{"label":"TCL1A","kind":"correlated"}],"visits":3,"openQuestions":["Does CD22 antigen site density (or cytoplasmic-only CD22) prospectively discriminate inotuzumab failure from CD22 CAR-T failure after CD19-directed therapy, given the two modalities were statistically equivalent on multivariate analysis (PM","Can consolidative allo-HSCT (or a second cellular product) after CD22 salvage convert the observed ~236-day median RFS into durable remission, and does CNS-directed prophylaxis reduce the sanctuary-site relapses seen after inotuzumab?","What is the actual incidence of therapy-driven myeloid lineage switch in KMT2A-rearranged ALL under menin inhibition versus under CD19 CAR-T, and does menin inhibition accelerate or suppress it?","Is there primary-sample or PDX (not review-level) evidence for menin inhibitor plus venetoclax or plus chemotherapy in KMT2A-rearranged ALL, with survival rather than synergy-index endpoints?","Does ZFP36L2-low status predict benefit from dexamethasone + trametinib or dexamethasone + GSI in primary T-ALL/PDX, and does ZFP36L2 loss raise BCL2 enough to confer venetoclax sensitivity (L1/L5 link)?","Is there ALL-specific clinical or PDX evidence for JAK inhibition in Ph-like/CRLF2-rearranged disease — still uncovered by this programme after three visits?"],"leads":[{"id":"L1","title":"ETV6-SE/CDKN1B loss as a biomarker for BCL-2 dependency: venetoclax + dexamethasone in ETV6-rearranged ALL","mechanism":"Glucocorticoid killing requires GR autoupregulation, BIM induction and BCL2 downregulation; lesions that block this step confer steroid resistance and create BCL2 dependency. ETV6 rearrangement [SOMATIC] disrupts the intragenic ETV6 super-enhancer loop to CDKN1B, lowering p27, activating NF-kB and raising BCL-2/BCL-XL (PMID:42525958). Independently, ZFP36L2-low T-ALL shows blunted GR upregulation, reduced BIM and failed BCL2 downregulation (PMID:42287749) — same effector node, different lesion. Venetoclax's anti-leukaemic effect in B-ALL tracks with collapse of both OXPHOS and glycolysis rather than with change in BCL-2 protein or global methylation, and is deepened by decitabine (PMID:42309","approach":"Biomarker-selected reinduction arms: (a) ETV6-rearranged or CDKN1B/p27-low B-ALL — venetoclax + dexamethasone +/- vincristine; (b) ZFP36L2-low or otherwise BIM-induction-deficient cases — venetoclax + dexamethasone, with GSI/trametinib as comparator (see new T-lineage lead); (c) venetoclax + decitabine as a metabolic co-targeting doublet in B-ALL. Pharmacodynamics must be functional, not expression-based: BH3 profiling plus Seahorse/OXPHOS and lactate flux, since BCL-2 protein level did not track synergy (PMID:42309255). Navitoclax only for BH3-defined BCL-XL-dominant cases (platelet BCL-XL dependence is the window limit) [KNOWN]. Normal tissue: BCL-2 loss depletes lymphocytes, spares most s","level":"CANDIDATE","confidence":0.6,"citations":[{"kind":"PMID","id":"42525958","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42287749","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42309255","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":39,"lastVisit":2,"lastNote":"Two independent [NEW] papers corroborate the druggable node: PMID:42287749 reaches the same BIM/BCL2 failure from ZFP36L2 loss in T-ALL, answering open question 6 in the affirmative; PMID:42309255 gives venetoclax combination data in B-ALL cell lines and a PDX scRNAseq readout, but relocates the mechanism to metabolism rather than BCL-2 expression, which invalidates BCL-2 protein level as the phar","history":[{"visit":2,"cycle":93,"status":"STRENGTHENED","note":"Two independent [NEW] papers corroborate the druggable node: PMID:42287749 reaches the same BIM/BCL2 failure from ZFP36L2 loss in T-ALL, answering open question 6 in the affirmative; PMID:42309255 gives venetoclax combination data in B-ALL cell lines and a PDX scRNAseq readout, but relocates the mechanism to metabolism rather than BCL-2 expression, which invalidates BCL-2 protein level as the phar"},{"visit":1,"cycle":39,"status":"NEW","note":"New this visit from PMID:42525958 [NEW]: first evidence the ETV6-SE→CDKN1B loop is broadly present in ALL and mechanistically links a tumour-suppressor-like lesion to a druggable apoptotic dependency, with PDX combination data. Tempered because the abstract reports only additive (not synergistic) effects and no survival/MRD endpoint."}]},{"id":"L2","title":"CD19 re-engagement sequencing: T-cell engager AZD0486 after CAR-T failure, triggered by NGS-MRD/B-cell recovery","mechanism":"Failure after CD19-directed therapy trifurcates [KNOWN/now evidenced]: (i) effector/persistence failure with CD19 retained — the majority, 65.1% of a 43-patient post-CD19 cohort (PMID:41963478), consistent with the CD19-retained case salvaged by donor-derived CD19 CAR-NK (PMID:41720609); (ii) true antigen loss via pre-existing CD19-negative progenitor-like subclones, splicing/mutational and epigenetic silencing (PMID:42023212), exemplified by CD19-negative post-blinatumomab relapse retaining cytoplasmic CD22 (PMID:42382092); (iii) myeloid lineage switch, enriched after CAR-T and associated with KMT2A rearrangement and bipotent progenitors (PMID:42023212, PMID:42593564). CD22 remains exploita","approach":"At every post-CD19 relapse: paired surface/cytoplasmic CD19 and CD22 flow, CD19 exon-2 sequencing, karyotype/KMT2A FISH, and a myeloid panel (CD33/CD117/MPO) to catch lineage switch. CD19-retained molecular relapse -> AZD0486/surovatamig monotherapy (NCT06137118) or allogeneic CD19 CAR-NK as HSCT bridge; CD19-lost -> CD22 CAR-T or inotuzumab, chosen on CD22 site density, prior hepatic/SOS risk and bridging feasibility rather than expected efficacy (equivalent per PMID:41963478). Because median RFS is ~8 months, pre-specify consolidative allo-HSCT (or second cellular product) in responders and mandate CNS-directed prophylaxis/imaging given sanctuary failure (PMID:42387626). Trigger by NGS-MRD","level":"DOSSIER","confidence":0.72,"citations":[{"kind":"NCT","id":"NCT06137118","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03876769","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05621291","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41720609","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42382092","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42541895","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41963478","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42387626","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42023212","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":39,"lastVisit":3,"lastNote":"Third evidence-bearing visit. PMID:41963478 [NEW] supplies the cohort-level answer to open question 3 (66% retain CD19; CD22 salvage CR 51%, RFS 236 days; InO == CD22 CAR), PMID:42387626 [NEW] extends InO activity to post-CAR-T/post-HSCT and identifies sanctuary-site failure, PMID:42023212 [NEW] adds myeloid lineage switch as a third escape route requiring a new assay. Two of my own claims were fa","history":[{"visit":3,"cycle":172,"status":"STRENGTHENED","note":"Third evidence-bearing visit. PMID:41963478 [NEW] supplies the cohort-level answer to open question 3 (66% retain CD19; CD22 salvage CR 51%, RFS 236 days; InO == CD22 CAR), PMID:42387626 [NEW] extends InO activity to post-CAR-T/post-HSCT and identifies sanctuary-site failure, PMID:42023212 [NEW] adds myeloid lineage switch as a third escape route requiring a new assay. Two of my own claims were fa"},{"visit":2,"cycle":93,"status":"STRENGTHENED","note":"Three [NEW] papers from an independent literature stream: PMID:41720609 directly instantiates the CD19-retained/effector-failure arm after CAR-T failure (single case, so anecdotal), PMID:42382092 instantiates the antigen-loss arm and forces a CD22 fallback into the design, and PMID:42541895 both validates engager benefit and undercuts my proposed MRD trigger endpoint. Promoted to CANDIDATE; still "},{"visit":1,"cycle":39,"status":"NEW","note":"New this visit; assembled from three [NEW] trials in the pack. Hypothesis is about sequencing and biomarker triggering, not a new agent — no efficacy data yet available to the desk, so confidence is capped."}]},{"id":"L3","title":"T-ALL subtype-directed therapy: CAR-T for relapsed T-ALL/LBL and ABL1-fusion-directed TKI","mechanism":"The KG anchor for ALL is dominated by T-lineage lesions (TAL1, STIL::TAL1, TLX1/TLX3, MYB, MLLT10, NUP214::ABL1) [SOMATIC], mostly transcription-factor rearrangements that are not directly druggable; the exception is NUP214::ABL1/ABL1-fusion T-ALL, a kinase-activating lesion analogous to BCR::ABL1, for which chemotherapy plus ABL TKI is the established paradigm (NCT03007147) [INFERRED for the T-ALL fusion].","approach":"Two parallel probes: (a) evaluate CTD402 CAR-T in relapsed/refractory T-ALL/LBL (NCT07070219), watching for fratricide and T-cell aplasia as the window-limiting toxicity; (b) screen T-ALL for ABL1 fusions/amplification and test imatinib or dasatinib addition to intensive chemotherapy, borrowing the Ph+ ALL backbone (NCT03007147). Resistance: ABL1 kinase-domain mutation, RAS/PI3K bypass; for CAR-T, target-antigen downregulation and lineage plasticity.","level":"LEAD","confidence":0.35,"citations":[{"kind":"NCT","id":"NCT07070219","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03007147","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":39,"lastVisit":1,"lastNote":"New this visit to cover the programme's T-lineage gap, which the KG anchor makes prominent. Weakest of the new leads: the TKI arm rests on an [INFERRED] analogy between NUP214::ABL1 and BCR::ABL1, and CTD402 has no reported clinical data.","history":[{"visit":1,"cycle":39,"status":"NEW","note":"New this visit to cover the programme's T-lineage gap, which the KG anchor makes prominent. Weakest of the new leads: the TKI arm rests on an [INFERRED] analogy between NUP214::ABL1 and BCR::ABL1, and CTD402 has no reported clinical data."}]},{"id":"L5","title":"ZFP36L2-low T-ALL: restoring glucocorticoid sensitivity with a gamma-secretase inhibitor or trametinib","mechanism":"ZFP36L2, an RNA-binding protein [SOMATIC candidate driver in T-ALL], is expressed lower in T-ALL than B-ALL; low expression associates with poor early response and higher relapse risk. Knockdown in T-ALL lines produced glucocorticoid resistance via failed GR upregulation, blunted BIM induction, impaired apoptosis and retained BCL2, and ZFP36L2 was required for GC-mediated suppression of (abstract truncated, apparently NOTCH) signalling; adding DAPT or trametinib restored drug sensitivity in vitro (PMID:42287749). [INFERRED] loss of an mRNA-destabilising protein permits accumulation of NOTCH1/MAPK-pathway transcripts that antagonise the GR programme.","approach":"Assay ZFP36L2 (RNA/protein) across T-ALL/ETP-ALL primary samples and PDX; test dexamethasone + trametinib and dexamethasone + a clinical-grade GSI in ZFP36L2-low versus -high PDX with survival and MRD endpoints. Because the node is BIM:BCL2, include dexamethasone + venetoclax as a third arm and cross-reference BH3 profiling (link to L1). Normal tissue: NOTCH inhibition causes secretory-cell metaplasia and GI toxicity, mitigable by intermittent dosing plus steroid, which is convenient here since steroid is the partner [KNOWN]; MEK inhibition gives rash and cardiac/ocular toxicity. Resistance: NOTCH-independent MYC maintenance, RAS/PI3K bypass, MCL1 rise.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42287749","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":93,"lastVisit":2,"lastNote":"New this visit from a [NEW] paper; the first entry in this programme that supplies a pharmacological dependency for T-lineage ALL rather than an expression correlation (partial answer to open question 4, though not for TAL1/STIL/TLX1/TLX3). Capped at 0.4: cell-line knockdown only, no primary-sample or in vivo pharmacology, and the abstract truncates the pathway claim so the NOTCH attribution is pr","history":[{"visit":2,"cycle":93,"status":"NEW","note":"New this visit from a [NEW] paper; the first entry in this programme that supplies a pharmacological dependency for T-lineage ALL rather than an expression correlation (partial answer to open question 4, though not for TAL1/STIL/TLX1/TLX3). Capped at 0.4: cell-line knockdown only, no primary-sample or in vivo pharmacology, and the abstract truncates the pathway claim so the NOTCH attribution is pr"}]},{"id":"L6","title":"KMT2A-rearranged infant ALL requires triplets, not venetoclax doublets — negative-result guardrail plus a triplet design","mechanism":"KMT2A fusions maintain leukaemia through a menin-dependent transcriptional programme [KNOWN]; a review of adult KMT2Ar B-ALL positions menin inhibitors as the mechanistically matched small molecule and names antigen loss and myeloid lineage switch as the subtype-specific immunotherapy resistance routes (PMID:42593564), converging with the post-CAR-T escape review that ties myeloid conversion to KMT2A rearrangement and epigenetic reprogramming (PMID:42023212). Against this, high-throughput screening showed venetoclax/ponatinib/trametinib pairwise synergy in KMT2Ar cell lines and CDX/PDX that failed in primary samples and, decisively, no doublet prevented PDX leukaemia outgrowth (PMID:42294111","approach":"Do not advance venetoclax-containing doublets in KMT2Ar ALL. Constructive design: menin inhibitor (revumenib/ziftomenib class [KNOWN]) as backbone, with venetoclax or a MEK inhibitor added on a reduced-intensity chemotherapy scaffold, dose-staggered for myelosuppression; primary endpoint PDX survival, not in vitro synergy indices. Pre-specify serial flow for myeloid lineage switch on therapy (menin inhibition is differentiation-promoting, so a switch could be therapy-driven [INFERRED]) and MEN1 kinase-domain-equivalent escape mutations plus MYC/MEIS1 reactivation as resistance readouts [KNOWN]. Normal tissue: menin is required for normal haematopoietic and endocrine (parathyroid, islet) prog","level":"CANDIDATE","confidence":0.45,"citations":[{"kind":"PMID","id":"42294111","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42593564","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42023212","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":93,"lastVisit":3,"lastNote":"Second evidence-bearing visit with two [NEW] independent (review-level) citations that supply the constructive half the lead lacked: a mechanistically matched agent class (menin inhibition) and a concrete resistance route (myeloid lineage switch tied to KMT2A). Evidence is review-grade, not primary, so confidence held below 0.5; the venetoclax-doublet guardrail from PMID:42294111 is retained verba","history":[{"visit":3,"cycle":172,"status":"STRENGTHENED","note":"Second evidence-bearing visit with two [NEW] independent (review-level) citations that supply the constructive half the lead lacked: a mechanistically matched agent class (menin inhibition) and a concrete resistance route (myeloid lineage switch tied to KMT2A). Evidence is review-grade, not primary, so confidence held below 0.5; the venetoclax-doublet guardrail from PMID:42294111 is retained verba"},{"visit":2,"cycle":93,"status":"NEW","note":"Entered primarily as a negative-result record so the desk never re-proposes venetoclax doublets in KMT2A-r infant ALL; low confidence because the constructive half (a triplet) is untested and toxicity in infants is the binding constraint."}]}],"retired":[{"title":"Low-confidence: exosomal MALAT1/METTL14 → HMGB1 axis as an NK-directed chemoresistance node","note":"Retired per the falsification rule pre-registered at visit 2: still a single laboratory, NK92-MI plus nude-mouse xenografts, long mechanistic chain, no independent replication surfacing across two visits of literature sweeps. Caveat stated openly — this visit's queries were not targeted at the axis, so the silence is weak rather than strong disconfirmation; the resurrect condition is documented.","cycle":172,"ts":"2026-08-20T00:05:40.531Z"}],"nextQueries":["(\"acute lymphoblastic leukemia\" AND (\"menin inhibitor\" OR revumenib OR ziftomenib OR SNDX-5613) AND (KMT2A OR MLL)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"acute lymphoblastic leukemia\" AND (CRLF2 OR \"Ph-like\" OR JAK2) AND (ruxolitinib OR \"JAK inhibitor\" OR dasatinib)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"B-cell acute lymphoblastic leukemia\" AND CD22 AND (\"antigen density\" OR \"site density\" OR \"CD22 CAR\") AND (relapse OR resistance)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-20T00:05:40.531Z"},{"key":"chronic lymphocytic leukemia","name":"chronic lymphocytic leukemia","mondo":{"id":"MONDO:0004948","name":"B-cell chronic lymphocytic leukemia"},"genes":[{"label":"BRAF","kind":"correlated"},{"label":"IGHG1","kind":"correlated"},{"label":"IGHV3-21","kind":"correlated"},{"label":"IGHV4-34","kind":"correlated"},{"label":"CCND1","kind":"correlated"},{"label":"ATM","kind":"correlated"},{"label":"TP53","kind":"correlated"},{"label":"RPS15","kind":"correlated"},{"label":"P2RX7","kind":"correlated"},{"label":"IKZF3","kind":"correlated"},{"label":"POT1","kind":"correlated"},{"label":"ARL11","kind":"correlated"}],"visits":3,"openQuestions":["What is the pretreatment prevalence of BTK A428D subclones in BTKi-exposed CLL, and what ddPCR/ctDNA VAF floor is required to exclude patients from degrader monotherapy?","Do BGB-16673 or NX-5948 cohorts show lower IgG nadirs and fewer opportunistic/fungal infections than covalent BTKi controls, as the selectivity argument predicts, or does total BTK removal worsen humoral deficiency?","Are CRBN/DDB1/neddylation-pathway losses or BTK loss-of-expression observed at all as degrader-specific escape, or is adenine-pocket binding failure the sole clinical route?","Does any primary CLL ex vivo dataset show ATR/CHK1/WEE1-inhibitor sensitivity, and is it restricted to CD40L/CpG-stimulated proliferation-centre mimics versus quiescent circulating cells? (retirement trigger for L6)","Has any MDM2 inhibitor been tested in CLL or SLL cells, and does p53 reactivation synergize with venetoclax specifically in TP53-wild-type cases without selecting TP53-mutant subclones?","Is Richter transformation enriched on BTK degraders, and does it co-occur with A428D or with TP53 disruption?"],"leads":[{"id":"L1","title":"BTK protein degradation for BTKi-resistant CLL/SLL with scaffold or kinase-impaired BTK mutants","mechanism":"Non-covalent BTKi resistance mutations L528W and T474I/L [SOMATIC] retain scaffolding function, so catalytic inhibition fails while CRBN-directed degradation removes the protein and collapses PLCG2/PKCbeta/NF-kB output; A428D remains excluded because the mutant aspartate clashes with the adenine-mimetic warhead shared by inhibitors and current degraders (PMID:42484277). Window refined this visit: PMID:42192981 attributes much of the covalent-BTKi infection burden to off-target T-cell/myeloid kinase inhibition and argues degraders/non-covalent agents are more selective and may preserve T-cell function, so the expected degrader toxicity may be closer to isolated XLA-like humoral deficiency tha","approach":"BGB-16673 (NCT05006716) and NX-5948 (NCT07221500) expansion with mandatory pretreatment ddPCR/ctDNA screen for BTK A428D at low VAF and serial BTK/PLCG2 sequencing at relapse. Newly elevated to primary safety endpoints: serial IgG/IgA/IgM nadirs, pathogen-stratified infection rates (bacterial vs viral vs invasive fungal) and T-cell subset/function assays versus covalent BTKi and pirtobrutinib controls. Still unmeasured and required: CRBN/DDB1 mutation, neddylation-pathway loss, BTK loss-of-expression as degrader-specific escapes.","level":"CANDIDATE","confidence":0.7,"citations":[{"kind":"PMID","id":"42252468","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42587792","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05006716","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07221500","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42484277","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42278639","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42192981","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":40,"lastVisit":3,"lastNote":"New CLL-specific review (PMID:42192981) sharpens the therapeutic-window argument but adds no efficacy or resistance data; deliberately NOT promoted to DOSSIER on a narrative review. Confidence 0.68 to 0.70.","history":[{"visit":3,"cycle":173,"status":"STRENGTHENED","note":"New CLL-specific review (PMID:42192981) sharpens the therapeutic-window argument but adds no efficacy or resistance data; deliberately NOT promoted to DOSSIER on a narrative review. Confidence 0.68 to 0.70."},{"visit":2,"cycle":94,"status":"STRENGTHENED","note":"New this visit: independent peer-reviewed serial-sequencing study confirms clinical degrader efficacy in BTKi-resistant CLL (supporting promotion) while falsifying my A428D coverage claim (forcing narrowing). Second evidence-bearing visit, 3+ verified citations, survived an attempted kill in modified form."},{"visit":1,"cycle":40,"status":"NEW","note":"New this visit: ASH 2025 summary reports rapid deep responses and established RP2Ds for bexobrutideg and BGB-16673 including high-risk subgroups; PROTAC design/selectivity rationale reviewed in PMID:42587792. Evidence is conference-abstract grade, single visit, so held at LEAD."}]},{"id":"L2","title":"Dual LYN/BTK inhibition to close Src-family redundancy after BTK degrader failure","mechanism":"Removing or inhibiting BTK leaves proximal BCR signalling partly intact via LYN-dependent SYK/PI3K flux; simultaneous LYN blockade should extinguish residual survival signalling in cells that have already escaped BTK-directed and BCL2-directed therapy. LYN is broadly expressed in myeloid cells and platelets, so myelosuppression and bleeding define the window.","approach":"Birletinib in post-BTKi/post-BCL2i/post-degrader CLL; need response duration, LYN target-engagement PD marker, and haematologic toxicity tables. Preclinical: primary CLL cells with L528W or PLCG2 mutations treated with LYN inhibition +/- BTK degrader, readout pBTK-independent pPLCG2/pERK.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42252468","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":40,"lastVisit":1,"lastNote":"New: reported high ORR after prior BTKi, BCL2i and BTK degrader exposure. Single conference-abstract source, no durability or n reported — deliberately low confidence.","history":[{"visit":1,"cycle":40,"status":"NEW","note":"New: reported high ORR after prior BTKi, BCL2i and BTK degrader exposure. Single conference-abstract source, no durability or n reported — deliberately low confidence."}]},{"id":"L3","title":"Preemptive dual BCL2/BTK blockade with next-generation agents to suppress BCL2 resistance mutations","mechanism":"Fixed-duration BTKi+BCL2i drives deep MRD clearance; a more potent BCL2 inhibitor (sonrotoclax) should reduce residual clone size below the threshold at which BCL2 G101V/D103Y [SOMATIC] and MCL1/BCL-xL rewiring are selected. New mechanistic breadth: BCL2 co-targeting also suppresses expansion of BTK resistance mutants including pan-resistant A428D (PMID:42484277), so the combination controls two independent escape axes, not one. Normal-tissue BCL2 dependence is platelet/lymphocyte-restricted — thrombocytopenia and tumour lysis define the window.","approach":"Randomized sonrotoclax+zanubrutinib vs venetoclax+acalabrutinib (NCT07277231), benchmarked against venetoclax monotherapy in R/R disease (NCT02966756) and long-term ibrutinib+venetoclax outcomes (NCT07774390). Required readout: paired-sample BCL2/BTK/PLCG2 mutation surveillance at MRD relapse, stratified by TP53/ATM status, with explicit reporting of BTK A428D VAF trajectories.","level":"LEAD","confidence":0.58,"citations":[{"kind":"NCT","id":"NCT07277231","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT02966756","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07774390","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42484277","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42278639","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":40,"lastVisit":2,"lastNote":"Corroboration is indirect (BTK-mutant clone control, not BCL2-mutant suppression), so held at LEAD rather than promoted; contemporary review PMID:42278639 supports MRD-guided time-limited doublets as the frontline frame.","history":[{"visit":2,"cycle":94,"status":"STRENGTHENED","note":"Corroboration is indirect (BTK-mutant clone control, not BCL2-mutant suppression), so held at LEAD rather than promoted; contemporary review PMID:42278639 supports MRD-guided time-limited doublets as the frontline frame."},{"visit":1,"cycle":40,"status":"NEW","note":"New this visit: registered phase 3 head-to-head gives a testable superiority hypothesis rather than a single-arm signal; mutation-surveillance component is my addition, not yet reported."}]},{"id":"L4","title":"Gut microbiome remodelling as a modifiable determinant of ibrutinib response and diarrhoea","mechanism":"Divergent longitudinal trajectories — saccharolytic/SCFA-associated taxa and carbohydrate-fermentation pathways enriched in responders versus bile-acid-modifying, proteolytic, inflammation-associated features in non-responders — suggest microbial metabolite tone modulates BCR-directed therapy efficacy and gut toxicity. [SPECULATIVE] causality; secondary bile acids and SCFAs could shape T/NK-cell fitness and epithelial integrity.","approach":"Prospective CLL-only cohort with baseline and serial metagenomics plus serum/faecal SCFA and bile-acid metabolomics during BTKi therapy; adjust for antibiotics, prior therapy and disease burden. If association survives, test dietary fibre or targeted consortium as a toxicity-mitigation adjunct.","level":"LEAD","confidence":0.22,"citations":[{"kind":"PMID","id":"42002835","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":40,"lastVisit":1,"lastNote":"New but weak: n=30 mixed haematologic malignancies, association-only, confounders unaddressed. Recorded so the desk does not overinterpret microbiome signals as causal.","history":[{"visit":1,"cycle":40,"status":"NEW","note":"New but weak: n=30 mixed haematologic malignancies, association-only, confounders unaddressed. Recorded so the desk does not overinterpret microbiome signals as causal."}]},{"id":"L5","title":"Anti-A428D strategies: BCL2 co-targeting, intermittent dosing to exploit the mutant's fitness cost, and non-adenine-mimetic BTK binders","mechanism":"A428D [SOMATIC] blocks the shared adenine-mimetic pharmacophore of BTK inhibitors and current PROTAC warheads, but the same steric clash with ATP impairs BTK function and the mutant clone is at a competitive disadvantage without BTK-directed pressure (PMID:42484277). Two exploitable corollaries: (i) apoptotic-threshold lowering with venetoclax mitigated A428D outgrowth, i.e. BCL2 dependence is retained in the resistant clone; (ii) removing selective pressure should let the fitness-disadvantaged clone contract, favouring MRD-guided fixed-duration or intermittent degrader schedules over continuous exposure [INFERRED]. (iii) A BTK ligand that is not adenine-mimetic (allosteric pocket, non-ATP-s","approach":"Add a degrader+venetoclax (or +sonrotoclax) arm to ongoing degrader expansions (NCT05006716, NCT07221500) with A428D VAF as the primary molecular endpoint; test on/off intermittent degrader dosing in A428D-competitive-fitness xenograft or barcoded primary-CLL competition assays with serial ddPCR; screen degrader libraries against recombinant BTK A428D for retained ternary-complex formation and Ub transfer. Report BCL2 G101V/D103Y co-emergence in the combination arm. Note the toxicity cost of stacking degrader neutropenia with venetoclax tumour lysis and thrombocytopenia.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42484277","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT05006716","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT07221500","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT07277231","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":94,"lastVisit":2,"lastNote":"Directly derived from the one strong new paper; the venetoclax-mitigation observation is theirs, the intermittent-dosing and non-adenine-mimetic-binder proposals are my inferences and untested.","history":[{"visit":2,"cycle":94,"status":"NEW","note":"Directly derived from the one strong new paper; the venetoclax-mitigation observation is theirs, the intermittent-dosing and non-adenine-mimetic-binder proposals are my inferences and untested."}]},{"id":"L6","title":"ATR/CHK1/WEE1 synthetic lethality in ATM-deleted (11q) and TP53-disrupted CLL","mechanism":"Biallelic ATM loss or TP53 disruption [SOMATIC] abolishes the G1/S checkpoint and increases dependence on the compensatory ATR-CHK1-WEE1 G2 axis; ATM loss is a stated sensitizer to ATR and PARP inhibition (PMID:42025253, PMID:40759474, PMID:40422251, PMID:42098732) and replication-stress-response inhibition engages cGAS-STING (PMID:41614897, PMID:41402978). Unresolved CLL-specific objection, now two visits old: circulating CLL cells are largely quiescent (G0), so replication-stress-dependent lethality may be confined to proliferation-centre cells. Germline discipline: pathogenic ATM variants occur in roughly 1/100 individuals (PMID:42025253), so heterozygous carriers [GERMLINE] within 11q-de","approach":"Unchanged substrate-first plan: ex vivo ATR- and WEE1-inhibitor sensitivity in primary CLL stratified by 11q/ATM biallelic status, TP53 status and Ki-67, unstimulated versus CD40L/IL-4/IL-21 or CpG proliferation-centre mimics; readouts gammaH2AX, pCHK1, micronuclei, IFN signature. Explicit kill criterion set: if the next targeted Europe PMC query returns no primary CLL ex vivo or clinical DDRi data, this lead is retired rather than carried further on pan-cancer reviews.","level":"LEAD","confidence":0.18,"citations":[{"kind":"PMID","id":"40759474","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40422251","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40240755","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41614897","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42025253","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42098732","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41402978","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":94,"lastVisit":3,"lastNote":"Second consecutive pack delivered only pan-cancer DDR reviews and zero CLL data; the absence is now itself evidence. Confidence 0.28 to 0.18 with a stated retirement trigger for visit 4.","history":[{"visit":3,"cycle":173,"status":"WEAKENED","note":"Second consecutive pack delivered only pan-cancer DDR reviews and zero CLL data; the absence is now itself evidence. Confidence 0.28 to 0.18 with a stated retirement trigger for visit 4."},{"visit":2,"cycle":94,"status":"NEW","note":"Opened to address KG anchors ATM/TP53 that no lead covered, but deliberately low confidence: pack contained only pan-cancer reviews, zero CLL data, and the quiescence objection could kill it. RPS15 and POT1 remain unaddressed."}]},{"id":"L7","title":"MDM2 inhibition to reactivate wild-type p53 in TP53-wild-type CLL, combined with BCL2 antagonism","mechanism":"Most CLL is TP53-wild-type at diagnosis [KNOWN]; p53 can be functionally suppressed post-translationally via MDM2 rather than mutated. PMID:42086932 reports that successive MDM2 inhibitor generations failed phase III in AML but produced spleen, symptom and molecular responses in TP53-wild-type myelofibrosis, and highlights rational combination with BCL-2 antagonists and interferons plus emerging MDM2 degraders. Mechanistic fit for CLL [INFERRED]: p53 reactivation raises PUMA/BAX/NOXA tone and should lower the apoptotic threshold cooperatively with venetoclax or sonrotoclax, potentially deepening MRD clearance in TP53-intact disease. Normal-tissue role of the MDM2-p53 loop is ubiquitous, so t","approach":"Ex vivo first: MDM2 inhibitor (navtemadlin/idasanutlin-class) sensitivity in primary CLL stratified by TP53 sequencing plus 17p FISH and by MDM2 expression, alone and with venetoclax/sonrotoclax, readout MDM2-p53 target induction (p21, MDM2, PUMA), BH3 profiling and apoptosis; explicitly test whether TP53-disrupted subclones are enriched under drug pressure using ddPCR on barcoded or serially passaged cultures. Only a demonstrated TP53-wild-type-restricted synergy plus an acceptable clonal-selection profile would justify a fixed-duration (not continuous) CLL arm alongside NCT07277231-style doublets. Do not propose in TP53-disrupted or 17p-deleted disease.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42086932","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT07277231","verified":true,"isNew":false,"addedVisit":3},{"kind":"PMID","id":"42187721","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":173,"lastVisit":3,"lastNote":"New this visit from a myeloid-focused review; zero CLL data exist in the pack, and the negative phase III AML history plus TP53-mutant clonal selection are recorded so the desk does not overrate it. Also logged as a use case for the degrader/molecular-glue modality expansion in PMID:42187721.","history":[{"visit":3,"cycle":173,"status":"NEW","note":"New this visit from a myeloid-focused review; zero CLL data exist in the pack, and the negative phase III AML history plus TP53-mutant clonal selection are recorded so the desk does not overrate it. Also logged as a use case for the degrader/molecular-glue modality expansion in PMID:42187721."}]}],"retired":[],"nextQueries":["(\"chronic lymphocytic leukemia\" OR \"CLL cells\") AND (\"ATR inhibitor\" OR ceralasertib OR berzosertib OR adavosertib OR WEE1 OR prexasertib) AND (\"primary cells\" OR \"ex vivo\" OR CD40L OR \"proliferation center\") AND SRC:MED","(\"chronic lymphocytic leukemia\" OR \"B-cell lymphoma\") AND (MDM2 OR navtemadlin OR idasanutlin OR siremadlin OR \"p53 reactivation\") AND (venetoclax OR BCL2 OR apoptosis) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"BTK degrader\" OR bexobrutideg OR \"BGB-16673\" OR \"NX-5948\") AND (immunoglobulin OR hypogammaglobulinemia OR infection OR neutropenia OR \"T cell\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-20T00:09:04.334Z"},{"key":"myelodysplastic syndrome","name":"myelodysplastic syndrome","mondo":{"id":"MONDO:0018881","name":"myelodysplastic syndrome"},"genes":[{"label":"SAMD9L","kind":"causal"},{"label":"SAMD9","kind":"causal"},{"label":"RPS14","kind":"causal"},{"label":"ASXL1","kind":"causal"},{"label":"GNB1","kind":"causal"},{"label":"SF3B1","kind":"causal"},{"label":"TET2","kind":"causal"},{"label":"GATA2","kind":"correlated"},{"label":"MYSM1","kind":"correlated"},{"label":"TP53","kind":"correlated"}],"visits":3,"openQuestions":["What are the actual response rates, duration and toxicity of emavusertib in MDS specifically (TakeAim Leukemia MDS cohort), and do spliceosome-mutant or U2AF1-like-signature patients respond preferentially?","Has any GSPT1-directed CELMoD (e.g. CC-90009-class) been dosed in MDS or post-MDS sAML, and what were the haematological toxicity and CRBN-loss resistance patterns that would bound an IRAK4-inhibitor combination?","Is any PRMT5 inhibitor in a myeloid-neoplasm clinical trial at all, and is there any quantitative measure of PRMT5-inhibition effect on normal human CD34+ self-renewal?","Do luspatercept or imetelstat reduce SF3B1/TET2/ASXL1 VAF in LR-MDS, and does baseline inflammasome/IL-1 activity predict failure of either agent?","Is there any published response data for XPO1 inhibitor plus venetoclax stratified by TP53 status in MDS, and does venetoclax add benefit in MDS-derived secondary AML?","Are there platelet-sparing BCL-xL modalities (lineage-directed degraders, intermittent dosing) with myeloid data, and does a BCL2:BCL2L1 ratio prospectively select responders?"],"leads":[{"id":"L1","title":"XPO1 inhibition (selinexor/eltanexor) plus venetoclax in HMA-refractory MDS, restricted to TP53-wild-type disease","mechanism":"XPO1 is overexpressed across MDS risk groups; blocking nuclear export retains p53 and other tumour suppressors nuclear, raises ROS and lowers the apoptotic threshold, synergising with BCL-2 blockade (PMID:42007609). [INFERRED] Efficacy should be conditional on wild-type TP53 [SOMATIC]. Real-world validation of ELN 2024 in non-intensive AML now quantifies the ceiling this lead must beat: HMA-venetoclax median OS 11.2 months overall but only 7.7 months in adverse-risk disease, with poor prognostic discrimination precisely in secondary AML arising from a prior myeloid neoplasm (PMID:42294112) — i.e. the MDS-progressed population. TP53-mutant clones remain the worst-outcome group in decitabine-t","approach":"Eltanexor/selinexor + venetoclax in R/R MDS (NCT06399640) with prospective TP53, complex-karyotype and sM-AML strata pre-specified rather than pooled; serial nuclear p53/p21 induction, BH3 profiling, TP53 VAF for clonal escape. Resistance: TP53 mutation/del(17p), MCL1 upregulation, XPO1 E571K.","level":"LEAD","confidence":0.52,"citations":[{"kind":"PMID","id":"42007609","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06399640","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41972336","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42294112","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":41,"lastVisit":2,"lastNote":"Small increment only: PMID:42294112 is NEW and independent but is AML registry data with no XPO1 or BH3 content. It supports the stratification design (adverse-risk and sM-AML must be separate strata) rather than the mechanism, so the lead stays at LEAD.","history":[{"visit":2,"cycle":95,"status":"STRENGTHENED","note":"Small increment only: PMID:42294112 is NEW and independent but is AML registry data with no XPO1 or BH3 content. It supports the stratification design (adverse-risk and sM-AML must be separate strata) rather than the mechanism, so the lead stays at LEAD."},{"visit":1,"cycle":41,"status":"NEW","note":"New lead from this visit: preclinical mechanism (PMID:42007609) plus an independent recruiting phase 1 in the same combination and population; mechanism is cell-line/GEO level only, so kept at LEAD."}]},{"id":"L2","title":"BCL-xL co-dependence as the venetoclax-resistance node in MDS with excess blasts — pursue platelet-sparing BCL-xL antagonism","mechanism":"Venetoclax/HMA failure in MDS-EB, MDS/MPN overlap and secondary AML is attributed to a shift of anti-apoptotic dependence from BCL-2 to BCL-xL; navitoclax added to venetoclax + decitabine addresses both (PMID:42189880, NCT05455294). [KNOWN] BCL-xL is the obligate survival protein of megakaryocytes/platelets, which is why only 25-50 mg navitoclax was deliverable and grade >=3 thrombocytopenia occurred in 69% — the window, not the target, is the problem in a cytopenic disease.","approach":"Use BH3 profiling / BCL2:BCL2L1 ratio on sorted CD34+ blasts to prospectively select BCL-xL-dependent MDS; then test platelet-sparing modalities (lineage-restricted BCL-xL degraders, pulsed intermittent dosing, or MCL1-sparing triplets) rather than continuous navitoclax. Resistance routes: MCL1 upregulation, monocytic differentiation, TP53 loss.","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"42189880","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":41,"lastVisit":1,"lastNote":"New lead. Abstract is truncated before efficacy data, so this is recorded as mechanistic/tolerability evidence only; the dose-limiting thrombocytopenia is deliberately logged so the desk never re-proposes unmodified navitoclax escalation in MDS.","history":[{"visit":1,"cycle":41,"status":"NEW","note":"New lead. Abstract is truncated before efficacy data, so this is recorded as mechanistic/tolerability evidence only; the dose-limiting thrombocytopenia is deliberately logged so the desk never re-proposes unmodified navitoclax escalation in MDS."}]},{"id":"L3","title":"Innate-immune kinase blockade (pacritinib: IRAK1/CSF1R/JAK2/FLT3) in MDS and MDS/MPN overlap","mechanism":"TRAF6-IRAK1/4 hyperactivation sustains del(5q) and spliceosome-mutant MDS; a mutation-agnostic U2AF1-like splicing program requires IRAK4 genetically (PMID:40333990). New this visit: preclinical IRAK4-inhibition data specifically in MDS plus clinical emavusertib (CA-4948) data from TakeAim Leukemia establish IRAK4 as a drugged target in myeloid disease (PMID:40634180). Counterweight: IRAK4 inhibitors give only modest single-agent clinical efficacy in AML (PMID:40670672), so monotherapy expectations must fall. CSF1R blockade covers the inflammatory monocyte/macrophage compartment and JAK2 the MPN-overlap component (NCT06303193); pacritinib activity in VEXAS (NCT06782373) is orthogonal support","approach":"Enrich NCT06303193 for del(5q), SF3B1/U2AF1/SRSF2 mutations and a transcriptome-derived U2AF1-like signature; PD = IRAK4-L/IRAK4-S isoform ratio, NF-kB targets, serum IL-6/TNF. Add a head-to-head preclinical arm of pacritinib versus emavusertib in the same MDS primary samples/PDX to test whether IRAK1 coverage substitutes for IRAK4 inhibition. Resistance: NRAS/KRAS activation, ASXL1/TET2 subclones signalling independently of IRAK4, MYD88-independent bypass.","level":"CANDIDATE","confidence":0.54,"citations":[{"kind":"NCT","id":"NCT06303193","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06782373","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07228624","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40333990","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40634180","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40670672","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":41,"lastVisit":3,"lastNote":"NEW PMID:40634180 supplies MDS-specific preclinical IRAK4 data and the first clinical IRAK4-selective agent, answering OQ2; NEW PMID:40670672 simultaneously caps single-agent expectations. Net small increase, held below promotion because the kinase pacritinib actually inhibits (IRAK1) is not the one genetically validated.","history":[{"visit":3,"cycle":174,"status":"STRENGTHENED","note":"NEW PMID:40634180 supplies MDS-specific preclinical IRAK4 data and the first clinical IRAK4-selective agent, answering OQ2; NEW PMID:40670672 simultaneously caps single-agent expectations. Net small increase, held below promotion because the kinase pacritinib actually inhibits (IRAK1) is not the one genetically validated."},{"visit":2,"cycle":95,"status":"STRENGTHENED","note":"Promoted: second evidence-bearing visit with NEW independent mechanistic literature (PMID:40333990) that replaces the previously [KNOWN]-only IRAK4 rationale with xenograft genetic validation and supplies a mutation-agnostic biomarker. Held at 0.52 because the data are AML, not MDS, and pacritinib may not hit the validated kinase."},{"visit":1,"cycle":41,"status":"NEW","note":"New lead built from three concordant trial records; no MDS efficacy data in the pack, and the IRAK4-L rationale is [KNOWN] background rather than cited, so confidence deliberately low."}]},{"id":"L4","title":"IDH1 inhibition (olutasidenib) as clonal interception in IDH1-mutant CCUS and lower-risk MDS/CMML","mechanism":"Mutant IDH1 [SOMATIC] produces 2-HG, inhibiting TET2 and KDM histone demethylases and blocking myeloid differentiation — epistatic with the TET2 anchor. IDH1/2-mutated MDS is now independently described as an emerging molecular subgroup with multiple trials underway (PMID:41143913), supporting the premise that this is a definable disease entity rather than an incidental mutation class. Treating at CCUS/lower-risk stage tests whether differentiation therapy prevents blast escalation rather than salvaging it (NCT06566742). Normal tissue: wild-type IDH1 is largely dispensable in haematopoiesis, giving a wide window; class risk is differentiation syndrome.","approach":"Single-agent olutasidenib with serial IDH1 VAF, 2-HG levels and single-cell clonal-architecture tracking to separate clonal clearance from differentiation without eradication; pre-specify progression-to-HR-MDS as the interception endpoint. Resistance: IDH2 isoform switching, second-site IDH1 dimer-interface mutations, RAS/RTK co-mutation.","level":"CANDIDATE","confidence":0.48,"citations":[{"kind":"NCT","id":"NCT06566742","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41143913","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":41,"lastVisit":3,"lastNote":"Promoted: second evidence-bearing visit with NEW independent literature (PMID:41143913) naming IDH1/2-mutant MDS as an emerging subgroup with active trials. Held at 0.48 — still no reported response or clonal-clearance data at the CCUS/LR-MDS stage anywhere in the pack.","history":[{"visit":3,"cycle":174,"status":"STRENGTHENED","note":"Promoted: second evidence-bearing visit with NEW independent literature (PMID:41143913) naming IDH1/2-mutant MDS as an emerging subgroup with active trials. Held at 0.48 — still no reported response or clonal-clearance data at the CCUS/LR-MDS stage anywhere in the pack."},{"visit":1,"cycle":41,"status":"NEW","note":"New lead; single recruiting trial as sole citation, so it stays a LEAD pending independent corroboration."}]},{"id":"L5","title":"PRMT5 inhibition to reverse U2AF1-like missplicing in MDS and MDS-derived secondary AML","mechanism":"PRMT5 methylates Sm/spliceosomal proteins and was the regulator implicated in the U2AF1-like splicing subtype; PRMT5 inhibition rescued leukaemic missplicing and inhibited growth, converging with the splicing program on IRAK4 (PMID:40333990). This is upstream splicing-program correction, distinct from direct spliceosome modulators that failed in SF3B1-mutant MDS (PMID:40124717). Normal tissue: [KNOWN] PRMT5 is broadly required for HSPC self-renewal, so the window is the central risk. A dedicated PRMT5-plus-myeloid literature probe this visit returned no myeloid clinical, trial or primary-sample data — the only retrieved PRMT5-inhibitor work was GSK3326595 co-delivered with an ATM inhibitor b","approach":"Keep as a preclinical-only question: PRMT5 inhibitors in MDS/sAML primary samples and PDX stratified by the U2AF1-like signature; PD = symmetric dimethyl-arginine marks, exon-level rescue, IRAK4 isoform shift; PRMT5i versus IRAK4i versus combination to test whether IRAK4 is the sole effector; quantify normal CD34+ colony formation to define the window. Resistance: MTAP/MAT2A adaptation, compensatory arginine methyltransferases, RAS co-mutation. [SPECULATIVE] The PRMT5i-driven DNA-damage/cGAS-STING link (PMID:42006004) is a possible secondary readout but is untested in myeloid tissue.","level":"LEAD","confidence":0.38,"citations":[{"kind":"PMID","id":"40333990","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40124717","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42006004","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":95,"lastVisit":3,"lastNote":"Weakened: a query designed to find myeloid PRMT5 data found none, answering OQ3 negatively. Deprioritised relative to the IRAK4 combination lead, which now has both clinical tooling and a mechanistic partner.","history":[{"visit":3,"cycle":174,"status":"WEAKENED","note":"Weakened: a query designed to find myeloid PRMT5 data found none, answering OQ3 negatively. Deprioritised relative to the IRAK4 combination lead, which now has both clinical tooling and a mechanistic partner."},{"visit":2,"cycle":95,"status":"NEW","note":"New lead created directly from this visit's pack; kept at LEAD because the only supporting data are preclinical and in AML, and no MDS-specific PRMT5 data exist in the pack."}]},{"id":"L6","title":"Disease-modifying combinations on the luspatercept/imetelstat backbone in lower-risk MDS, with clonal VAF reduction as the endpoint","mechanism":"LR-MDS treatment is currently non-curative and aimed at transfusion burden and quality of life; luspatercept (ActRII ligand trap relieving SMAD2/3-mediated erythroid maturation arrest) and imetelstat (telomerase/TERT antagonist) are the two agents since 2020 that reduce RBC transfusion dependence, and both are discussed as potentially disease-modifying (PMID:41348013, PMID:41300977). In SF3B1-mutant LR-MDS the clone arises in the most primitive compartment and expands through the whole myeloid lineage, so symptom-level responses need not touch the clone; iron overload from ring-sideroblastic ineffective erythropoiesis adds independent morbidity (PMID:40124717). [INFERRED] The testable hypoth","approach":"Retrospective and prospective comparison of SF3B1/TET2/ASXL1 VAF trajectories and single-cell clonal architecture under luspatercept versus imetelstat versus sequential use in non-del(5q) LR-MDS; stratify by IPSS-M and by baseline ferritin to test whether iron chelation adds benefit. Resistance: emergence of RUNX1/RAS subclones, TP53 acquisition, blast escalation to HR-MDS.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"41348013","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41300977","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40124717","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":95,"lastVisit":2,"lastNote":"New lead from three concordant NEW reviews; deliberately framed as a biomarker/sequencing question because the agents themselves are already standard of care and the reviews are narrative, not comparative.","history":[{"visit":2,"cycle":95,"status":"NEW","note":"New lead from three concordant NEW reviews; deliberately framed as a biomarker/sequencing question because the agents themselves are already standard of care and the reviews are narrative, not comparative."}]},{"id":"L7","title":"IRAK4 inhibition combined with CELMoD-mediated GSPT1 degradation in MDS-EB and MDS-derived secondary AML — convergent c-Myc destabilization","mechanism":"An unbiased screen of 2803 drugs in isogenic IRAK4-deficient versus wild-type AML cells identified the CELMoD CC-885 as top hit; among its cereblon substrates GSPT1 loss was the dominant effector, reducing translation efficiency of short-half-life proteins including c-Myc, while IRAK4 inhibition independently decreased c-Myc protein stability — synergy confirmed in vitro, in vivo and in AML patient cells (PMID:40670672). [INFERRED] In MDS the same node is attractive because the U2AF1-like/IRAK4-dependent leukaemic stem-cell program (PMID:40333990) is MYC-dependent and because IRAK4 monotherapy is only modestly active clinically (PMID:40634180). Normal tissue: [KNOWN] GSPT1/eRF3a is an essent","approach":"Test emavusertib plus a GSPT1-directed CELMoD in MDS-EB and post-MDS sAML primary cells and PDX, stratified by U2AF1-like splicing signature and spliceosome genotype; PD = c-Myc protein half-life, GSPT1 degradation, NF-kB targets, IRAK4-L/S ratio. Mandatory window assay: paired normal CD34+ CFU-GM/BFU-E and megakaryocyte colony formation at matched exposures; intermittent rather than continuous CELMoD dosing to spare progenitors. Resistance: CRBN loss/mutation, cereblon-pathway (CUL4/DDB1) alterations, MYC amplification or MYC-independent survival, RAS pathway activation.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"40670672","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40634180","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40333990","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":174,"lastVisit":3,"lastNote":"New lead created directly from this visit's pack; the data are AML (cell lines, xenograft, patient cells) with no MDS cohort and no clinical combination data, so it enters at LEAD. Explicitly records that unmodified IRAK4 monotherapy escalation should not be re-proposed.","history":[{"visit":3,"cycle":174,"status":"NEW","note":"New lead created directly from this visit's pack; the data are AML (cell lines, xenograft, patient cells) with no MDS cohort and no clinical combination data, so it enters at LEAD. Explicitly records that unmodified IRAK4 monotherapy escalation should not be re-proposed."}]},{"id":"L8","title":"Inflammasome-driven HSC pyroptosis and stromal reprogramming as the upstream target in lower-risk MDS","mechanism":"Two concordant 2025 reviews place aberrant innate immune activation upstream of clonal expansion: inflammatory signalling drives HSPCs out of quiescence into stress haematopoiesis, promotes pyroptosis of hataematopoietic stem cells and acquisition of recurrent genetic abnormalities, and reprograms mesenchymal stromal cells to support dysplastic clones, with an immunosuppressive milieu enabling immune evasion in higher-risk disease (PMID:40563403, PMID:40349084). [KNOWN] The canonical MDS axis is S100A8/A9-TLR4-NLRP3-caspase-1-GSDMD, driving IL-1beta/IL-18 release and death of non-mutant progenitors — i.e. cytopenia is partly inflammatory, not purely clonal, so blocking it could restore effec","approach":"Correlative first: in LR-MDS marrow, quantify GSDMD cleavage, caspase-1 activity, IL-1beta/IL-18 and S100A8/A9 in sorted CD34+ and stromal fractions, and test whether high inflammasome activity predicts cytopenia depth and luspatercept/imetelstat failure independent of IPSS-M. Then a biomarker-selected pilot of IL-1 pathway blockade (or an NLRP3 inhibitor) in inflammasome-high, transfusion-dependent LR-MDS, with erythroid response and non-mutant progenitor recovery (single-cell VAF-resolved) as endpoints. Resistance/failure modes: clone-intrinsic inflammation-independent expansion, TNF/IFN redundancy, blast escalation masking benefit.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"40563403","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40349084","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":174,"lastVisit":3,"lastNote":"New lead from two NEW concordant reviews. Deliberately entered low and framed as a correlative-first programme because the supporting evidence is narrative review only — no interventional inflammasome data in MDS appear anywhere in the pack.","history":[{"visit":3,"cycle":174,"status":"NEW","note":"New lead from two NEW concordant reviews. Deliberately entered low and framed as a correlative-first programme because the supporting evidence is narrative review only — no interventional inflammasome data in MDS appear anywhere in the pack."}]}],"retired":[],"nextQueries":["(emavusertib OR \"CA-4948\") AND (myelodysplastic OR MDS OR \"TakeAim\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(GSPT1 OR \"CC-90009\" OR eragidomide OR CELMoD) AND (myelodysplastic OR \"acute myeloid leukemia\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","((NLRP3 OR inflammasome OR S100A9 OR \"IL-1beta\" OR anakinra) AND (myelodysplastic OR \"lower-risk MDS\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-20T00:12:50.338Z"},{"key":"multiple myeloma","name":"multiple myeloma","mondo":{"id":"MONDO:0009693","name":"plasma cell myeloma"},"genes":[{"label":"LIG4","kind":"correlated"},{"label":"CCND1","kind":"correlated"}],"visits":3,"openQuestions":["Does catalytic p300 KAT inhibition or dual p300/CBP degradation suppress the IRF4 network more deeply than inobrodib in primary myeloma, and is an IRF4 target-gene signature (or H2BNTac/H3K27ac) a usable clinical PD readout?","Does t(11;14)/CCND1 [SOMATIC] or 1q status predict response to p300/CBP inhibition, and does the inobrodib+venetoclax synergy seen in AML reproduce in BCL2-dependent myeloma?","Does the ex vivo functional immune phenotype (PMID:42463945) predict benefit from antigen switching versus non-immunological salvage, and is it concordant with surface BCMA/GPRC5D density and TNFRSF17 copy number?","What is the mechanism/target of AZD0305 (NCT06106945) — still unstated after three visits?","Is there any +1q-stratified randomised or registry comparison of isatuximab versus daratumumab, and does +1q-associated CD38 downregulation/CDC impairment abolish benefit from either?","Is LIG4 [SOMATIC-likely] alteration in myeloma an exploitable NHEJ-deficiency state (PARP/POLQ/ATR) or only a genomic-instability correlate?"],"leads":[{"id":"L1","title":"Antigen-escape-adapted BCMA immunotherapy: pre-specify BCMA density/shedding and switch antigen rather than re-treat","mechanism":"Prolonged BCMA engagement selects TNFRSF17 biallelic loss, ECD mutations, gamma-secretase shedding and transcriptional downregulation; restored responses on antigen switching within the same T-cell pool imply recoverable antigen escape [INFERRED]. New evidence constrains this: an image-based ex vivo BM-MNC assay resolving synapse productivity and T-cell morphologic trajectory stratified clinical response and time on therapy for teclistamab/talquetamab, with ~40% primarily refractory (PMID:42463945), and review-level practice now recommends assessing both BCMA expression and T-cell exhaustion before sequencing (PMID:41396414). Hence primary refractoriness is substantially T-cell-intrinsic, no","approach":"Unchanged backbone (elranatamab or belantamab mafodotin, NCT05714839, NCT06106945) with mandatory paired progression biopsies scored for surface BCMA density, sBCMA, TNFRSF17 copy number/ECD mutation and plasma-cell-identity signature, but now co-registered with the ex vivo functional phenotype (PMID:42463945); randomise biomarker-triggered antigen switch (talquetamab/cevostamab) vs empiric switch vs gamma-secretase-inhibitor-augmented re-treatment, with the analysis pre-stratified by antigen-loss vs immune-incompetent mode. Salvage benchmark: melflufen-dex ORR 28-33% (PMID:42270486); EMD benchmark 38.5-58.3% ORR (PMID:42359424). Resistance/toxicity: complete TNFRSF17 deletion, GPRC5D loss, ","level":"CANDIDATE","confidence":0.7,"citations":[{"kind":"PMID","id":"42434875","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42415463","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05714839","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06106945","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42561120","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42401497","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42487061","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42463945","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41396414","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":42,"lastVisit":3,"lastNote":"Held at CANDIDATE, not promoted: the density-triggered switch remains unmeasured in every cited dataset, and PMID:42463945 supplies a competing, prospectively validated T-cell-competence predictor that explains part of what I attributed to antigen escape. Confidence trimmed 0.72->0.70.","history":[{"visit":3,"cycle":175,"status":"WEAKENED","note":"Held at CANDIDATE, not promoted: the density-triggered switch remains unmeasured in every cited dataset, and PMID:42463945 supplies a competing, prospectively validated T-cell-competence predictor that explains part of what I attributed to antigen escape. Confidence trimmed 0.72->0.70."},{"visit":2,"cycle":97,"status":"STRENGTHENED","note":"Promoted: three NEW independent datasets show bidirectional antigen switching works (GPRC5D->BCMA ORR 58%, PMID:42401497; talquetamab durable in prior-TCR cohort, PMID:42561120; cevostamab active with 47.5% prior BCMA, PMID:42487061). None measured antigen density, so the biomarker-triggered element of the lead is still unproven; cevostamab had treatment-related grade 5 HLH/DIC."},{"visit":1,"cycle":42,"status":"NEW","note":"New this visit; P9 supplies a modality-resolved resistance taxonomy that makes escape route the design variable rather than an afterthought. AZD0305 mechanism not stated in the trial record — unverified."}]},{"id":"L2","title":"Genotype-directed choice of anti-CD38 antibody: isatuximab for 1q21-amplified myeloma, daratumumab as immune primer before T-cell redirection","mechanism":"Isatuximab binds near the CD38 catalytic site, inhibiting ectoenzyme activity with enhanced internalisation, FOXM1 suppression and ROS-mediated direct killing; daratumumab acts predominantly Fc-dependently with trogocytic loss of CD38/VLA-4. +1q is now recognised as high-risk (R2-ISS) and is associated with CD38 downregulation, impaired complement-dependent cytotoxicity and immunosuppression (PMID:39945832) — which predicts reduced benefit from Fc/complement-dependent killing and therefore makes any +1q-preferential isatuximab effect necessarily complement-independent [INFERRED]. CD38 is on normal plasma cells, NK cells, activated T cells, low on erythroid/endothelium.","approach":"+1q-stratified reanalysis of daratumumab phase 3 datasets (NCT03937635, NCT04566328, NCT07485647) with a pre-specified iFISH copy-number threshold (gain vs amp, >=20% vs >=50% cells) since no cut-off is standardised (PMID:39945832); prospective isatuximab-vs-daratumumab randomisation restricted to +1q with FOXM1, CD38 ectoenzyme activity, ROS and CD55/CD59 pharmacodynamics; sequence daratumumab-induced CD38/VLA-4 trogocytosis ahead of T-cell redirection, informed by maintenance anti-CD38 paradigms (PMID:41348019).","level":"LEAD","confidence":0.52,"citations":[{"kind":"PMID","id":"42587741","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04566328","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03937635","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07485647","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"39945832","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41348019","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":42,"lastVisit":2,"lastNote":"NEW +1q review supplies the mechanistic constraint that makes the hypothesis falsifiable (CD38 downregulation + impaired CDC in +1q) and confirms +1q as R2-ISS high-risk, but still no head-to-head randomised or stratified outcome data; held below 0.6.","history":[{"visit":2,"cycle":97,"status":"STRENGTHENED","note":"NEW +1q review supplies the mechanistic constraint that makes the hypothesis falsifiable (CD38 downregulation + impaired CDC in +1q) and confirms +1q as R2-ISS high-risk, but still no head-to-head randomised or stratified outcome data; held below 0.6."},{"visit":1,"cycle":42,"status":"NEW","note":"New; P10 converts 'interchangeable anti-CD38' into a falsifiable biomarker hypothesis. Review-level evidence only — no head-to-head randomised data cited."}]},{"id":"L3","title":"p300/CBP bromodomain inhibition (inobrodib) as a transcription-addiction attack orthogonal to proteasome, IMiD and BCMA pressure","mechanism":"Transcriptional-network and quantitative interactome mapping identify p300 as the dominant coactivator of IRF4, the most abundant myeloma-specific dependency; optimised p300 KAT inhibitors collapse the IRF4 programme, selectively spare normal cells, and inhibit IRF4 activity more completely and at lower exposure than existing p300/CBP bromodomain inhibitors (PMID:41248492). Dual p300/CBP degradation eliminates H2BNTac/H3K27ac at hyperactive enhancers and outperforms bromodomain-only or single-paralog targeting in enhancer-addicted tumours, without evident murine toxicity (PMID:41044247); myeloma is super-enhancer-driven (PMID:41268574). p300/CBP is broadly required for haematopoietic/epithel","approach":"Continue tracking NCT07772024 (InoPd vs SAT) but treat inobrodib as a possibly under-powered probe: pre-specify an IRF4/MYC target-gene signature plus H3K27ac/H2BNTac PD readouts in serial marrows, and run head-to-head KAT inhibitor vs bromodomain inhibitor vs p300/CBP degrader profiling on primary myeloma including BCMA-low/antigen-escaped and penta-refractory samples. Test inobrodib+venetoclax in t(11;14)/CCND1 [SOMATIC] disease, extrapolating the inobrodib+venetoclax+gilteritinib LSC-eradication result in DNMT3A/FLT3 AML (PMID:42139346), and combine with BET/CDK7-9 inhibition (PMID:41268574) or with T-cell engagers in immune-competent patients. Resistance: CBP/EP300 paralog compensation, ","level":"CANDIDATE","confidence":0.62,"citations":[{"kind":"NCT","id":"NCT07772024","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41248492","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41044247","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42139346","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"39825161","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41268574","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":42,"lastVisit":3,"lastNote":"Promoted on four NEW papers: PMID:41248492 gives the myeloma-specific p300-IRF4 dependency and selective window; PMID:41044247 and PMID:41248492 together argue the bromodomain modality is inferior to KAT inhibition/degradation, so a negative InoPd phase 3 would not falsify the target; PMID:42139346 supports the venetoclax combination.","history":[{"visit":3,"cycle":175,"status":"STRENGTHENED","note":"Promoted on four NEW papers: PMID:41248492 gives the myeloma-specific p300-IRF4 dependency and selective window; PMID:41044247 and PMID:41248492 together argue the bromodomain modality is inferior to KAT inhibition/degradation, so a negative InoPd phase 3 would not falsify the target; PMID:42139346 supports the venetoclax combination."},{"visit":1,"cycle":42,"status":"NEW","note":"New; a phase 3 first-in-class registrational trial is the strongest signal in the pack for a non-immunological mechanism. Mechanistic rationale is [KNOWN], not pack-cited — needs literature verification next visit."}]},{"id":"L4","title":"XPO1 inhibition (selinexor) added to VRd for high-risk NDMM with extramedullary/plasma-cell-leukaemia biology — depth of response is the limiting problem","mechanism":"XPO1 blockade traps nuclear export of tumour suppressors and oncoprotein mRNAs, restoring nuclear p53/IkB and reducing MYC translation [KNOWN]; EMD/PCL escapes the marrow niche and responds poorly to VRd.","approach":"Kill criterion set: unless a randomised XVRd-vs-VRd dataset with MRD 10^-5/10^-6 and PET-defined extramedullary response appears by the next evidence-bearing visit, retire. Any surviving role is as a chemo-immunotherapy-sparing comparator benchmarked against bispecific EMD activity (PMID:42359424, PMID:42419103).","level":"LEAD","confidence":0.22,"citations":[{"kind":"PMID","id":"42544613","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42419103","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42359424","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":42,"lastVisit":3,"lastNote":"Further weakened: 16.7% post-induction MRD negativity (n=30, single-arm) against a now-quantified 38-58% ORR bar for bispecifics in EMD (different line of therapy, so not a formal refutation, but the opportunity cost is explicit). Flagged for retirement next visit.","history":[{"visit":3,"cycle":175,"status":"WEAKENED","note":"Further weakened: 16.7% post-induction MRD negativity (n=30, single-arm) against a now-quantified 38-58% ORR bar for bispecifics in EMD (different line of therapy, so not a formal refutation, but the opportunity cost is explicit). Flagged for retirement next visit."},{"visit":2,"cycle":97,"status":"WEAKENED","note":"Weakened: the single-arm XVRd cohort achieved only 16.7% MRD negativity after induction (n=30, observational), and immunotherapeutic dual targeting now sets a higher efficacy bar in the same EMD/PCL niche. Kept on the board only as a chemo-immunotherapy-sparing comparator."},{"visit":1,"cycle":42,"status":"NEW","note":"New but deliberately capped low: n=30, single-arm, observational, no control, and the MRD-negativity rate undercuts the headline ORR. Recorded so a later visit cannot over-read the response rate."}]},{"id":"L5","title":"RBMS1-PDPK1-beta-catenin axis and CCL2-driven M2 macrophage polarisation as a stromal-immune target in the myeloma niche","mechanism":"RBMS1 binds the PDPK1 3'UTR, stabilising its mRNA and activating β-catenin signalling; RBMS1 drives proliferation, colony formation and cell-cycle progression in RPMI8226/MM1S/KMS11 and increases CCL2 secretion with M2 polarisation of tumour-associated macrophages in NOG xenografts, and marks poor survival. PDPK1 (PDK1) is a master AGC-kinase activator required in normal metabolism/immunity — a narrow window that argues for niche-directed rather than systemic inhibition [INFERRED].","approach":"Validate RBMS1/PDPK1 dependency by CRISPR in primary myeloma with stromal co-culture; test PDPK1 inhibition and CCR2 blockade for reversal of M2 skewing and for enhancement of T-cell-redirecting therapy; assess whether the RBMS1-high state overlaps the BCMA-low 'plasma cell identity escape' phenotype. Resistance: AKT/SGK bypass, redundant chemokine recruitment (CCL3/CSF1).","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42277590","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":42,"lastVisit":1,"lastNote":"New; single preclinical paper, bioinformatics-anchored, no inhibitor tested — held at low confidence pending independent replication and a pharmacological arm.","history":[{"visit":1,"cycle":42,"status":"NEW","note":"New; single preclinical paper, bioinformatics-anchored, no inhibitor tested — held at low confidence pending independent replication and a pharmacological arm."}]},{"id":"L6","title":"Simultaneous dual-antigen T-cell engagement (BCMA+GPRC5D) for extramedullary and antigen-heterogeneous myeloma, with infection prophylaxis as the co-primary des","mechanism":"Concurrent teclistamab+talquetamab is hypothesised to reduce antigen escape, enhance synapse formation and distribute exhaustion across two receptors (PMID:42419103) [SPECULATIVE]. Newly quantified context: pooled ORR for single-antigen BCMA/GPRC5D bispecifics in baseline EMD is 38.5% (elranatamab) to 58.3% (teclistamab) across 4 prospective trials/144 patients (PMID:42359424), i.e. the bar dual targeting must clear is now numerically defined rather than assumed to be low. Cost is additive on-target toxicity and serious infection.","approach":"Randomise dual-TCE versus sequential single-antigen TCE in EMD/PCL with PET-defined extramedullary response and MRD 10^-6 as co-primaries, powered against the 38-58% pooled EMD ORR (PMID:42359424); mandate single-cell BCMA/GPRC5D co-expression mapping of extramedullary versus marrow lesions, ex vivo functional immune phenotyping at baseline (PMID:42463945), and a pre-specified infection-mitigation arm (IVIG, PJP/HSV/antifungal prophylaxis, response-adapted dose reduction); compare fixed-duration cevostamab-style dosing (PMID:42487061) with continuous dosing.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42419103","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42561120","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42487061","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42359424","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42463945","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":97,"lastVisit":3,"lastNote":"NEW meta-analysis (PMID:42359424) supplies the single-antigen EMD benchmark that makes the dual-targeting claim testable; still single-arm phase 2 underneath, so only +0.05.","history":[{"visit":3,"cycle":175,"status":"STRENGTHENED","note":"NEW meta-analysis (PMID:42359424) supplies the single-antigen EMD benchmark that makes the dual-targeting claim testable; still single-arm phase 2 underneath, so only +0.05."},{"visit":2,"cycle":97,"status":"NEW","note":"New this visit from the RedirecTT-1 commentary; capped at 0.4 because the underlying trial is single-arm phase 2, the mechanisms are the authors' own hypotheses, and serious infection is substantial. Directly competes with L4 in the EMD niche."}]},{"id":"L7","title":"Functional ex vivo immune profiling as a treatment-assignment assay: route immune-incompetent myeloma away from T-cell engagers","mechanism":"Image-based multiplex immunofluorescence of patient BM mononuclear cells exposed to teclistamab or talquetamab quantifies plasma-cell lysis, T-cell expansion, morphology and spatial T-cell/plasma-cell engagement, yielding three phenotypes (non-responder, cytotoxic, cytotoxic-expansive) along a resting->polarised->effector trajectory that separates productive from abortive synapses and stratified clinical response and time on therapy (PMID:42463945). Mechanistic claim: primary refractoriness reflects synapse/effector-differentiation failure rather than antigen absence, so patients in the non-responder phenotype should gain nothing from a second engager or a second antigen [INFERRED]. Engager-","approach":"Prospective assay-guided allocation study: run the ex vivo assay at engager-eligible relapse; randomise non-responder-phenotype patients to a non-immunological arm (p300/CBP KAT inhibition or InoPd, NCT07772024; belantamab mafodotin, NCT05714839; melflufen) versus standard engager, with ORR and time-to-next-therapy as endpoints, and cytotoxic/cytotoxic-expansive patients to engager sequencing. Add analytical validation: concordance with flow BCMA/GPRC5D density, TNFRSF17 status, exhaustion immunophenotype (PMID:41396414), and reproducibility across centres. Test whether ex vivo phenotype is modifiable by a treatment-free interval, IMiD priming or checkpoint/IL-15 support. Resistance/failure ","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42463945","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41396414","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42309027","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT07772024","verified":true,"isNew":false,"addedVisit":3},{"kind":"NCT","id":"NCT05714839","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":175,"lastVisit":3,"lastNote":"New this visit; split off from L1 because the predictive variable is T-cell function, not antigen. Capped at 0.45: single-centre discovery cohort, no prospective assay-guided allocation yet.","history":[{"visit":3,"cycle":175,"status":"NEW","note":"New this visit; split off from L1 because the predictive variable is T-cell function, not antigen. Capped at 0.45: single-centre discovery cohort, no prospective assay-guided allocation yet."}]}],"retired":[],"nextQueries":["(\"multiple myeloma\") AND (\"inobrodib\" OR \"CCS1477\" OR \"p300 degrader\" OR \"EP300\" OR \"CREBBP\") AND (\"venetoclax\" OR \"t(11;14)\" OR \"IRF4 signature\" OR \"pharmacodynamic\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"multiple myeloma\") AND (\"BCMA\" OR \"TNFRSF17\" OR \"GPRC5D\") AND (\"antigen density\" OR \"receptor quantification\" OR \"soluble BCMA\" OR \"copy number loss\") AND (\"bispecific\" OR \"CAR T\") AND SRC:MED AND PUB_YEAR:[2025 TO 202","(\"multiple myeloma\") AND (\"1q21\" OR \"gain(1q)\" OR \"amp(1q)\") AND (\"isatuximab\" OR \"daratumumab\") AND (\"CD38 expression\" OR \"complement\" OR \"progression-free survival\") AND SRC:MED"],"updatedAt":"2026-08-20T00:16:32.931Z"},{"key":"waldenstrom macroglobulinemia","name":"Waldenstrom macroglobulinemia","mondo":{"id":"MONDO:0100280","name":"Waldenstrom macroglobulinemia"},"genes":[{"label":"MYD88","kind":"causal"}],"visits":3,"openQuestions":["What are the actual WM-specific response rates, durations and genotype subsets behind PMID:42509106's claim of BTK-degrader, non-covalent BTKi and BCL-2 inhibitor efficacy in cBTKi-refractory WM - i.e. what are the BGB-16673 and sonrotoclax","What is the frequency of BTK C481S/T474I/L528W and PLCG2 alleles at progression in WM specifically, and does BGB-16673 clear L528W-bearing WM clones?","Is there any WM primary-cell BH3 profiling or MCL1/BCL2L1 dependency map to convert the BCL2 lead from review-level assertion to mechanism, and does MYD88 L265P NF-kB output actually drive BCL2/MCL1 transcription in WM?","Can CD20xCD3 bispecifics be given safely in high-IgM WM without hyperviscosity/flare during step-up dosing, and does the CD20-low plasmacytic compartment predict escape?","What is the true CXCR4-mutation prevalence in systematically tested WM cohorts, and does 68Ga-pentixafor uptake in BTKi-treated WM track CXCR4 S338* and MYD88 MRD rather than bulk?","Does TME/stromal-mediated BTKi resistance (PMID:41721839) operate in WM marrow, and is it degradation-sensitive via the VCAM-1/ILK scaffold?"],"leads":[{"id":"L1","title":"Pentixafor-guided CXCR4 antagonism to eradicate BTKi-persistent WM clones","mechanism":"Somatic WHIM-like CXCR4 truncating mutations (S338*) sustain AKT/ERK signalling and marrow niche retention downstream of MYD88 L265P, blunting BTKi efficacy in double-mutant disease (PMID:42102951); CXCR4 is [SOMATIC] here, its normal HSC-retention/neutrophil-egress role defining the window.","approach":"Prospective 68Ga-pentixafor PET/CT-stratified addition of mavorixafor or ulocuplumab to zanubrutinib in PET-positive/M-protein-responding patients; use single-tube MAS-qPCR for simultaneous MYD88 L265P/CXCR4 S338* stratification and marrow MRD (PMID:42102951, reading quantitative claims cautiously given PMID:42493305); endpoints delta-TLU/delta-MTV plus ddPCR MRD. Resistance routes: CXCR4-independent NF-kB (TNFAIP3/A20 loss, CARD11), CXCR7/ACKR3 switch.","level":"LEAD","confidence":0.56,"citations":[{"kind":"PMID","id":"42113823","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42352898","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07169331","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42102951","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42493305","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42544657","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":43,"lastVisit":2,"lastNote":"Feasibility strengthened by a cheap single-tube MYD88/CXCR4 assay, but not promoted: no new pentixafor imaging data, the assay paper carries a corrigendum, and PMID:42544657 found CXCR4 mutations in only 3/17 tested patients (vs MYD88 82.4%), suggesting the addressable population may be smaller than 30-40%.","history":[{"visit":2,"cycle":98,"status":"STRENGTHENED","note":"Feasibility strengthened by a cheap single-tube MYD88/CXCR4 assay, but not promoted: no new pentixafor imaging data, the assay paper carries a corrigendum, and PMID:42544657 found CXCR4 mutations in only 3/17 tested patients (vs MYD88 82.4%), suggesting the addressable population may be smaller than 30-40%."},{"visit":1,"cycle":43,"status":"NEW","note":"New this visit: PMID:42113823 shows 93% imaging/M-protein concordance with chemoimmunotherapy but discordance under BTKi in 18 patients — direct evidence of an imaging-detectable, CXCR4-expressing BTKi-persistent compartment."}]},{"id":"L2","title":"BTK degradation and non-covalent BTK occupancy for BTKi-resistant MYD88-mutant WM","mechanism":"Covalent BTKi resistance arises at C481 with activating PLCG2 alleles; non-covalent BTKi select T474I/L528W that cross-resist zanubrutinib and acalabrutinib (PMID:38578606, PMID:41594662). Kinase-dead alleles retain BTK's non-catalytic scaffolding of TLR9, HCK, VCAM-1 and ILK (PMID:39062757); because HCK bridges the MYD88 L265P myddosome to BTK, catalytic inhibition cannot abolish adaptor output whereas chimeric degradation removes the protein [INFERRED]. A second, non-mutational resistance axis is stromal/TME support, immunosuppressive niche and bypass signalling (PMID:41721839), which degradation of the VCAM-1/ILK scaffold may also address [INFERRED]. Window set by BTK in B-cell developmen","approach":"Enrich WM strata in BGB-16673 (NCT05006716) and nemtabrutinib (NCT04728893) with mandatory paired BTK/PLCG2/CXCR4 sequencing and MYD88 L265P ddPCR MRD at progression; report WM-specific L528W/T474I incidence, which is still unmeasured. Pharmacodynamics: HCK phosphorylation, TLR9-driven NF-kB target genes, and marrow adhesion/VCAM-1 readouts to test the scaffolding hypothesis. Exploratory fixed-duration degrader + next-generation BCL2 inhibitor arm (see L5).","level":"DOSSIER","confidence":0.68,"citations":[{"kind":"NCT","id":"NCT05006716","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04728893","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42352898","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"38478390","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"38578606","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39062757","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39456530","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42509106","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41594662","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41721839","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":43,"lastVisit":3,"lastNote":"Promoted to DOSSIER: PMID:42509106 [NEW] is the first WM-specific statement that BTK degraders and non-covalent BTKi are active in patients refractory to covalent BTKi, answering the standing 'CLL-extrapolation only' objection; PMID:41594662 and PMID:41721839 [NEW] independently re-confirm the C481/PLCG2/non-C481 resistance topology and add TME-driven resistance as a co-dominant axis. Residual gap","history":[{"visit":3,"cycle":176,"status":"STRENGTHENED","note":"Promoted to DOSSIER: PMID:42509106 [NEW] is the first WM-specific statement that BTK degraders and non-covalent BTKi are active in patients refractory to covalent BTKi, answering the standing 'CLL-extrapolation only' objection; PMID:41594662 and PMID:41721839 [NEW] independently re-confirm the C481/PLCG2/non-C481 resistance topology and add TME-driven resistance as a co-dominant axis. Residual gap"},{"visit":2,"cycle":98,"status":"STRENGTHENED","note":"Promoted: four new independent reviews corroborate both the cross-resistance topology of non-C481 alleles and the kinase-independent scaffolding rationale for degraders. Caveat recorded — all allele-frequency data are CLL-derived; WM-specific L528W/T474I incidence remains unmeasured, so the WM claim is extrapolation."},{"visit":1,"cycle":43,"status":"NEW","note":"New: two recruiting trials give a concrete clinical vehicle; PMID:42352898 names BTKi resistance as the principal unmet need in WM."}]},{"id":"L3","title":"Bypassing BTK entirely: MALT1/IRAK4 blockade downstream of the L265P myddosome","mechanism":"MYD88 L265P signals via IRAK1/4 and HCK to BTK and onward to CARD11-BCL10-MALT1; protease inhibition or IRAK4 degradation acts distal/parallel to the ATP-C481 site and should be indifferent to kinase-domain mutations including scaffolding-competent L528W (PMID:39062757). Normal-tissue risk: MALT1 loss impairs Treg fitness (murine autoimmunity) [KNOWN].","approach":"Do not build further clinical rationale until EXS73565's target is disclosed (NCT06980116). Reduce to a preclinical question: benchmark MALT1 protease inhibition versus IRAK4 degradation in MYD88 L265P WM lines and BTK-L528W isogenic derivatives, with NF-kB target-gene and IRF4 readouts.","level":"LEAD","confidence":0.26,"citations":[{"kind":"NCT","id":"NCT06980116","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42352898","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40723181","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39062757","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":43,"lastVisit":3,"lastNote":"Weakened: second consecutive visit with EXS73565's molecular target undisclosed, and no fresh MALT1/IRAK4 data in the pack. Meanwhile the degrader and BCL2 leads gained WM-specific support, so this downstream-node hypothesis loses relative priority. Retire at visit 4 unless the target is disclosed or WM-model data appear.","history":[{"visit":3,"cycle":176,"status":"WEAKENED","note":"Weakened: second consecutive visit with EXS73565's molecular target undisclosed, and no fresh MALT1/IRAK4 data in the pack. Meanwhile the degrader and BCL2 leads gained WM-specific support, so this downstream-node hypothesis loses relative priority. Retire at visit 4 unless the target is disclosed or WM-model data appear."},{"visit":2,"cycle":98,"status":"STRENGTHENED","note":"Only marginal: MALT1 inhibitors appear in a CLL novel-target survey (PMID:40723181), and the scaffolding data give a mechanistic reason to act downstream of BTK. EXS73565's target is still undisclosed in the pack, so the MALT1 attribution remains [KNOWN, low confidence] and blocks promotion."},{"visit":1,"cycle":43,"status":"NEW","note":"New lead, deliberately low confidence: the pack does not disclose EXS73565's mechanism; my MALT1 attribution is [KNOWN, low confidence] and must be verified before any promotion."}]},{"id":"L4","title":"BTKi-based salvage for histologic transformation of WM to non-GCB DLBCL, including immune-privileged sites","mechanism":"Transformed WM is overwhelmingly non-GCB/ABC-like (86.7%), the immunophenotype most dependent on chronic active BCR–MYD88 NF-κB signalling; CNS and testicular involvement (33.3%) matches MYD88/CD79B-mutant immune-privileged-site lymphoma biology, where CNS-penetrant BTKi have precedent [KNOWN].","approach":"Prospective evaluation of ibrutinib or a CNS-penetrant BTKi with chemoimmunotherapy in transformed WM, stratified by MYD88/CD79B genotype and CNS involvement; correlate with Bing-Neel management.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"41797694","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":43,"lastVisit":1,"lastNote":"New: single-centre retrospective, n=15, OS benefit for BTKi-based regimens (p=0.007) but severe selection/immortal-time bias risk and no genotyping reported — hypothesis only.","history":[{"visit":1,"cycle":43,"status":"NEW","note":"New: single-centre retrospective, n=15, OS benefit for BTKi-based regimens (p=0.007) but severe selection/immortal-time bias risk and no genotyping reported — hypothesis only."}]},{"id":"L5","title":"BCL2-axis dependence and MRD-guided fixed duration in post-BTKi WM","mechanism":"MYD88 L265P-driven NF-kB output plausibly sustains BCL2/MCL1 transcription, predicting a BTK-degrader + BCL2-inhibitor synthetic dependency [INFERRED]. CLL escape from venetoclax proceeds via AKT-dependent stabilisation of alternative anti-apoptotic family members, disrupted BAK/BAX pore formation, and BCL2 point mutations (PMID:41741806); next-generation agents (sonrotoclax, lisaftoclax) and MRD-guided fixed duration are advancing (PMID:41303291). WM-level clinical plausibility now asserted (PMID:42509106). Normal tissue: BCL2 in lymphocyte and platelet survival - cytopenias, TLS.","approach":"WM-specific BH3 profiling and MCL1/BCL2L1 dependency mapping in MYD88 L265P and MYD88/CXCR4 double-mutant primary cells; then fixed-duration BTK-degrader (NCT05006716) plus sonrotoclax with MYD88 L265P ddPCR MRD as primary endpoint, imaging response reported alongside IgM to avoid IgM/imaging discordance. Explicitly do NOT build a chemo-plus-BCL2i backbone: PMID:42255257 showed venetoclax added to R-GDP in R/R LBCL gave no EFS/OS advantage over R-GDP alone.","level":"CANDIDATE","confidence":0.45,"citations":[{"kind":"PMID","id":"41741806","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41303291","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT05006716","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42509106","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42255257","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":98,"lastVisit":3,"lastNote":"Promoted from LEAD to CANDIDATE on PMID:42509106 [NEW], which states BCL-2 inhibitors show promising efficacy in cBTKi-exposed/refractory WM - the first non-CLL anchor. Held at 0.45 because the evidence is review-level with no ORR, no genotype stratification and no BH3 data. PMID:42255257 [NEW] recorded as a negative design constraint: BCL2i + salvage chemo did not improve EFS/OS in aggressive B-c","history":[{"visit":3,"cycle":176,"status":"STRENGTHENED","note":"Promoted from LEAD to CANDIDATE on PMID:42509106 [NEW], which states BCL-2 inhibitors show promising efficacy in cBTKi-exposed/refractory WM - the first non-CLL anchor. Held at 0.45 because the evidence is review-level with no ORR, no genotype stratification and no BH3 data. PMID:42255257 [NEW] recorded as a negative design constraint: BCL2i + salvage chemo did not improve EFS/OS in aggressive B-c"},{"visit":2,"cycle":98,"status":"NEW","note":"New but deliberately low: the entire evidence base here is CLL-derived, with no WM venetoclax efficacy or BCL2 dependency data in this pack. Must be validated with WM-specific data before any promotion; recorded so the desk does not mistake CLL extrapolation for WM evidence."}]},{"id":"L6","title":"MYD88-node-independent T-cell redirection (CD20xCD3 bispecifics, CD19/CD22 CAR-T) for multi-refractory and transformed WM","mechanism":"Every resistance allele the programme has catalogued - BTK C481S/T474I/L528W, PLCG2, CXCR4 S338*, BCL2 point mutations - lies inside the MYD88 L265P/BCR-NF-kB/apoptotic axis. T-cell redirection kills by perforin/granzyme delivery independent of that axis, so it should be genotype-agnostic [INFERRED]. Glofitamab monotherapy activity is now reported in Richter transformation (PMID:42024463), the closest available analogue to histologic transformation of WM; CAR-T and bispecific preliminary reports in WM are described as encouraging (PMID:42509106, PMID:42278551). Normal-tissue window: CD20/CD19/CD22 are pan-B antigens - prolonged B-cell aplasia and hypogammaglobulinaemia layered on the immune ","approach":"WM/LPL-specific expansion cohorts of a CD20xCD3 bispecific and of CD19- or CD22-directed CAR-T (NCT06340737), enrolling patients refractory to covalent BTKi, non-covalent BTKi/degrader and BCL2i; mandatory step-up dosing with plasmapheresis eligibility and serial serum IgM/viscosity during cycle 1; endpoints MYD88 L265P ddPCR marrow MRD plus imaging response, with flow quantification of CD20 vs CD138 compartments pre- and post-therapy to test the plasmacytic-escape hypothesis. Include transformed-WM (non-GCB DLBCL) and Bing-Neel strata.","level":"LEAD","confidence":0.38,"citations":[{"kind":"PMID","id":"42024463","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42509106","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42278551","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT06340737","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":176,"lastVisit":3,"lastNote":"New this visit from PMID:42024463 [NEW] (glofitamab in Richter transformation) plus PMID:42509106 [NEW] flagging encouraging preliminary CAR-T/bispecific data in WM. Deliberately opened at 0.38: the direct efficacy datum is in Richter transformation, not WM, and no WM bispecific trial appears in this pack. Value is that it is the only lead orthogonal to the entire MYD88-NF-kB-BCL2 node.","history":[{"visit":3,"cycle":176,"status":"NEW","note":"New this visit from PMID:42024463 [NEW] (glofitamab in Richter transformation) plus PMID:42509106 [NEW] flagging encouraging preliminary CAR-T/bispecific data in WM. Deliberately opened at 0.38: the direct efficacy datum is in Richter transformation, not WM, and no WM bispecific trial appears in this pack. Value is that it is the only lead orthogonal to the entire MYD88-NF-kB-BCL2 node."}]}],"retired":[],"nextQueries":["(\"Waldenstrom\" OR \"lymphoplasmacytic lymphoma\") AND (\"BGB-16673\" OR \"BTK degrader\" OR sonrotoclax OR pirtobrutinib) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"Waldenstrom\" OR \"lymphoplasmacytic lymphoma\") AND (glofitamab OR mosunetuzumab OR epcoritamab OR \"CAR-T\" OR \"bispecific antibody\") AND SRC:MED","(\"Waldenstrom\" OR \"MYD88 L265P\") AND (\"BH3 profiling\" OR MCL1 OR \"BCL2 dependency\" OR \"CXCR4 mutation\" OR pentixafor) AND SRC:MED"],"updatedAt":"2026-08-20T00:20:10.457Z"},{"key":"diffuse large b-cell lymphoma","name":"diffuse large B-cell lymphoma","mondo":{"id":"MONDO:0018905","name":"diffuse large B-cell lymphoma"},"genes":[{"label":"BCL6","kind":"correlated"},{"label":"BCL2","kind":"correlated"},{"label":"ALK","kind":"correlated"},{"label":"XPO1","kind":"correlated"}],"visits":3,"openQuestions":["In ABC-DLBCL lines and PDX, does a basal MALT1-activity readout (BCL10 cleavage fragment, MALT1-dependent NF-kB target output) predict safimaltib/CRD-1441551-class response as it did in ATL, and does CARD11 gain-of-function predict sensitiv","What is the DLBCL-specific ORR/CR and Treg/autoimmune toxicity profile of safimaltib (JNJ-67856633) in reported early-phase R/R B-cell malignancy cohorts?","Do BTK-degrader-resistant DLBCL models retain MALT1 dependency, and which resistance alleles (CRBN/E3 loss versus distal CARD11/PLCG2) segregate with MALT1-inhibitor sensitivity?","Is there any DLBCL cohort-level efficacy or emergent-mutation data for BGB-16673 or NX-5948, broken down by LymphGen genotype and prior BTKi class?","Which pre-CAR-T or post-CAR-T T-cell fitness parameters predict bispecific failure, given the 6.5-month median OS after 2L CAR-T relapse - and does frontline ctDNA-selected glofitamab avoid that exhaustion penalty?","Does dual EZH1/EZH2 inhibition (tulmimetostat) show EZH2-mutation-restricted benefit in GCB/EZB lymphoma, and does it overlap the BEBT-908 EZB hypothesis?"],"leads":[{"id":"L1","title":"METTL3 inhibition to reverse rituximab resistance in double-expressor DLBCL","mechanism":"METTL3-deposited m6A on CTNNB1, read by YTHDF2, raises β-catenin, which transactivates MYC, which drives BCL2 promoter activity, producing the MYC/BCL2 double-expressor rituximab-resistant state [SOMATIC].","approach":"STM2457 + rituximab and + venetoclax in an isogenic RTX-resistant DE-DLBCL panel; MeRIP-seq for CTNNB1 site dependence with β-catenin rescue for epistasis. Park unless independent replication appears.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42242087","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":44,"lastVisit":2,"lastNote":"A dedicated 2023-2026 Europe PMC query for DLBCL m6A/METTL3/STM2457 returned no new papers, so the axis remains a single cell line (U-2932) plus one xenograft, with the YTHDF2-stabilisation claim still contradicting canonical YTHDF2 decay function. Downgraded 0.45 to 0.35 for failure to replicate under targeted search.","history":[{"visit":2,"cycle":99,"status":"WEAKENED","note":"A dedicated 2023-2026 Europe PMC query for DLBCL m6A/METTL3/STM2457 returned no new papers, so the axis remains a single cell line (U-2932) plus one xenograft, with the YTHDF2-stabilisation claim still contradicting canonical YTHDF2 decay function. Downgraded 0.45 to 0.35 for failure to replicate under targeted search."},{"visit":1,"cycle":44,"status":"NEW","note":"New this visit from PMID:42242087; single cell line (U-2932) plus one xenograft, and the claimed YTHDF2-mediated mRNA stabilisation contradicts canonical YTHDF2 decay function [KNOWN], so mechanism is provisional."}]},{"id":"L2","title":"OGT/O-GlcNAc dependency as a synthetic-lethal partner in DLBCL","mechanism":"High OGT expression stratifies survival across three cohorts (n=2,090); OGT overexpression/knockdown and pharmacological inhibition alter proliferation and apoptosis in OCI-LY3 (ABC-like) and SU-DHL-4 (GCB), with O-GlcNAc/phospho cross-talk on anti-apoptotic and epigenetic regulators [SOMATIC]. Normal tissue: OGT is essentially ubiquitous and developmentally required [KNOWN] — window is the central risk.","approach":"OGT inhibitor (e.g. OSMI-class) combined with venetoclax or BTK inhibition/degradation; test whether O-GlcNAc removal destabilises MCL1/BCL2 or NF-κB components. Read out therapeutic index in normal B and haematopoietic progenitors before any in vivo claim. Resistance: OGA downregulation restoring O-GlcNAc tone, nutrient/HBP flux compensation.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42593144","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":44,"lastVisit":1,"lastNote":"New from PMID:42593144; correlative-plus-cell-line evidence only, and the normal-tissue essentiality of OGT keeps confidence low until a combination window is demonstrated.","history":[{"visit":1,"cycle":44,"status":"NEW","note":"New from PMID:42593144; correlative-plus-cell-line evidence only, and the normal-tissue essentiality of OGT keeps confidence low until a combination window is demonstrated."}]},{"id":"L3","title":"BTK degradation plus BCL2/NF-κB co-targeting in ABC/MCD-like DLBCL","mechanism":"Chronic active BCR-NF-kB signalling (MYD88/CD79B-mutant) with BCL2 as the apoptotic gate [SOMATIC]. Covalent BTKi resistance via C481S/PLCG2 (PMID:39456530); pirtobrutinib defeated by T474/L528 with zanubrutinib/acalabrutinib cross-resistance (PMID:38578606); L528W is kinase-inactivating, implying scaffold signalling [INFERRED]. Degraders remove scaffold plus kinase (PMID:39941922, PMID:40719810) and PROTACs are advancing clinically in haematologic malignancy (PMID:41845415), but the clinical centre of gravity remains MCL/CLL (PMID:41986622).","approach":"Continue tracking NCT05006716 for a genotype-annotated DLBCL expansion readout; propose degrader substitution for ibrutinib in a ViPOR-like backbone (NCT03223610). Do not attempt covalent-BTKi salvage after non-covalent failure. Escape to expect: CARD11/PLCG2 gain-of-function (hand off to L6), cereblon/E3 loss, BCL2 mutation, MCL1 upregulation.","level":"CANDIDATE","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT05006716","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03223610","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"39941922","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"38578606","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39456530","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40719810","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41845415","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41986622","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":44,"lastVisit":3,"lastNote":"A dedicated 2024-2026 query for BGB-16673/NX-5948/NX-2127/BTK-degrader in DLBCL returned only generic TPD reviews - no DLBCL ORR, no LymphGen breakdown, no emergent-mutation sequencing. Second consecutive visit of class-level CLL/MCL-weighted corroboration only; downgraded 0.55 to 0.50 for failure to produce DLBCL-specific evidence under targeted search.","history":[{"visit":3,"cycle":177,"status":"WEAKENED","note":"A dedicated 2024-2026 query for BGB-16673/NX-5948/NX-2127/BTK-degrader in DLBCL returned only generic TPD reviews - no DLBCL ORR, no LymphGen breakdown, no emergent-mutation sequencing. Second consecutive visit of class-level CLL/MCL-weighted corroboration only; downgraded 0.55 to 0.50 for failure to produce DLBCL-specific evidence under targeted search."},{"visit":2,"cycle":99,"status":"STRENGTHENED","note":"Four independent NEW reviews convert the previously [KNOWN] premises (degraders beat kinase-domain mutations; scaffold function matters) into cited claims, and add the cross-resistance constraint. Caveat: all corroboration is CLL/SLL, review-level; zero DLBCL-specific efficacy or emergent-mutation data in this pack, so confidence rises only to 0.55."},{"visit":1,"cycle":44,"status":"NEW","note":"New this visit; both trials are recruiting and mechanistically complementary, but no DLBCL-specific efficacy data are in this pack — level capped at LEAD."}]},{"id":"L4","title":"Dual PI3K/HDAC inhibition (BEBT-908/ifupinostat) + rituximab in R/R DLBCL","mechanism":"Simultaneous PI3K-AKT survival blockade and HDAC inhibition, with expected hyperacetylation of p53 and increased antigen-presentation/immunogenicity [KNOWN, unverified in this pack]. Now in a randomised phase 3 against salvage immunochemotherapy.","approach":"Follow NCT06792253 readout; prospectively ask whether benefit concentrates in GCB/EZB or in TP53-wildtype disease. Resistance: PTEN-independent AKT reactivation, MYC-driven bypass, HDAC-inhibitor class toxicity limiting exposure.","level":"LEAD","confidence":0.35,"citations":[{"kind":"NCT","id":"NCT06792253","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":44,"lastVisit":1,"lastNote":"New; pivotal-stage trial anchor only — no biomarker or mechanistic data in the pack, so this is a tracking lead.","history":[{"visit":1,"cycle":44,"status":"NEW","note":"New; pivotal-stage trial anchor only — no biomarker or mechanistic data in the pack, so this is a tracking lead."}]},{"id":"L5","title":"Biomarker-adaptive early T-cell redirection in high-risk frontline DLBCL","mechanism":"Early residual disease (interim PET non-CR, ctDNA-high) marks chemo-refractory biology; CD20xCD3 engagers redirect T cells independently of chemosensitivity [KNOWN]. New constraint: after 2L CAR-T relapse, salvage ORR was 39.1% with CR 27.6% and median OS only 6.5 months (PFS 3.4 months) despite bispecific-based regimens in 65% of 231 treated patients, and 35% of relapses occurred within 2 months (PMID:42099680). [INFERRED] Engager efficacy depends on T-cell fitness that prior CAR-T and refractory disease have already consumed, so redirection must be deployed before, not after, that exhaustion.","approach":"Compare interim-PET (Pola-R-CHP, CD5+ cohort) versus ctDNA (glofitamab+R-CHP, NCT04980222) as the selector for frontline engager intensification; use early relapse (<6 months) and T-cell phenotype (exhaustion markers, TGF-b/M2 macrophage content) as covariates. Resistance: CD20 loss/antigen escape, T-cell exhaustion, immunosuppressive TME.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42482660","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04980222","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42532836","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42247321","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42099680","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":44,"lastVisit":3,"lastNote":"First real-world outcome data for T-cell redirection after 2L CAR-T failure; the dismal 6.5-month OS reframes the lead from 'engagers as chemo-independent salvage' to 'engagers must be moved earlier', which is exactly the NCT04980222 design. Modest confidence rise as the supporting datum is retrospective registry data in a different line of therapy.","history":[{"visit":3,"cycle":177,"status":"STRENGTHENED","note":"First real-world outcome data for T-cell redirection after 2L CAR-T failure; the dismal 6.5-month OS reframes the lead from 'engagers as chemo-independent salvage' to 'engagers must be moved earlier', which is exactly the NCT04980222 design. Modest confidence rise as the supporting datum is retrospective registry data in a different line of therapy."},{"visit":1,"cycle":44,"status":"NEW","note":"New; CD5+ Pola-R-CHP data are retrospective (n=32, HR 18.1 implausibly wide), so the lead rests on the trial design plus engager class data, not on that HR."}]},{"id":"L6","title":"MALT1 protease inhibition to bypass proximal BCR-resistance mutations in ABC/MCD-DLBCL","mechanism":"CARD11-BCL10-MALT1 drives NF-kB downstream of BTK/PKCb in ABC-DLBCL, with MALT1 acting through both scaffold and protease functions; aberrant MALT1 activation is implicated specifically in DLBCL (PMID:41783325) [SOMATIC]. CARD11 gain-of-function and PLCG2 mutations, the named escapes from BTK inhibition/degradation (PMID:39456530), lie upstream of or at MALT1 and should remain MALT1-dependent [INFERRED]. Critically, in ATL models a selective protease inhibitor (CRD-1441551) killed only 2/8 models, with response tracking constitutive MALT1-NF-kB activation (PMID:42542590) - so dependency is heterogeneous and must be measured, not assumed. Normal tissue: MALT1 protease activity is required for","approach":"Safimaltib/JNJ-67856633-class protease inhibitors alone and with venetoclax in CARD11-mutant and BTK-degrader-resistant ABC-DLBCL lines and PDX, prospectively stratified by a basal MALT1-activity signature (BCL10 cleavage fragment, MALT1-dependent NF-kB target output) rather than CARD11 genotype; parallel Treg count/function and cytokine readouts. Resistance: NF-kB-independent JAK/STAT3 or MYC bypass, scaffold-only MALT1 signalling insensitive to protease inhibition, upstream reactivation.","level":"CANDIDATE","confidence":0.5,"citations":[{"kind":"PMID","id":"40723181","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39456530","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41783325","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42542590","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":99,"lastVisit":3,"lastNote":"First DLBCL-specific MALT1 source plus first in vivo dose-response dataset for a selective protease inhibitor. Promoted for independent NEW corroboration on a second evidence-bearing visit; confidence capped at 0.5 because the response-heterogeneity data are ATL/TCR-driven, not BCR-driven DLBCL, and safimaltib activity is described only as preliminary.","history":[{"visit":3,"cycle":177,"status":"STRENGTHENED","note":"First DLBCL-specific MALT1 source plus first in vivo dose-response dataset for a selective protease inhibitor. Promoted for independent NEW corroboration on a second evidence-bearing visit; confidence capped at 0.5 because the response-heterogeneity data are ATL/TCR-driven, not BCR-driven DLBCL, and safimaltib activity is described only as preliminary."},{"visit":2,"cycle":99,"status":"NEW","note":"New this visit; created specifically to cover the CARD11/PLCG2 escape lane named by L3. Pack evidence is a CLL review listing MALT1 as an investigational target — no DLBCL-specific data cited, so confidence deliberately low."}]},{"id":"L7","title":"Dual EZH1/EZH2 inhibition (tulmimetostat) in EZB/GCB-DLBCL and germinal-centre lymphoma","mechanism":"EZH2 gain-of-function (Y646 class) is an EZB/GCB-DLBCL driver locking germinal-centre transcriptional programmes via H3K27me3 [KNOWN, SOMATIC]; dual EZH1/EZH2 blockade is intended to prevent EZH1-mediated compensation that limits single-target inhibition [KNOWN, unverified in this pack]. Normal tissue: EZH2 is required for GC B-cell development and haematopoiesis, so window is B-cell and marrow toxicity [KNOWN].","approach":"Track NCT04104776 lymphoma cohorts for EZH2-mutant versus wild-type response separation; prospectively ask whether tulmimetostat activity phenocopies or exceeds tazemetostat-class benefit and whether it overlaps the EZB signal sought for BEBT-908 (L4, NCT06792253). Resistance: EZH2 secondary mutation, PRC2-independent SWI/SNF rewiring, loss of H3K27me3 dependency.","level":"LEAD","confidence":0.3,"citations":[{"kind":"NCT","id":"NCT04104776","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":177,"lastVisit":3,"lastNote":"Opened as a tracking lead from a new trial anchor to service the standing EZB-genotype question; trial registration only, no mechanistic or biomarker data in this pack, hence low confidence.","history":[{"visit":3,"cycle":177,"status":"NEW","note":"Opened as a tracking lead from a new trial anchor to service the standing EZB-genotype question; trial registration only, no mechanistic or biomarker data in this pack, hence low confidence."}]}],"retired":[],"nextQueries":["(safimaltib OR \"JNJ-67856633\" OR \"MALT1 inhibitor\") AND (\"diffuse large B-cell lymphoma\" OR DLBCL OR \"activated B-cell\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"BGB-16673\" OR \"NX-5948\" OR \"BTK degrader\") AND (\"large B-cell\" OR DLBCL) AND (\"overall response\" OR resistance OR mutation) AND SRC:MED","(tulmimetostat OR \"CPI-0209\" OR \"EZH1/EZH2\") AND lymphoma AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-20T00:23:37.632Z"},{"key":"follicular lymphoma","name":"follicular lymphoma","mondo":{"id":"MONDO:0018906","name":"follicular lymphoma"},"genes":[{"label":"BCL2","kind":"correlated"},{"label":"IGH","kind":"correlated"},{"label":"HLA-DRB1","kind":"correlated"},{"label":"BCL6","kind":"correlated"}],"visits":3,"openQuestions":["What is the molecular basis of CD20 loss after frontline mosunetuzumab (MS4A1 truncating/splice mutation vs promoter methylation vs transcriptional downregulation vs trogocytosis), and is it clonally selected from a pre-existing subclone?","Does CD19-directed therapy (surovatamig, CD19 CAR-T) retain efficacy specifically in biopsy-proven CD20-loss FL, and conversely does prior CD20 engager exposure impair CD19 CAR-T fitness?","Why does histologic transformation account for half the failures of frontline engager therapy — is engager pressure selecting TP53/MYC-altered or germinal-centre-exit clones, or is it unmasking pre-existing composite/high-grade disease?","Can fixed-duration engager therapy be stopped safely using an immune biomarker (memory:effector CTL ratio, Vbeta skewing) rather than PET alone, and does this reduce late antigen escape?","In STAT6-mutant, CD23-high FL, does IL4R (dupilumab) or JAK1 blockade kill or merely cytostatically blunt tumour cells, and does concurrent JAK inhibition antagonise engager-mediated T-cell degranulation?","Does HLA-DR/beta-2M protein loss or CIITA/B2M mutation predict lenalidomide-based failure while sparing engager response, in systemic FL rather than cutaneous follicle-centre lymphoma?"],"leads":[{"id":"L1","title":"CD3 bispecific engagers displace chemoimmunotherapy in t(14;18)/BCL2-driven FL","mechanism":"IGH::BCL2 [SOMATIC] blocks intrinsic mitochondrial apoptosis, the pathway chemotherapy and part of rituximab activity depend on [KNOWN]; CD20xCD3 crosslinking delivers granzyme/perforin killing that is BCL2- and MHC-independent [INFERRED]. Now demonstrated prospectively as chemo-free frontline therapy: mosunetuzumab x8 in untreated indolent B-NHL (88% FL) gave ORR 100%/CR 71% alone, CR 86% with response-adapted polatuzumab vedotin+obinutuzumab, 2-year PFS 89%, OS 100%, CRS all grade 1 (PMID:42600120), complementing R/R epcoritamab+R2 superiority over an adjusted R2/CIT control (PMID:42415230) and 4/4 FL responses with epcoritamab under serial CTL/Vbeta monitoring (PMID:42278654). Activity is","approach":"Treat NCT06337318 (mosunetuzumab vs rituximab, low burden) and NCT06549595 (surovatamig+rituximab vs R-CHOP/R-CVP/BR) as the randomised confirmations. Prespecify: (i) paired progression biopsies with CD20/CD19 IHC plus CD20 (MS4A1) truncating/splice sequencing, (ii) transformation histology and MYC/TP53 status, (iii) baseline CD8 TCF1+ stem-like vs TOX/PD-1-hi fraction and granzyme B+ CD4 CTL, (iv) Vbeta repertoire and memory:effector CTL ratio at fixed-duration stop (PMID:42278654) as a candidate discontinuation biomarker. Expected resistance: CD20 loss, histologic transformation, trogocytosis, exhaustion, Treg-rich follicular niche.","level":"DOSSIER","confidence":0.78,"citations":[{"kind":"NCT","id":"NCT06337318","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06549595","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42415230","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT04663347","verified":false,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42600120","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42278654","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42315502","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42527721","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":45,"lastVisit":3,"lastNote":"Promoted: first prospective frontline chemo-free engager data [NEW] (PMID:42600120) plus independent real-world/correlative support [NEW] (PMID:42315502, PMID:42278654) on a third evidence-bearing visit; survived my own kill attempts (external-control design, engager+IMiD confounding) which this single-agent dataset removes. Still discounted for n=42 single-arm, 34-month follow-up, pending randomi","history":[{"visit":3,"cycle":178,"status":"STRENGTHENED","note":"Promoted: first prospective frontline chemo-free engager data [NEW] (PMID:42600120) plus independent real-world/correlative support [NEW] (PMID:42315502, PMID:42278654) on a third evidence-bearing visit; survived my own kill attempts (external-control design, engager+IMiD confounding) which this single-agent dataset removes. Still discounted for n=42 single-arm, 34-month follow-up, pending randomi"},{"visit":2,"cycle":100,"status":"STRENGTHENED","note":"Promoted on new independent literature (PMID:42415230, [NEW]) showing an engager-containing chemo-free regimen beating R2/CIT in R/R FL. Explicitly discounted for external-control design and for testing engager+lenalidomide rather than engager alone; resistance biology still unmeasured."},{"visit":1,"cycle":45,"status":"NEW","note":"New lead created from two [NEW] phase 3 registrations that move engagers into low-burden and previously untreated FL; no literature available this visit, so mechanism is stated as inference, not demonstrated."}]},{"id":"L2","title":"BTK degradation vs occupancy: is chronic active BCR signalling a maintenance dependency in FL?","mechanism":"FL retains an antigen-experienced BCR; BTK inhibitors give only modest single-agent FL activity [KNOWN]. CARD11 gain-of-function supplies CBM/NF-kB signalling downstream and independent of BTK [KNOWN] and is enriched in multi-extranodal POD24-prone FL (PMID:41137062), an a priori resistant subset concentrated among the highest-risk patients [INFERRED]. Degraders (BGB-16673) remove scaffold plus catalytic function and retain activity against C481S/T474I/L528W [KNOWN]. BTK is required for normal B-cell development (XLA) and myeloid FcgR signalling: infection, bleeding, atrial fibrillation define the window.","approach":"Read NCT05100862 (zanubrutinib+anti-CD20 vs R2) and the FL cohort of NCT05006716 with prespecified CARD11/TNFAIP3/CD79B/PLCG2 genotyping and a BCR-signalling GEP score. Any FL BTK regimen must now be benchmarked against single-agent frontline mosunetuzumab (CR 71%, 2-year PFS 89%, all-grade-1 CRS; PMID:42600120), not against chemoimmunotherapy.","level":"LEAD","confidence":0.24,"citations":[{"kind":"NCT","id":"NCT05006716","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05100862","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41137062","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42415230","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42600120","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":45,"lastVisit":3,"lastNote":"Weakened again: no FL-specific BTK or degrader response data in this pack, while PMID:42600120 [NEW] raised the chemo-free efficacy/toxicity bar; retirement is likely next visit unless the NCT05006716 FL cohort reports subset-defined activity.","history":[{"visit":3,"cycle":178,"status":"WEAKENED","note":"Weakened again: no FL-specific BTK or degrader response data in this pack, while PMID:42600120 [NEW] raised the chemo-free efficacy/toxicity bar; retirement is likely next visit unless the NCT05006716 FL cohort reports subset-defined activity."},{"visit":2,"cycle":100,"status":"WEAKENED","note":"Weakened: FL-specific data show CARD11 lesions concentrated in high-risk extranodal/POD24 disease (a structural BTK bypass), and the engager+R2 efficacy bar rose, while no FL-specific BTK or degrader response data appeared in the pack."},{"visit":1,"cycle":45,"status":"NEW","note":"New lead from two [NEW] trials; deliberately framed as a dependency question rather than an assertion, because FL is less BTK-addicted than CLL/MCL and the pack contains no FL-specific response data."}]},{"id":"L3","title":"MHC class II (HLA-DRB1 anchor) status as the stratifier splitting immunomodulatory from MHC-independent immunotherapy in FL","mechanism":"HLA-DRB1 is in the Monarch correlated set; CREBBP/EZH2/KMT2D loss reduces MHC class II and blunts CD4 surveillance [KNOWN]; CD4 CTLs kill in a strictly MHC-II-dependent manner (PMID:41436233). New genetic support in follicle-centre lymphoma: an integrated PCFCL/FL_CI series defines a subgroup (44% of PCFCL) carrying immune-evasion mutations in CIITA, B2M, IRF8 and FAS [SOMATIC], i.e. direct genetic ablation of class II (CIITA) and class I (B2M) presentation, while FL_CI resembled systemic FL with CREBBP 90%/KMT2D 90% (PMID:42256548). FL-specific sequencing links CREBBP/KMT2D/CARD11/STAT6 to downregulated immune pathways and POD24 (PMID:41137062). Prediction: presentation-null FL is relativel","approach":"HLA-DR/DQ and beta-2M IHC plus CIITA/B2M/CREBBP/EZH2/KMT2D genotyping on archival tissue from NCT02390869 (R2 vs R maintenance) and the R2 comparator arm of NCT05100862, contrasted with engager-treated cohorts (NCT06337318). Quantify granzyme B+ CD4 CTL as the mediator (PMID:41436233). Preclinical: EZH2 or HDAC3 inhibition to re-induce class II, testing additivity with lenalidomide but not with an engager. Expected resistance: CIITA-independent silencing, Treg dominance, class I loss removing CD8 arm but leaving engager killing intact.","level":"CANDIDATE","confidence":0.52,"citations":[{"kind":"NCT","id":"NCT02390869","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05100862","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41436233","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41137062","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42256548","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT06337318","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":45,"lastVisit":3,"lastNote":"Promoted on PMID:42256548 [NEW], which supplies recurrent CIITA/B2M mutations in a follicle-centre lymphoma subgroup — the first genetic (not inferred) antigen-presentation lesion in this programme. Discounted: PCFCL is a distinct skin-limited entity from systemic FL, and no paper yet measures HLA-DR protein against lenalidomide response.","history":[{"visit":3,"cycle":178,"status":"STRENGTHENED","note":"Promoted on PMID:42256548 [NEW], which supplies recurrent CIITA/B2M mutations in a follicle-centre lymphoma subgroup — the first genetic (not inferred) antigen-presentation lesion in this programme. Discounted: PCFCL is a distinct skin-limited entity from systemic FL, and no paper yet measures HLA-DR protein against lenalidomide response."},{"visit":2,"cycle":100,"status":"STRENGTHENED","note":"Mechanistic half now cited (MHC-II-restricted CD4 CTLs) and FL-specific correlation of CREBBP/KMT2D with immune-pathway downregulation added; promotion withheld because neither paper measures MHC-II protein or lenalidomide response in FL."},{"visit":1,"cycle":45,"status":"NEW","note":"New, most speculative lead; built by joining the HLA-DRB1 KG anchor to two [NEW] trials with lenalidomide arms. Needs literature confirmation of the CREBBP/EZH2-MHC-II axis in FL next visit before it earns any promotion."}]},{"id":"L4","title":"POD24/multi-extranodal FL as a distinct dependency class: STAT6-IL-4/JAK and CARD11-NF-kB on an MHC-independent effector backbone","mechanism":"Activating STAT6 hotspot mutations [SOMATIC] amplify TFH-derived IL-4/IL-13 signalling via JAK1/JAK3-STAT6, a BCR-independent survival input [KNOWN]. New: in follicle-centre lymphoma genomics, a subgroup is defined by activating STAT6 plus CREBBP mutations and is uniformly CD23+/CD10+ (PMID:42256548) — CD23/FCER2 is the canonical IL-4-STAT6 target gene, so the mutation now has a validated in-tissue pathway readout rather than an assumed one [INFERRED]. A systematic review positions STAT6 as the node coupling Th2-type microenvironment to chemoresistance in haematologic malignancy (PMID:41838170). FL cohort data tie STAT6/CARD11/KMT2D/CREBBP to multi-extranodal, POD24-prone disease with immune","approach":"Genotype STAT6/CARD11 in POD24 and extranodal FL and test CD23/FCER2 and CCL17 as surrogate IL-4-pathway activity markers, calibrated against the CD23+ STAT6-mutant phenotype (PMID:42256548). Ex vivo: FL primary cells with autologous TFH or IL-4 +/- ruxolitinib/itacitinib or dupilumab, then combine with mosunetuzumab/epcoritamab in autologous killing assays, testing whether JAK inhibition blunts T-cell degranulation (intermittent vs continuous dosing). Expected resistance: STAT5/IL-21 substitution, CARD11-driven NF-kB, lipid rewiring.","level":"CANDIDATE","confidence":0.46,"citations":[{"kind":"PMID","id":"41137062","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41337699","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42256548","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41838170","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":100,"lastVisit":3,"lastNote":"Promoted on two [NEW] items: PMID:42256548 independently recovers activating STAT6 in follicle-centre lymphoma with the predicted CD23/FCER2 output, and PMID:41838170 supplies the STAT6/Th2 chemoresistance frame. Still no FL data on IL4R or JAK blockade, and the STAT6 subgroup evidence is cutaneous, so held below DOSSIER.","history":[{"visit":3,"cycle":178,"status":"STRENGTHENED","note":"Promoted on two [NEW] items: PMID:42256548 independently recovers activating STAT6 in follicle-centre lymphoma with the predicted CD23/FCER2 output, and PMID:41838170 supplies the STAT6/Th2 chemoresistance frame. Still no FL data on IL4R or JAK blockade, and the STAT6 subgroup evidence is cutaneous, so held below DOSSIER."},{"visit":2,"cycle":100,"status":"NEW","note":"New lead built from FL-specific mutation/microenvironment genomics; addresses open question 6 by naming a druggable axis (IL-4/JAK-STAT6) in the high-risk subset rather than treating POD24 as a purely prognostic label."}]},{"id":"L5","title":"Antigen/lineage escape, not exhaustion, is the dominant engager failure mode in FL — sequence CD20 to CD19 and biopsy-confirm every 'relapse'","mechanism":"In the only prospective frontline engager cohort, all four progressions were escape events: 2 CD20 loss and 2 histologic transformation (PMID:42600120). This predicts that FL engager failure is target- or phenotype-driven rather than primarily T-cell-intrinsic, and is therefore correctable by switching the cytotoxic antigen (CD19 engager surovatamig, CD19 CAR-T) rather than by immune reinvigoration [INFERRED]; CD19-directed bispecific/CAR activity persists in FL after prior CD20-directed and CAR-T exposure in real-world series (PMID:42315502) and sequencing frameworks now treat antigen alternation explicitly (PMID:42527721). Confounder: apparent post-engager relapse can be an unmasked synchr","approach":"Mandate biopsy at first progression with clonality (IGH-seq) comparison to baseline, MS4A1 and CD19 sequencing (truncating/splice/promoter methylation), CD20/CD19 surface density by quantitative flow, and monocyte CD20 acquisition as a trogocytosis readout. Nested question in NCT06549595: does a CD19xCD3 engager plus rituximab (antigen separation) delay antigen-loss progression versus CD20-directed engager? Retreatment cohort: CD20-loss progressors to CD19 CAR-T or surovatamig; transformation progressors to pola/CAR-T rather than re-engagement. Expected resistance: dual CD19/CD20 loss, lineage plasticity, TP53-driven transformation.","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"42600120","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42315502","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42529676","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42527721","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT06549595","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":178,"lastVisit":3,"lastNote":"New lead created directly from the escape-mechanism data in PMID:42600120 [NEW]; converts open question 1 from speculation into a measurable, sequenceable programme and records the composite-lymphoma confound (PMID:42529676) so the desk does not misattribute escape.","history":[{"visit":3,"cycle":178,"status":"NEW","note":"New lead created directly from the escape-mechanism data in PMID:42600120 [NEW]; converts open question 1 from speculation into a measurable, sequenceable programme and records the composite-lymphoma confound (PMID:42529676) so the desk does not misattribute escape."}]}],"retired":[],"nextQueries":["(\"follicular lymphoma\" AND (\"CD20 loss\" OR MS4A1 OR \"antigen escape\" OR trogocytosis) AND (mosunetuzumab OR epcoritamab OR odronextamab OR \"CAR T\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"follicular lymphoma\" AND (\"histologic transformation\" OR \"transformed\") AND (bispecific OR \"T-cell engager\" OR TP53 OR MYC) AND (genomic OR clonal OR biopsy)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","((\"follicular lymphoma\" OR \"germinal center B-cell\") AND (CIITA OR B2M OR \"HLA-DR\" OR \"MHC class II\") AND (lenalidomide OR \"immune evasion\" OR \"antigen presentation\")) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"updatedAt":"2026-08-20T00:27:33.266Z"},{"key":"mantle cell lymphoma","name":"mantle cell lymphoma","mondo":{"id":"MONDO:0018876","name":"mantle cell lymphoma"},"genes":[{"label":"CCND1","kind":"correlated"},{"label":"ATM","kind":"correlated"},{"label":"IGH","kind":"correlated"}],"visits":3,"openQuestions":["Does CM272 or UHRF1 knockdown demethylate the miR-146a promoter, restore miR-146a-5p and re-sensitise ibrutinib-tolerant MCL, i.e. are L1 and L9 one node?","Is UHRF1 dependence restricted to SOX11-positive MCL, and does SOX11 knockdown phenocopy UHRF1 loss (epistasis)?","Is HR/ATM/BRCA2 deficiency a resistance modifier for the palbociclib arm of L6, as germline BRCA2 data in breast cancer suggest?","Is eprenetapopt+palbociclib synergy TP53-genotype-restricted (mut vs null vs wildtype), and is RB1 loss or cyclin E-CDK2 the dominant escape route?","What are the disclosed targets of EXS73565 (NCT06980116) and ABBV-291 (NCT06667687) — still unanswered after two visits?","In post-CD19 CAR-T relapse, what fraction retain CD19 by biopsy, and does adding a non-covalent BTKi (NCT07673367) rescue T-cell-failure relapses specifically?"],"leads":[{"id":"L1","title":"Restore miR-146a-5p / block MAPK-ERK+PI3K-AKT to reverse non-genetic ibrutinib resistance","mechanism":"Ibrutinib-tolerant MCL loses miR-146a-5p with MAPK-ERK/PI3K-AKT hyperactivation independent of BTK/PLCG2 mutation; promoter hypermethylation proposed but unproven. UHRF1, the DNMT1 maintenance-methylation partner [KNOWN], is upregulated in MCL and druggable with CM272 (PMID:41876725) and is downregulated by eprenetapopt+palbociclib (PMID:42068675), giving two non-nucleoside routes to test promoter demethylation.","approach":"In ibrutinib-resistant lines/PDX, apply CM272, UHRF1 shRNA, or eprenetapopt+palbociclib and read miR-146a promoter methylation (bisulfite/MSP), miR-146a-5p RT-qPCR, pERK/pAKT, then ibrutinib re-challenge; compare with azacitidine/decitabine. Secondary arms: intermittent trametinib or PI3Kdelta inhibitor + covalent/non-covalent BTKi; IRAK1/TRAF6/NF-kB as proximal node. Window: miR-146a is a physiological NF-kB brake (immunosuppression); MEK/PI3K toxicity argues intermittent dosing.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42335205","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42340653","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42068675","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41876725","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":46,"lastVisit":3,"lastNote":"Still no direct MCL miR-146a/methylation data, but CM272 (PMID:41876725) converts the UHRF1-methylation bridge from inference into a one-experiment test; confidence back to 0.50.","history":[{"visit":3,"cycle":179,"status":"STRENGTHENED","note":"Still no direct MCL miR-146a/methylation data, but CM272 (PMID:41876725) converts the UHRF1-methylation bridge from inference into a one-experiment test; confidence back to 0.50."},{"visit":2,"cycle":101,"status":"WEAKENED","note":"A targeted Europe PMC query for MCL + miR-146a/methylation/azacitidine returned no new supporting evidence this visit; lead still rests on one primary paper, so confidence drops 0.55->0.45. Retained because PMID:42068675 supplies a testable UHRF1-methylation bridge."},{"visit":1,"cycle":46,"status":"NEW","note":"New this visit from PMID:42335205 (multi-model convergence: 3 resistant lines + PDX + patient biopsies), the only pack item with primary mechanistic data."}]},{"id":"L2","title":"BTK degradation (BGB-16673) for MCL progressing on covalent and non-covalent BTK inhibitors","mechanism":"Chimeric degraders eliminate BTK protein rather than occupying the ATP or allosteric site, so kinase-domain (C481S) and non-covalent-selective (L528W, T474) mutants and scaffold-function BTK should remain vulnerable [INFERRED from mechanism; KNOWN mutation spectrum].","approach":"Track NCT05006716 MCL expansion cohort for ORR/duration stratified by prior BTKi class and baseline BTK genotype; correlate ctDNA BTK/PLCG2 clearance with response. Normal tissue: BTK is required for B-cell and myeloid FcR signalling - expect hypogammaglobulinaemia/infection, and note the zanubrutinib ocular-surface signal (PMID:42574588) as a class question. Anticipated escape: BCR-independent NF-kB (miR-146a axis above), CRBN/E3-ligase loss, BCL2 co-dependence.","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT05006716","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42340653","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":46,"lastVisit":1,"lastNote":"New; trial-anchored, no efficacy data in pack - deliberately low confidence.","history":[{"visit":1,"cycle":46,"status":"NEW","note":"New; trial-anchored, no efficacy data in pack - deliberately low confidence."}]},{"id":"L3","title":"BCL2 co-targeting with BTK inhibition: sonrotoclax + zanubrutinib in R/R MCL","mechanism":"CCND1 [SOMATIC] translocation-driven proliferative stress plus BCR-dependent survival creates dual dependence; BH3 mimetic lowers the apoptotic threshold that BTKi alone leaves intact, targeting drug-tolerant persister cells named in PMID:42340653.","approach":"Randomised phase 3 NCT06742996 readouts (PFS, MRD negativity by ctDNA) with pre-specified TP53-altered subgroup; preclinically test whether miR-146a-low/ERK-high resistant models retain BH3-mimetic sensitivity. Normal tissue: BCL2 dependence in lymphocytes and (for BCL-XL cross-reactivity) platelets - cytopenias, TLS. Resistance: BCL2 G101V/D103Y, MCL1 or BCL-XL upregulation.","level":"LEAD","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT06742996","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42340653","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":46,"lastVisit":1,"lastNote":"New; phase 3 with placebo control is the strongest trial-level evidence in the pack.","history":[{"visit":1,"cycle":46,"status":"NEW","note":"New; phase 3 with placebo control is the strongest trial-level evidence in the pack."}]},{"id":"L4","title":"Antigen-switch salvage after CD19 CAR-T failure: CD79b ADC, CD20xCD3, ROR1 ADC","mechanism":"Post-CAR-T relapse is driven partly by CD19 antigen loss/downmodulation and T-cell exhaustion; redirecting to independent B-cell surface antigens (CD79b, CD20, ROR1) bypasses CD19 escape while ADC payloads act independent of host T-cell fitness.","approach":"Prospective post-CAR-T cohort with paired biopsy CD19/CD20/CD79b/ROR1 IHC and flow before salvage; sequence Pola-R-Benda (durable >20-month CR reported, PMID:42564502) vs mosunetuzumab+polatuzumab (PMID:42532836) vs zilovertamab vedotin +/- nemtabrutinib (NCT05458297) vs CD19xCD3 surovatamig (NCT06564038) - the last only if CD19 is retained. Normal tissue: ROR1 is oncofetal with minimal adult expression (best window); CD79b/CD20 are B-lineage-restricted, cost is prolonged B-cell aplasia. Resistance: second antigen loss, MDR1-mediated MMAE efflux.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42564502","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42532836","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05458297","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06564038","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":46,"lastVisit":1,"lastNote":"New; anchored on one case report plus guideline-level and trial evidence - hypothesis-generating only, n=1 for Pola-R-Benda.","history":[{"visit":1,"cycle":46,"status":"NEW","note":"New; anchored on one case report plus guideline-level and trial evidence - hypothesis-generating only, n=1 for Pola-R-Benda."}]},{"id":"L5","title":"First-line cellular therapy for TP53-altered / p53-overexpressing high-risk MCL","mechanism":"TP53 [SOMATIC] alteration confers chemoresistance to cytarabine/anthracycline-based induction and short PFS regardless of fitness; CAR-T efficacy is not p53-dependent, so moving brexu-cel forward after abbreviated BTKi+rituximab induction should decouple outcome from chemosensitivity [INFERRED].","approach":"Follow CARMAN (PMID:42581349) Arm A vs TRIANGLE-like Arm B and the Window-3 pilot (NCT05495464) for PFS and MRD in TP53-altered patients; require baseline TP53 sequencing plus p53 IHC and serial ctDNA. Normal tissue: lymphodepletion + CD19 CAR-T toxicity (CRS/ICANS, B-cell aplasia) is the window-limiting cost in first line. Resistance: CD19 loss, poor T-cell fitness after prior chemo - an argument for the abbreviated chemo-free induction.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42581349","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05495464","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42555305","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":46,"lastVisit":1,"lastNote":"New; both trials are ongoing with no efficacy data yet - lead records the design question, not an answer.","history":[{"visit":1,"cycle":46,"status":"NEW","note":"New; both trials are ongoing with no efficacy data yet - lead records the design question, not an answer."}]},{"id":"L6","title":"Eprenetapopt + palbociclib in TP53-altered, CCND1-driven MCL: redox/replication-stress synthetic lethality","mechanism":"CCND1 [SOMATIC] translocation makes cyclin D1-CDK4/6 the proliferative engine; palbociclib arrests and disrupts DNA repair/replication control (PMID:38279263) while eprenetapopt reactivates mutant p53 and depletes glutathione, raising ROS; the combination's activity in mut/del-TP53 MCL cells and CDX was shown to be mediated by UHRF1 downregulation (PMID:42068675). Independent MCL data now establish UHRF1 itself as an oncogenic driver whose loss causes apoptosis and G2/M arrest and whose pharmacological inhibition regresses MCL xenografts (PMID:41876725), so the proposed mediator is a bona fide dependency rather than a correlate.","approach":"Confirm in TP53-mutant vs wildtype vs null MCL lines/PDX (including ibrutinib- and venetoclax-resistant derivatives); benchmark eprenetapopt+palbociclib head-to-head against CM272 and against UHRF1 shRNA for UHRF1 protein, global 5mC, G2/M fraction and apoptosis; score RB1 status, cyclin E/CDK2, NRF2/SLC7A11 and now HR status (BRCA2/ATM) as resistance modifiers, since germline BRCA2 mutation confers CDK4/6i resistance in breast cancer (PMID:42115772); triplet with zanubrutinib or a BH3 mimetic; biomarker-selected phase 1 in TP53-altered R/R MCL after BTKi/CAR-T failure. Window: palbociclib neutropenia, APR-246 GSH depletion, UHRF1/DNMT1 loss risks global hypomethylation in proliferating marr","level":"CANDIDATE","confidence":0.6,"citations":[{"kind":"PMID","id":"42068675","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"38279263","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41876725","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42115772","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":101,"lastVisit":3,"lastNote":"Promoted: second evidence-bearing visit with new independent MCL data (PMID:41876725) validating UHRF1 as the mediating dependency; PMID:42115772 adds a concrete falsification test (HR-deficient MCL may resist the CDK4/6i arm).","history":[{"visit":3,"cycle":179,"status":"STRENGTHENED","note":"Promoted: second evidence-bearing visit with new independent MCL data (PMID:41876725) validating UHRF1 as the mediating dependency; PMID:42115772 adds a concrete falsification test (HR-deficient MCL may resist the CDK4/6i arm)."},{"visit":2,"cycle":101,"status":"NEW","note":"New: the only MCL-specific primary paper in this pack, and the first affirmative answer to open question 3 (CDK4/6 dependence is actionable, but the partner is a p53/redox agent rather than BTKi/venetoclax)."}]},{"id":"L8","title":"Non-covalent BTK inhibition around CD19 CAR-T: nemtabrutinib + brexu-cel in R/R MCL","mechanism":"BTKi exposure improves T-cell fitness and reduces exhaustion markers, and BTKi bridging lowers tumour bulk and cytokine burden before lymphodepletion [KNOWN]; nemtabrutinib retains activity against C481S and non-covalent-relevant BTK genotypes, so it can be continued through apheresis and infusion in patients who have already failed covalent BTKi (PMID:42340653).","approach":"Follow NCT07673367 for ORR/CR, MRD by ctDNA, CRS/ICANS rates and CAR-T expansion kinetics versus historical brexu-cel; pre-specify prior-BTKi class, BTK/PLCG2 genotype and TP53 status; paired biopsy CD19 expression at relapse to separate antigen loss from T-cell failure (feeds L4). Window: added BTK inhibition on top of CAR-T deepens hypogammaglobulinaemia and infection risk; nemtabrutinib off-target kinase liabilities.","level":"LEAD","confidence":0.4,"citations":[{"kind":"NCT","id":"NCT07673367","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42340653","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":101,"lastVisit":2,"lastNote":"New trial in this pack; directly addresses open questions 4 and 5 by testing whether BTKi-refractory disease can be rescued by combining a non-covalent BTKi with CAR-T rather than switching antigen. No efficacy data yet.","history":[{"visit":2,"cycle":101,"status":"NEW","note":"New trial in this pack; directly addresses open questions 4 and 5 by testing whether BTKi-refractory disease can be rescued by combining a non-covalent BTKi with CAR-T rather than switching antigen. No efficacy data yet."}]},{"id":"L9","title":"SOX11-UHRF1 chromatin axis as a direct dependency in SOX11-positive MCL (CM272; LSD1 as second node)","mechanism":"SOX11, the MCL lineage transcription factor, binds the UHRF1 promoter and transactivates it; UHRF1 is overexpressed in MCL specimens, correlates with SOX11 and Ki-67 and with worse OS, and its knockdown induces apoptosis, G2/M arrest and loss of motility/invasion, while CM272 (dual G9a/DNMT1 inhibitor [KNOWN]) inhibits MCL xenograft progression with tolerable safety (PMID:41876725). A parallel eraser node is implicated: IRAIN overexpression suppresses MCL growth while lowering LSD1, cyclin D1 and CDK2 and inducing p21 (PMID:42265322), suggesting LSD1 supports the same proliferative programme. [INFERRED] SOX11-negative leukemic non-nodal MCL should be far less dependent, making SOX11 a built-","approach":"Panel of SOX11-high vs SOX11-negative MCL lines/PDX (JeKo-1, Mino, Granta-519, Z-138) treated with CM272, UHRF1 degradation/knockdown and an LSD1 inhibitor: read UHRF1/DNMT1 protein, global and locus-specific 5mC, H3K9me2, cell cycle, apoptosis, and SOX11 ChIP at the UHRF1 promoter; test SOX11 knockdown for epistasis; combine CM272 with zanubrutinib, venetoclax and palbociclib; in vivo dose-fractionation to separate antitumour effect from marrow hypomethylation. Correlate UHRF1/SOX11 IHC with survival in an independent MCL cohort. Window: UHRF1 is largely proliferation-restricted; expected on-target costs are myelosuppression and global hypomethylation; G9a inhibition may derepress immune/vi","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"41876725","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42265322","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":179,"lastVisit":3,"lastNote":"New this visit: first MCL-specific in vivo evidence that a chromatin maintenance factor is a tractable target, with a transcription-factor-based patient selector; LSD1 carried as a subordinate arm because the IRAIN work is in vitro overexpression only.","history":[{"visit":3,"cycle":179,"status":"NEW","note":"New this visit: first MCL-specific in vivo evidence that a chromatin maintenance factor is a tractable target, with a transcription-factor-based patient selector; LSD1 carried as a subordinate arm because the IRAIN work is in vitro overexpression only."}]}],"retired":[{"title":"ATR/CHK1/WEE1 inhibition in ATM-altered, replication-stressed MCL — hypothesis without MCL data","note":"Retired on the pre-committed rule: a third visit with a query explicitly targeting WEE1/PKMYT1/CHK1/CDK2/cyclin E in MCL returned only pan-cancer reviews and zero MCL efficacy data; recorded as a dead end so the desk stops spending queries on it.","cycle":179,"ts":"2026-08-20T00:30:55.225Z"}],"nextQueries":["(\"mantle cell lymphoma\" OR \"B-cell lymphoma\") AND (CM272 OR UHRF1 OR SOX11) AND SRC:MED","\"mantle cell lymphoma\" AND (LSD1 OR KDM1A OR iadademstat OR \"G9a\" OR EHMT2 OR DNMT1) AND SRC:MED","\"mantle cell lymphoma\" AND (\"BGB-16673\" OR \"BTK degrader\" OR sonrotoclax OR \"CD19 loss\" OR \"CAR T relapse\") AND SRC:MED"],"updatedAt":"2026-08-20T00:30:55.225Z"},{"key":"hodgkin lymphoma","name":"Hodgkin lymphoma","mondo":{"id":"MONDO:0004952","name":"Hodgkins lymphoma"},"genes":[{"label":"KLHDC8B","kind":"correlated"}],"visits":3,"openQuestions":["What are BCL2, BCL-xL and MCL1 protein levels and BH3-profiling dependencies in adult primary HRS cells, and do they differ between BV-naive, BV-refractory and PD-1-refractory cHL?","At venetoclax exposures that kill HRS cells, is the rosetting CD4/CD8 and macrophage compartment spared, or does BCL2 inhibition antagonise the T-cell-dependent efficacy of PD-1 blockade in cHL?","In serial BV-exposed cHL biopsies, is acquired resistance dominated by ABCB1/efflux upregulation, impaired endocytic/endosomal processing, or CD30 loss — and at what CD30 H-score does BV fail?","Is the senescence-like HRS transcriptional programme (PMID:41538304) present in adult cHL and does it predict poor response to antimitotic MMAE payloads, arguing for non-antimitotic payloads or senolytic combinations?","Does LAG-3+ T-cell density or MHC class II loss discriminate non-CR in existing BV+nivolumab±ipilimumab cohorts, or should the checkpoint-resistance axis be abandoned for the apoptosis axis?","Are EBV+ and EBV- cHL distinct with respect to BCL2 family dependence and BV/checkpoint resistance mechanisms?"],"leads":[{"id":"L1","title":"CD30 ADC + PD-1 (± CTLA-4) blockade as chemotherapy-sparing backbone in classical Hodgkin lymphoma","mechanism":"HRS cells show strong uniform CD30, reduced B-cell markers and 9p24.1-driven PD-L1 with NF-κB/JAK-STAT/PI3K lesions (PMID:42122242). Beyond payload cytotoxicity, BV depletes CD30+ tumour-infiltrating Tregs and activates DC- and CD8-mediated antitumour immunity while inducing immunogenic cell death, including in CD30- bystanders via IFNα/γ response amplification (PMID:41762706) — a direct immunological rationale for pairing with PD-1 blockade. Expected resistance: CD30 loss/heterogeneity, efflux-transporter upregulation, impaired endosomal processing, BCL2 upregulation, and IFN-pathway blunting [INFERRED].","approach":"Interrogate NCT01896999 and NCT05675410 banked specimens: CD30 H-score, 9p24.1 copy number, B2M/HLA-I, and now pre/post-treatment Treg (FOXP3+CD30+) depletion and IFN-response signature as depth-of-response correlates; ctDNA clearance and on-treatment biopsy as endpoints. Both agents approved.","level":"CANDIDATE","confidence":0.72,"citations":[{"kind":"NCT","id":"NCT01896999","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05675410","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42432844","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42070121","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42355593","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41762706","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42122242","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":47,"lastVisit":3,"lastNote":"Promoted: new independent evidence this visit that BV's mechanism includes CD30+ Treg depletion and DC/CD8 activation (PMID:41762706), plus HRS phenotype confirmation (PMID:42122242). Real-world attenuation (PMID:42432844) still frames this as a selection problem.","history":[{"visit":3,"cycle":181,"status":"STRENGTHENED","note":"Promoted: new independent evidence this visit that BV's mechanism includes CD30+ Treg depletion and DC/CD8 activation (PMID:41762706), plus HRS phenotype confirmation (PMID:42122242). Real-world attenuation (PMID:42432844) still frames this as a selection problem."},{"visit":1,"cycle":47,"status":"NEW","note":"New this visit. Real-world cohort PMID:42432844 tempers the effect size: BV-containing regimens in R/R cHL gave ORR 82.5% vs 76.9% (ns), identical CR ~60%, and an EFS gain (22.5 vs 11.2 mo) that lost significance after adjustment — so the lead is framed as a selection problem, not a universal benefit claim."}]},{"id":"L2","title":"Spatial/topological TME architecture as the assignment biomarker for the 10-20% of cHL that fails to reach CR","mechanism":"cHL is a paucicellular tumour whose behaviour is dictated by the surrounding niche: macrophage and Treg proximity to HRS cells, PD-L1+ macrophage-HRS contact zones, and CD8 exclusion determine checkpoint responsiveness [INFERRED]. Digital image analysis and computational pathology now permit objective quantification of these topological relationships and integration with scRNAseq, spatial transcriptomics, liquid biopsy and PET/CT (PMID:42358815).","approach":"Retrospective/prospective correlative overlay on banked biopsies from NCT05675410 and NCT01896999: build a topology score (HRS-macrophage nearest-neighbour distance, PD-L1+ niche density, CD8 infiltration gradient) and test whether it, not IPS, predicts failure to achieve CR and benefit from BV+nivo versus chemotherapy. No new drug exposure required.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42358815","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05675410","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":47,"lastVisit":1,"lastNote":"New this visit; the only pack paper offering HL-specific mechanistic biology. Review-level evidence only — no validated score, no prospective test, so confidence is capped.","history":[{"visit":1,"cycle":47,"status":"NEW","note":"New this visit; the only pack paper offering HL-specific mechanistic biology. Review-level evidence only — no validated score, no prospective test, so confidence is capped."}]},{"id":"L4","title":"PD-1/LAG-3 co-blockade for checkpoint-refractory classical Hodgkin lymphoma stratified by MHC class I/II status","mechanism":"Unchanged: HRS cells frequently lose surface MHC class II while sustaining a CD4-dominant rosette containing LAG-3+ exhausted T cells; PD-1 and LAG-3 enforce exhaustion through non-redundant signalling and dual blockade restores T-cell function in other tumours (PMID:41846252). In cHL, 9p24.1-driven PD-L1/PD-L2 plus LAG-3 ligand availability predicts additive benefit in the PD-1-refractory subset [INFERRED]. Antigen-presentation failure may also be extrinsic (DC cross-presentation suppressed by PGE2/VEGF/IL-6/IL-10), which would blunt any T-cell-checkpoint approach (PMID:41758201).","approach":"Unchanged, but now contingent: before proposing nivolumab+relatlimab in post-PD-1 cHL, quantify LAG-3+ T-cell density and HRS-proximate topology together with MHC-I/II on banked NCT01896999 specimens; if LAG-3 density does not discriminate non-CR, retire in favour of the BCL2/ADC axis.","level":"LEAD","confidence":0.34,"citations":[{"kind":"PMID","id":"41846252","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT01896999","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42070121","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41758201","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":102,"lastVisit":3,"lastNote":"A query aimed specifically at HL + LAG-3/CIITA/PD-1-refractory returned no HL-specific LAG-3 data — an informative null. Lead remains pure pan-tumour extrapolation; one more empty visit and it retires.","history":[{"visit":3,"cycle":181,"status":"WEAKENED","note":"A query aimed specifically at HL + LAG-3/CIITA/PD-1-refractory returned no HL-specific LAG-3 data — an informative null. Lead remains pure pan-tumour extrapolation; one more empty visit and it retires."},{"visit":2,"cycle":102,"status":"NEW","note":"New this visit from P4. Directly addresses open question 6 (pharmacologically re-addressable PD-1 resistance) with approved agents; capped at LEAD because the supporting paper is a pan-tumour mechanistic review with no cHL-specific clinical data."}]},{"id":"L5","title":"Non-internalizing / extracellularly-cleaved CD30 ADC for CD30-low or endocytosis-impaired relapse after brentuximab vedotin","mechanism":"BV requires CD30 binding, internalization and lysosomal cathepsin release. Impaired endosomal processing and upregulated drug efflux transporters are now directly observed in BV-resistant CD30+ malignant cells from paired patient biopsies (PMID:41762706), converting a postulated bottleneck into a measured one; generic ADC-resistance mapping supports the same categories (PMID:41630503, PMID:41090103). Non-internalizing conjugates release payload extracellularly via protease/reduction-triggered linkers and rely on bystander diffusion (PMID:41866709) — attractive in cHL where HRS cells are <1-10% of cellularity and bystander killing of the supportive infiltrate is part of the mechanism (PMID:42","approach":"Build CD30-targeted MMP/legumain- or reduction-triggered extracellular-linker conjugates; benchmark against BV in isogenic CD30-high/low HL lines, in endocytosis-impaired and ABCB1-overexpressing derivatives, and in primary HRS-containing biopsy cultures; pair with non-MMAE payloads insensitive to antimitotic escape given the senescence-like HRS state (PMID:41538304). Define the CD30 H-score threshold below which internalizing ADCs fail.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"41866709","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42070121","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42432844","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42355593","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41762706","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41630503","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41538304","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":102,"lastVisit":3,"lastNote":"Strengthened by patient-derived evidence that impaired endosomal processing plus efflux upregulation are the operative BV-resistance mechanisms in CD30+ lymphoma (PMID:41762706); still no CD30 non-internalizing construct exists, so confidence stays modest.","history":[{"visit":3,"cycle":181,"status":"STRENGTHENED","note":"Strengthened by patient-derived evidence that impaired endosomal processing plus efflux upregulation are the operative BV-resistance mechanisms in CD30+ lymphoma (PMID:41762706); still no CD30 non-internalizing construct exists, so confidence stays modest."},{"visit":2,"cycle":102,"status":"NEW","note":"New this visit from P3. Concept-level only — the source is a linker-technology review with no CD30 or HL construct; value is that it names a synthetic solution to the exact resistance route predicted for L1."}]},{"id":"L6","title":"CD30 ADC + BCL2 inhibition to break the senescence/apoptosis-resistant HRS state","mechanism":"Purified primary pediatric HRS cells show upregulated senescence genes with coordinate downregulation of proapoptotic and mitosis genes, and venetoclax augments HRS apoptosis ex vivo (PMID:41538304) — an intrinsic apoptotic block that also explains why an antimitotic payload (MMAE) underperforms in a low-proliferation, senescence-like compartment [INFERRED]. In CD30+ CTCL, BCL2 is upregulated in all tumour cells from non-responding lesions and BV synergises with BCL2 inhibitors (PMID:41762706), nominating BCL2 as the shared node of ADC resistance across CD30+ lymphomas. Senescent-cell antiapoptotic-pathway logic predicts co-dependence on BCL-xL/MCL1 [SPECULATIVE]. Therapeutic window is the c","approach":"BH3 profiling and BCL2/BCL-xL/MCL1 protein IHC on primary HRS cells and paired BV-exposed biopsies; test BV ± venetoclax (and MCL1/BCL-xL inhibitors) in CD30-high/low HL lines and primary HRS-containing biopsy cultures, reading HRS kill versus off-target loss of rosetting CD4/CD8 T cells and macrophages; define pulsed/intermittent venetoclax schedules that preserve T-cell viability before any clinical proposal in R/R post-BV/post-PD-1 cHL.","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"41538304","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41762706","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41090103","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":181,"lastVisit":3,"lastNote":"New from P3+P8: first HL-primary-cell pharmacology in this programme plus independent BV/BCL2i synergy in a CD30+ lymphoma. Capped at LEAD — HL data are pediatric, ex vivo, and immune-cell apoptosis is an explicit window liability.","history":[{"visit":3,"cycle":181,"status":"NEW","note":"New from P3+P8: first HL-primary-cell pharmacology in this programme plus independent BV/BCL2i synergy in a CD30+ lymphoma. Capped at LEAD — HL data are pediatric, ex vivo, and immune-cell apoptosis is an explicit window liability."}]}],"retired":[{"title":"NK-directed targeting of MHC-I-deficient HRS cells (CD30 NK engagers / CAR-NK)","note":"Retired as pre-announced: no HL-specific supporting datum across three evidence-bearing visits and the only HL-relevant genetic evidence contradicts the missing-self premise. Recorded so the desk does not re-generate it.","cycle":181,"ts":"2026-08-20T00:38:01.845Z"}],"nextQueries":["(\"Hodgkin\" AND (venetoclax OR BCL2 OR \"BH3 profiling\" OR navitoclax OR MCL1)) AND SRC:MED AND PUB_YEAR:[2019 TO 2026]","(\"Hodgkin\" AND (senescence OR \"cell of origin\" OR \"Reed-Sternberg\" ) AND (transcriptome OR \"single-cell\")) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","((\"brentuximab\" AND (ABCB1 OR \"P-glycoprotein\" OR efflux OR endosomal OR \"CD30 loss\")) AND (Hodgkin OR lymphoma)) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"updatedAt":"2026-08-20T00:38:01.845Z"},{"key":"polycythemia vera","name":"polycythemia vera","mondo":{"id":"MONDO:0009891","name":"acquired polycythemia vera"},"genes":[{"label":"JAK2","kind":"causal"}],"visits":3,"openQuestions":["Do rusfertide/divesiran/sapablursen reduce thrombotic EVENTS in PV, or only phlebotomy frequency — and does iron-restricted microcytosis leave residual thrombotic risk at hematocrit <45% (PMID:42381746)?","Is there any registered or planned MDM2-inhibitor trial in PV (as opposed to MF/AML), and what TP53 NGS depth, VAF threshold and monitoring interval should serve as a pre-specified stopping rule given therapy-promoted multihit TP53 evolutio","What do primary bomedemstat and givinostat PV trial reports show for JAK2 VAF, marrow histology and thrombotic events — versus mere count control equivalent to hydroxyurea?","What is BEBT-507's molecular target and class (NCT07012109), still undisclosed across three consecutive packs?","Is JAK2 V617F VAF change a validated surrogate for thrombosis- or fibrosis-free survival, and what standardised dPCR/NGS thresholds should PV trials pre-specify?","Given 87% of thrombotic events occur at or before PV diagnosis and 90% are arterial, is any clone-directed agent testable in the pre-diagnostic window, or is antithrombotic optimisation the only accessible lever?"],"leads":[{"id":"L1","title":"Selectivity-optimized JAK2 inhibition for molecular (allele-burden) response in JAK2 V617F PV","mechanism":"Somatic JAK2 V617F/exon-12 drives constitutive EPOR/MPL/G-CSFR-JAK-STAT5 signalling in HSCs [SOMATIC][KNOWN]; type I pan-JAK1/2 inhibitors control counts and cytokines but permit heterodimer-mediated inhibitor-persistent signalling and rarely deplete the clone [KNOWN]. A next-generation-selectivity review confirms structural divergence is exploitable but locates the best covalent handle at JAK3 Cys909, not JAK2 (PMID:41907306), so a truly mutant-selective JAK2 chemotype remains unproven; BEBT-507's class is still undisclosed [SPECULATIVE].","approach":"Continue tracking NCT07232290 (flonoltinib 75/100/125 mg) and NCT07012109 with Ruxo-BEAT (NCT02577926) as type I comparator, but the endpoint framework must change: PMID:42176929 shows V617F allele burden correlates with thrombosis/fibrosis non-uniformly and assays are unstandardised, so demand pre-specified digital-PCR/NGS methodology, serial CD34+ colony genotyping, and correlation of VAF change with clinical events rather than treating VAF drop as intrinsic benefit. Resistance: JAK1/TYK2 heterodimer persistence, TET2/DNMT3A/ASXL1 subclones, TP53-driven post-PV MF. Window: JAK2 is obligate for erythro/thrombo/granulopoiesis, so on-target cytopenias bound dosing.","level":"LEAD","confidence":0.4,"citations":[{"kind":"NCT","id":"NCT07232290","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07012109","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT02577926","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41907306","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42176929","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":49,"lastVisit":2,"lastNote":"Weakened twice over: the selectivity review does not identify a JAK2-specific covalent handle or BEBT-507's class (open question 1 unresolved), and the surrogate endpoint the lead was built on (VAF) is itself of unvalidated clinical meaning with unstandardised assays.","history":[{"visit":2,"cycle":103,"status":"WEAKENED","note":"Weakened twice over: the selectivity review does not identify a JAK2-specific covalent handle or BEBT-507's class (open question 1 unresolved), and the surrogate endpoint the lead was built on (VAF) is itself of unvalidated clinical meaning with unstandardised assays."},{"visit":1,"cycle":49,"status":"NEW","note":"New lead from three [NEW] trial registrations; first visit, no literature retrieved, so no corroboration beyond registry entries."}]},{"id":"L2","title":"LSD1/KDM1A inhibition on a hypomethylating backbone to break the MPN stem-cell differentiation block","mechanism":"KDM1A/LSD1 in the GFI1B corepressor complex sustains an immature megakaryocyte/erythroid transcriptional program in MPN progenitors; inhibition forces differentiation with mutant-clone and antifibrotic effects in models [KNOWN]. Two independent reviews now place bomedemstat, an LSD1 inhibitor, among disease-modifying PV agents expected to reduce or eliminate phlebotomy dependence (PMID:40872603, PMID:41144126), so PV applicability is no longer purely extrapolated from advanced MPN. Adding decitabine/cedazuridine layers DNMT1 depletion, plausibly synergistic in TET2/DNMT3A-mutant HMA-sensitive disease [INFERRED].","approach":"Two reads: NCT06661915 (randomised ASTX727 +/- iadademstat in advanced MPN, with mandated marrow biopsy and biospecimens) for the epigenetic-combination question, and primary bomedemstat PV trial reports — which I have not yet retrieved and which the reviews only summarise. Demand JAK2 VAF by standardised dPCR, marrow fibrosis grade, megakaryocyte morphology, and thrombotic events as co-primary correlatives, not count response alone. Window: LSD1 is required for normal erythroid and megakaryocyte maturation, so thrombocytopenia is the predicted on-target dose limit — potentially therapeutic in PV, unlike in MF.","level":"CANDIDATE","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT06661915","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40872603","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41144126","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":49,"lastVisit":3,"lastNote":"Promoted: first PV-specific evidence for the LSD1 class (bomedemstat named as a disease-modifying PV agent in two independent 2025 reviews), converting the previous MF/advanced-MPN extrapolation into an indication-matched hypothesis. Held at 0.5 because the support is review-level, not primary trial data.","history":[{"visit":3,"cycle":182,"status":"STRENGTHENED","note":"Promoted: first PV-specific evidence for the LSD1 class (bomedemstat named as a disease-modifying PV agent in two independent 2025 reviews), converting the previous MF/advanced-MPN extrapolation into an indication-matched hypothesis. Held at 0.5 because the support is review-level, not primary trial data."},{"visit":1,"cycle":49,"status":"NEW","note":"New lead from [NEW] NCI randomized phase 2; note the trial is advanced MPN, so PV-specific applicability is an extrapolation."}]},{"id":"L3","title":"BET/NF-kB inhibition added to JAK inhibition — test extension from myelofibrosis into high-risk PV","mechanism":"BRD4-dependent transcription sustains NF-kB-driven inflammatory cytokine output and megakaryocyte-fibrogenic programs downstream of JAK2 V617F; BET inhibition plus ruxolitinib targets the cytokine circuit JAK inhibition alone does not extinguish [KNOWN].","approach":"Pooled MF combination data now give the class a quantitative signal: BMS-986158 plus ruxolitinib reached SVR35 90% in JAK-inhibitor-naive patients, second only to selinexor, with grade 3/4 thrombocytopenia the tracked class toxicity (PMID:41761659); Novartis pelabresib+ruxolitinib phase 3 (NCT07357727) continues after mixed prior phase 3 experience [KNOWN]. PV-relevant test remains untried: a hydroxyurea-resistant/intolerant PV cohort with thrombotic events and VAF as endpoints. Window: BRD4 is ubiquitously required — GI toxicity and thrombocytopenia are class limits [KNOWN].","level":"LEAD","confidence":0.4,"citations":[{"kind":"NCT","id":"NCT07357727","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41761659","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":49,"lastVisit":2,"lastNote":"First independent efficacy evidence for the BETi+JAKi mechanism (BMS-986158 SVR35 90%), but still entirely MF; cross-indication extension to PV remains inference, so it stays a LEAD.","history":[{"visit":2,"cycle":103,"status":"STRENGTHENED","note":"First independent efficacy evidence for the BETi+JAKi mechanism (BMS-986158 SVR35 90%), but still entirely MF; cross-indication extension to PV remains inference, so it stays a LEAD."},{"visit":1,"cycle":49,"status":"NEW","note":"New but deliberately low-confidence: the only pack citation is an MF trial; cross-indication extension to PV is untested [INFERRED]."}]},{"id":"L4","title":"Hepcidin/hemojuvelin axis as a pharmacologic lever on PV erythrocytosis","mechanism":"Relative hepcidin deficiency permits iron-avid PV erythropoiesis (PMID:41100735); hepcidin mimetics restrict transferrin-bound iron and suppress red-cell mass without phlebotomy's procedural burden. Multiple-dose rusfertide 60 mg SC weekly in healthy subjects produces mechanism-based, injection-site-independent decreases in serum iron, TSAT, hemoglobin and hematocrit with modest accumulation and only injection-site reactions/fatigue/headache (PMID:39888264) [KNOWN]. Independent support for the axis as a general erythron throttle comes from high-altitude polycythemia, where hepcidin suppression plus sustained HIF drives EPO-independent erythrocytosis (PMID:42028782) [INFERRED].","approach":"Still need PV outcome data with thrombotic events as primary interest: a targeted query for rusfertide/divesiran/sapablursen plus thrombosis/viscosity/red-cell-mass returned no event-level data, only PK/PD and narrative reviews positioning hepcidin mimetics as phlebotomy replacements (PMID:40872603). Demand whole-blood viscosity or isotopic red-cell mass alongside hematocrit, event rates, serial VAF, and iron-restriction symptom capture (restless legs, pica, fatigue). Hazard retained: PMID:42381746 documents extensive pulmonary embolism in iron-deficient JAK2+ PV at Hct 45.9%/MCV 66.5 fL, so hematocrit may be a corrupted surrogate under this very intervention.","level":"CANDIDATE","confidence":0.52,"citations":[{"kind":"NCT","id":"NCT05320198","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41100735","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42381746","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39888264","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40872603","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42028782","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":49,"lastVisit":3,"lastNote":"New PK/PD confirms deliverability and dose-independence of injection site, and reviews now position hepcidin mimetics as phlebotomy-displacing; but the thrombotic-event question is untouched, so confidence rises only marginally and no promotion beyond CANDIDATE.","history":[{"visit":3,"cycle":182,"status":"STRENGTHENED","note":"New PK/PD confirms deliverability and dose-independence of injection site, and reviews now position hepcidin mimetics as phlebotomy-displacing; but the thrombotic-event question is untouched, so confidence rises only marginally and no promotion beyond CANDIDATE."},{"visit":2,"cycle":103,"status":"STRENGTHENED","note":"Promoted: new independent Blood review establishes low hepcidin as PV pathophysiology and names three agonists in clinical development, second evidence-bearing visit with new citations. Confidence held at 0.5 rather than higher because the same pack supplies a mechanistic hazard — thrombosis at normal hematocrit in iron-restricted PV."},{"visit":1,"cycle":49,"status":"NEW","note":"New lead built on an inverse-mechanism trial; recorded explicitly so the desk never mis-signs DISC-0974 as a PV agent."}]},{"id":"L5","title":"MDM2 inhibition (p53 reactivation) in TP53-wildtype JAK2 V617F PV","mechanism":"JAK-STAT activation in JAK2 V617F CD34+ progenitors suppresses functionally intact p53 via MDM2 overexpression; MDM2 antagonism (navtemadlin, siremadlin, idasanutlin) reactivates p53 and induces apoptosis of TP53-wild-type mutant progenitors, i.e. clone-directed rather than signalling-directed (PMID:42086932, PMID:41793151) [KNOWN]. Class lessons now explicit: negative phase III in AML, hematologic toxicity as dose limit, TP53-mutant clonal selection as resistance route (PMID:42086932); MPN transformation proceeds via multihit TP53 acquisition promoted by inflammation and by therapy itself (PMID:41939253), so the agent could in principle accelerate the event it aims to prevent [INFERRED].","approach":"Adapt POIESIS (NCT06479135) to PV: hydroxyurea-resistant/intolerant, TP53-WT (deep-coverage NGS, VAF limit of detection pre-specified), randomised add-on to best available cytoreduction with a run-in to isolate drug contribution; endpoints hematocrit control without phlebotomy, symptom score, JAK2 VAF by standardised dPCR, thrombotic events. Serial TP53 NGS at fixed intervals as a stopping rule, not a correlative. Window: p53 is required for normal HSC stress response and gut epithelial turnover — nausea/emesis and thrombocytopenia are on-target and bound dosing; PV patients are long-lived and low-risk-per-year, so a transformation-accelerating hazard is less tolerable than in MF.","level":"CANDIDATE","confidence":0.45,"citations":[{"kind":"PMID","id":"41761659","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41902804","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42086932","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41793151","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41939253","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41144126","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT06479135","verified":false,"isNew":false,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":103,"lastVisit":3,"lastNote":"Promoted on new independent evidence: a dedicated MDM2/myeloid-cancer review confirming the JAK-STAT-MDM2-p53 axis and its failure modes, plus a phase III design template in TP53-WT MF. Confidence capped at 0.45 because PV-specific support remains review-level and PMID:41939253 supplies a therapy-driven TP53-multihit hazard.","history":[{"visit":3,"cycle":182,"status":"STRENGTHENED","note":"Promoted on new independent evidence: a dedicated MDM2/myeloid-cancer review confirming the JAK-STAT-MDM2-p53 axis and its failure modes, plus a phase III design template in TP53-WT MF. Confidence capped at 0.45 because PV-specific support remains review-level and PMID:41939253 supplies a therapy-driven TP53-multihit hazard."},{"visit":2,"cycle":103,"status":"NEW","note":"New lead generated by the ruxolitinib-combination meta-analysis; PV relevance is [INFERRED] from MF activity plus the known MDM2/wild-type-p53 biology of JAK2-mutant progenitors, and the TP53-selection hazard is recorded up front."}]},{"id":"L6","title":"Interferon in PV is a patient-selection problem, not a universal disease-modifier","mechanism":"Ropeginterferon alfa-2b is presumed to deplete JAK2 V617F HSCs via interferon-driven cycling and immune clearance [KNOWN], but pooled RCT evidence (3 trials, 522 patients) shows no statistically significant advantage over hydroxyurea for complete hematologic response, partial molecular response, or JAK2 VAF reduction — benefit was significant only versus phlebotomy alone (PMID:42566639). Molecular response is therefore not a class property of interferon in unselected PV.","approach":"Reframe rather than discard: test whether molecular response is confined to a definable subgroup — low baseline VAF, absent TET2/DNMT3A/ASXL1/TP53 co-mutations, younger patients, and exposure beyond 2-3 years — using standardised dPCR (PMID:42176929) and event endpoints. Single-arm ET data (EXCEED-ET, 60.2% durable modified-ELN response, NCT05482971 as reported in PMID:42306077) cannot substitute for a randomised PV molecular endpoint. Contextual anchor: thrombosis dominates PV outcome and 87% of events occur at or before diagnosis, arterial in 90.7% (PMID:42262970), so pre-diagnostic arterial risk is where any disease-modifying claim must be tested. Window: interferon autoimmunity, depressi","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42566639","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42306077","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42262970","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41902804","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":103,"lastVisit":2,"lastNote":"Recorded specifically as a negative-evidence lead so the desk never again assumes interferon > hydroxyurea on molecular endpoints in unselected PV; the surviving hypothesis is biomarker-defined selection.","history":[{"visit":2,"cycle":103,"status":"NEW","note":"Recorded specifically as a negative-evidence lead so the desk never again assumes interferon > hydroxyurea on molecular endpoints in unselected PV; the surviving hypothesis is biomarker-defined selection."}]},{"id":"L7","title":"HDAC inhibition (givinostat) as non-cytotoxic cytoreduction in JAK2 V617F PV","mechanism":"Class I/II HDAC inhibition suppresses JAK2 V617F-driven erythroid and megakaryocyte colony formation and downmodulates JAK2/STAT5 output by destabilising the mutant signalling module [KNOWN]; givinostat is now positioned in independent reviews as a disease-modifying PV agent capable of sustained hematologic control and reduction of phlebotomy need (PMID:40872603, PMID:41144126). Distinct chemistry and distinct epigenetic node from LSD1 inhibition, so tracked separately rather than folded into L2 [INFERRED].","approach":"Retrieve primary givinostat PV trial data (phase 2 long-term follow-up and any registered phase 3) and ask whether hematologic response is accompanied by JAK2 VAF reduction, marrow histologic change, or event reduction — or is merely count control by another route, in which case it competes with hydroxyurea on toxicity alone. Comparator framing: hydroxyurea-resistant/intolerant PV, since that is the unmet-need cohort. Resistance/window: HDACs are ubiquitously required for normal transcription — thrombocytopenia, diarrhoea, fatigue and QT effects are the class ceiling [KNOWN]; expected escape via TET2/DNMT3A/ASXL1 subclones unaffected by count control.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"40872603","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41144126","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":182,"lastVisit":3,"lastNote":"New lead created because two independent PV-focused reviews in this pack name givinostat alongside hepcidin mimetics, MDM2 and LSD1 inhibitors as disease-modifying candidates; evidence is review-level only, so it enters at the bottom of the ladder pending primary trial retrieval.","history":[{"visit":3,"cycle":182,"status":"NEW","note":"New lead created because two independent PV-focused reviews in this pack name givinostat alongside hepcidin mimetics, MDM2 and LSD1 inhibitors as disease-modifying candidates; evidence is review-level only, so it enters at the bottom of the ladder pending primary trial retrieval."}]}],"retired":[],"nextQueries":["(\"polycythemia vera\") AND (bomedemstat OR givinostat) AND (\"allele burden\" OR JAK2 OR thrombosis OR phlebotomy) AND SRC:MED","(rusfertide OR divesiran OR sapablursen) AND (\"phase 3\" OR VERIFY OR randomized) AND (thrombosis OR \"adverse events\" OR \"iron deficiency\") AND SRC:MED","(\"myeloproliferative\" OR \"polycythemia vera\") AND (\"TP53\" AND (\"clonal selection\" OR \"multihit\" OR \"clonal evolution\")) AND (navtemadlin OR \"MDM2\") AND SRC:MED"],"updatedAt":"2026-08-20T00:41:34.264Z"},{"key":"essential thrombocythemia","name":"essential thrombocythemia","mondo":{"id":"MONDO:0005029","name":"essential thrombocythemia"},"genes":[{"label":"SH2B3","kind":"correlated"},{"label":"CALR","kind":"correlated"},{"label":"TP53","kind":"correlated"},{"label":"JAK2","kind":"correlated"},{"label":"TET2","kind":"correlated"},{"label":"MPL","kind":"correlated"}],"visits":3,"openQuestions":["Does the 21% haemorrhage rate on bomedemstat in ET track platelet nadir/overshoot, or does LSD1 inhibition produce functionally defective megakaryocytes or acquired von Willebrand physiology - and can platelet-guided or intermittent dosing ","What is the magnitude, per-driver-genotype distribution (CALR vs JAK2 V617F vs MPL) and HSC-fraction localisation of the bomedemstat VAF reductions, and does MK-3543-006 (NCT06079879) reproduce them against BAT?","Do the clinical mutCALR TCEs (INCA033989, NCT05936359) achieve the stem-cell-level, serially transplantable mutant depletion demonstrated by DX1-2C11, or only mature-cell debulking - and at what CRS/cytopenia cost in chronic-phase ET?","Which escape routes emerge under mutCALR-directed pressure: epitope-negative CALR clones, MPL/TpoR downregulation, or outgrowth of TET2/ASXL1-mutant CALR-wild-type clones?","Is there any ET-specific evidence that any agent delays post-ET myelofibrosis or leukaemic transformation, and does the Ruxo-BEAT (NCT02577926) high-risk ET arm add anything to the negative ruxolitinib-in-ET record?","Does ropeginterferon molecular response in ET differ by driver genotype, and can a dose-intensified schedule match bomedemstat's allele-burden signal without added toxicity?"],"leads":[{"id":"L1","title":"Mutant-CALR neoepitope-directed immunotherapy in CALR-mutant ET","mechanism":"CALR exon 9 frameshift [SOMATIC] yields a single shared mutant C-terminal neoantigen that binds and activates MPL/TpoR and is displayed on the surface of disease-initiating progenitors; wild-type CALR remains ER-luminal, preserving its essential chaperone/Ca2+ function. The neoantigen is functional and absent from normal physiology (PMID:40857671), so antibody, TCE, CAR T, vaccine and ADC formats can all be clone-restricted.","approach":"Chronic-phase ET: reversible-exposure formats (INCA033989 mono or +ruxolitinib, NCT05936359; TCE) with CALR VAF and HSC-fraction clonality as primary readout, not platelet count; require demonstration of mutant stem/progenitor depletion with durability in serial-transplant-equivalent assays as the preclinical bar set by DX1-2C11 (PMID:41532194). Reserve CAR T (PMID:42384776) for post-ET MF/blast phase. Test IFN priming to raise surface epitope density; pre-specify surveillance for epitope-negative, MPL-low and TET2/ASXL1-mutant CALR-wild-type escape.","level":"DOSSIER","confidence":0.76,"citations":[{"kind":"PMID","id":"42001411","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05936359","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42384776","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42509808","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41532194","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40857671","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"39682299","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":50,"lastVisit":3,"lastNote":"Third evidence-bearing visit with two independent new sources: a murine mutCALR-CD3 bispecific depletes mutant stem/progenitors in CALRdel52 mice with mutant-burden reduction sustained in secondary recipients, and a Blood review consolidates five clone-selective formats. Survived a genuine kill attempt: the same new paper states the two clinical phase 1 TCEs lacked preclinical evidence of HSC depl","history":[{"visit":3,"cycle":183,"status":"STRENGTHENED","note":"Third evidence-bearing visit with two independent new sources: a murine mutCALR-CD3 bispecific depletes mutant stem/progenitors in CALRdel52 mice with mutant-burden reduction sustained in secondary recipients, and a Blood review consolidates five clone-selective formats. Survived a genuine kill attempt: the same new paper states the two clinical phase 1 TCEs lacked preclinical evidence of HSC depl"},{"visit":2,"cycle":104,"status":"STRENGTHENED","note":"Independent new modality: mutCALR CAR T selectively depletes mutCALR+ patient stem cells without harming healthy HSCs, works in a fibrotic chimeroid TME, and improves xenograft survival; a shared CALR exon 9 C-terminus mRNA vaccine design adds a third format and an explicit clonality/escape criterion. Two evidence-bearing visits, four citations -> CANDIDATE."},{"visit":1,"cycle":50,"status":"NEW","note":"New programme lead: review evidence of selective mutant-clone activity with molecular remissions plus an active phase 1 agent; only route in this pack aimed at clonal eradication rather than count control"}]},{"id":"L2","title":"LSD1/KDM1A inhibition to dismantle the megakaryocytic dependency in ET","mechanism":"LSD1 in GFI1B/RCOR corepressor complexes is required for megakaryocyte maturation and MPN progenitor self-renewal [KNOWN]; inhibition reduces platelet and leukocyte output and, per new phase 2 data, lowers CALR/JAK2/MPL VAF independent of driver genotype, implying pressure on the clone and not only on terminal megakaryopoiesis [INFERRED]","approach":"Read out MK-3543-006 (NCT06079879) vs BAT for response, thrombosis, VAF and grade 3/4 cytopenias; in parallel run a dedicated haemostasis substudy (platelet aggregometry, VWF:RCo/antigen ratio, PFA) to determine whether the 21% haemorrhage rate is nadir-driven or reflects LSD1-arrested dysfunctional megakaryocytes; test iadademstat + ASTX727 in advanced/post-ET MF (NCT06661915); consider intermittent or platelet-count-guided dosing to widen the window; report VAF change per driver genotype and in the sorted HSC fraction","level":"CANDIDATE","confidence":0.6,"citations":[{"kind":"NCT","id":"NCT06079879","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06661915","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41758981","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40181550","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":50,"lastVisit":3,"lastNote":"Promoted on the first ET-specific efficacy dataset: 49/64 (77%) response at 24 weeks, 72% durable platelet control, 85% durable WBC control, stable haemoglobin, and VAF reduction in 39/46 (85%) evaluable. Counterweight recorded so the desk does not re-propose uncritically: 47% grade 3/4 AEs and 21% haemorrhagic events by week 24 in a near-normal-life-expectancy disease; VAF magnitude, genotype bre","history":[{"visit":3,"cycle":183,"status":"STRENGTHENED","note":"Promoted on the first ET-specific efficacy dataset: 49/64 (77%) response at 24 weeks, 72% durable platelet control, 85% durable WBC control, stable haemoglobin, and VAF reduction in 39/46 (85%) evaluable. Counterweight recorded so the desk does not re-propose uncritically: 47% grade 3/4 AEs and 21% haemorrhagic events by week 24 in a near-normal-life-expectancy disease; VAF magnitude, genotype bre"},{"visit":1,"cycle":50,"status":"NEW","note":"New: a randomised phase 3 in ET specifically, the most advanced non-JAK asset for this disease; efficacy unreported so confidence capped"}]},{"id":"L3","title":"Ropeginterferon alfa-2b as driver-agnostic clonal control backbone in ET","mechanism":"Type I interferon drives MPN-mutant HSCs out of quiescence and preferentially depletes them, producing hematologic plus molecular responses; durable complete molecular remission is emerging as a disease-modification endpoint rather than a surrogate.","approach":"Use EXCEED-ET (NCT05482971) as backbone/comparator; test a high-initial-dose accelerated-titration (HIDAT) schedule in ET and report molecular response separately for JAK2 V617F, CALR and MPL; combine with a mutCALR-directed agent in CALR ET and with LSD1 inhibition in HU-failure ET.","level":"LEAD","confidence":0.62,"citations":[{"kind":"PMID","id":"42306077","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05482971","verified":false,"isNew":false,"addedVisit":1},{"kind":"PMID","id":"41951941","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41060606","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40646417","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":50,"lastVisit":2,"lastNote":"New reviews consolidate ropegIFN superiority over HU and over phlebotomy-only and legitimise durable CMR as a goal, and report rapid JAK2V617F VAF decline with the HIDAT schedule - but all of this is PV, not ET, and no per-genotype molecular data exist. Only a modest nudge; the ET-specific and CALR/MPL molecular-response gap is unresolved.","history":[{"visit":2,"cycle":104,"status":"STRENGTHENED","note":"New reviews consolidate ropegIFN superiority over HU and over phlebotomy-only and legitimise durable CMR as a goal, and report rapid JAK2V617F VAF decline with the HIDAT schedule - but all of this is PV, not ET, and no per-genotype molecular data exist. Only a modest nudge; the ET-specific and CALR/MPL molecular-response gap is unresolved."},{"visit":1,"cycle":50,"status":"NEW","note":"New: first North American, mutation-agnostic ET dataset including treatment-naive patients; single-arm design and unreported per-genotype molecular data are the limits"}]},{"id":"L4","title":"MDM2 inhibition to reactivate wild-type p53 in chronic-phase MPN","mechanism":"TP53 is typically wild-type in chronic-phase ET [KNOWN]; MDM2 blockade restores p53/p21 signalling, imposing senescence/apoptosis on driver-mutant progenitors","approach":"Test siremadlin ± JAK inhibitor in ET/pre-fibrotic models; monitor TP53-mutant subclone selection and cytopenias; deprioritise until PV data mature","level":"LEAD","confidence":0.32,"citations":[{"kind":"PMID","id":"41761659","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42078583","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41144126","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":50,"lastVisit":3,"lastNote":"Only new support is a narrative PV review listing MDM2 inhibitors among emerging agents; no ET data, and it is now clearly behind L2 for driver-agnostic clonal control. Confidence trimmed to reflect opportunity cost, not new contradiction.","history":[{"visit":3,"cycle":183,"status":"WEAKENED","note":"Only new support is a narrative PV review listing MDM2 inhibitors among emerging agents; no ET data, and it is now clearly behind L2 for driver-agnostic clonal control. Confidence trimmed to reflect opportunity cost, not new contradiction."},{"visit":1,"cycle":50,"status":"NEW","note":"New but weakest: mechanistic support from an MPL-W515L ET model via p53/p21 and clinical signal only in JAK-inhibitor-exposed myelofibrosis (ruxolitinib+siremadlin SVR35 45%); no ET clinical data, and p53 reactivation risks selecting TP53-mutant clones"}]},{"id":"L5","title":"HIF-1-driven GLUT1/GLUT3 glucose-transport dependency in JAK2V617F ET","mechanism":"JAK2 V617F [SOMATIC] induces HIF-1-dependent metabolic reprogramming with increased glycolytic flux; Slc2a1 (GLUT1) and Slc2a3 (GLUT3) loss or pharmacological blockade impairs proliferation and viability and induces apoptosis in JAK2V617F cells, primary patient cells and Jak2V617F knock-in mice, with additive effect alongside ruxolitinib. Normal tissue: GLUT1 is the erythrocyte and blood-brain-barrier transporter (germline haploinsufficiency causes GLUT1-deficiency encephalopathy) and GLUT3 is neuronal [KNOWN] - the window is the central problem.","approach":"Test CNS-sparing/partially selective GLUT1 (or GLUT1+3) inhibitors, and downstream nodes (HIF-1alpha, LDHA, MCT1/4), in JAK2V617F ET progenitor assays and Jak2V617F knock-in mice with platelet count and allele burden as endpoints; combine with ruxolitinib or interferon. Restrict to JAK2V617F ET; CALR/MPL ET is a negative control. Expected resistance: fatty-acid/glutamine oxidation switch, GLUT4/GLUT14 upregulation, HIF-2 compensation.","level":"LEAD","confidence":0.33,"citations":[{"kind":"PMID","id":"42337564","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":104,"lastVisit":2,"lastNote":"New mechanistic lead from this pack; genotype-restricted and window-limited, hence low confidence, but it is the only non-immunological, non-epigenetic vulnerability with in vivo and primary-cell support in the programme.","history":[{"visit":2,"cycle":104,"status":"NEW","note":"New mechanistic lead from this pack; genotype-restricted and window-limited, hence low confidence, but it is the only non-immunological, non-epigenetic vulnerability with in vivo and primary-cell support in the programme."}]}],"retired":[],"nextQueries":["(bomedemstat OR \"MK-3543\" OR \"IMG-7289\") AND (bleeding OR hemorrhage OR \"von Willebrand\" OR \"platelet function\" OR \"allele frequency\") AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","(INCA033989 OR \"JNJ-88549968\" OR \"mutant calreticulin\") AND (\"phase 1\" OR \"first-in-human\" OR \"clinical trial\" OR \"variant allele frequency\") AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","(ropeginterferon OR \"interferon alfa\") AND \"essential thrombocythemia\" AND (CALR OR MPL OR \"molecular response\" OR \"allele burden\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-20T00:44:50.049Z"},{"key":"primary myelofibrosis","name":"primary myelofibrosis","mondo":{"id":"MONDO:0009692","name":"primary myelofibrosis"},"genes":[{"label":"CALR","kind":"causal"},{"label":"MPL","kind":"causal"},{"label":"JAK2","kind":"causal"},{"label":"SH2B3","kind":"causal"},{"label":"TET2","kind":"correlated"}],"visits":3,"openQuestions":["Does mutCALR TCE/CAR efficacy and stem-cell depletion hold in a fibrosis-competent mammalian MF model with marrow reticulin/collagen grade as the endpoint, and do the two human TCE phase 1 programmes show CALR VAF decline without prolonged ","Is the NLRP3 dependency shown for JAK2V617F fibrosis shared by CALR- and MPL-mutant and triple-negative MF, and which agent (canakinumab/anakinra vs small-molecule NLRP3 inhibitor) is the right first test on top of ruxolitinib?","Does the inverse NLRP3-expression/thrombosis association (P10) predict a real vascular hazard of NLRP3 blockade, and how would a trial monitor it alongside the known infection risk?","Can PIM1 inhibition collapse the JAK2V617F-HIF-1 regulon in vivo and reduce fibrosis grade and VAF, and does the HIF1-MPN-BP signature prospectively identify pre-blast-phase patients for enrichment?","Does SENTRY (NCT04562389) selinexor+ruxolitinib survive its randomised control arm, and does response segregate by TP53 wild-type status?","Does the pelabresib phase 3 (NCT07357727) report fibrosis-grade or VAF change, and at what haemoglobin cost?"],"leads":[{"id":"L1","title":"Mutant CALR neoepitope-directed immunotherapy in CALR-mutant PMF","mechanism":"Somatic CALR exon 9 frameshift generates a single shared neomorphic positively charged C-terminus that binds and constitutively activates TpoR/MPL and is displayed on the surface of disease-initiating MPN progenitors only; wild-type CALR is ER-lumenal, so the epitope is absent from the normal proteome [SOMATIC]","approach":"Prioritise surface-protein-directed arms (bispecific T-cell engagers, CAR T, ADCs) over peptide-HLA arms (vaccine/TCR) in advanced disease, because MHC-I antigen-presentation-machinery defects (peptide generation/loading, MHC-I integrity, epigenetic silencing) would spare the antibody-based arms; keep the shared exon 9 mRNA vaccine for lower-risk HLA-defined patients. Endpoints must be CALR VAF and marrow reticulin/collagen grade, not SVR35. Strictly driver-stratified (excludes JAK2/MPL-mutant and most triple-negative). Resistance/toxicity: subclonal CALR, epitope shedding or antigen-density loss in blast phase, T-cell exhaustion in the inflamed fibrotic marrow, ASXL1/TP53-mutant CALR-wild-t","level":"DOSSIER","confidence":0.82,"citations":[{"kind":"PMID","id":"42001411","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42237068","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42384776","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42509808","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41700001","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41532194","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40857671","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41798678","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42038747","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41972741","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":51,"lastVisit":3,"lastNote":"P4 [NEW] is the decisive primary result: murine mutCALR bispecific TCE DX1-2C11 activates T cells within 24h, cuts platelets, depletes mutant stem/progenitor cells in marrow and spleen, and the burden reduction persists in secondary recipients - the stem-cell depletion that the authors state was absent from all prior TCE preclinical work. Independently framed by three NEW 2026 reviews (P1, P5, P6)","history":[{"visit":3,"cycle":184,"status":"STRENGTHENED","note":"P4 [NEW] is the decisive primary result: murine mutCALR bispecific TCE DX1-2C11 activates T cells within 24h, cuts platelets, depletes mutant stem/progenitor cells in marrow and spleen, and the burden reduction persists in secondary recipients - the stem-cell depletion that the authors state was absent from all prior TCE preclinical work. Independently framed by three NEW 2026 reviews (P1, P5, P6)"},{"visit":2,"cycle":105,"status":"STRENGTHENED","note":"Promoted on two independent NEW lines: P7 shows a mutCALR CAR T depletes mutCALR+ stem cells from MF patient samples without harming healthy HSC, improves xenograft survival, and — answering my visit-1 objection — loses no potency in a fibrotic human chimeroid marrow model, plus a method to boost surface mutCALR in accelerated/blast phase; P6 independently anchors a shared CALR exon 9 C-terminus m"},{"visit":1,"cycle":51,"status":"NEW","note":"New lead from P9 review reporting selective activity and molecular remissions across modalities; P3 supplies the driver-frequency denominator (JAK2>CALR>MPL, ~33% triple-negative) that bounds eligibility. Corrects KG anchor: CALR here is somatic, not germline."}]},{"id":"L2","title":"BET bromodomain inhibition (pelabresib) added to ruxolitinib","mechanism":"BRD4-dependent transcription of NF-kB/inflammatory cytokine and TGF-beta programmes in MPN HSPCs and marrow stroma sustains fibrosis and constitutional symptoms independently of JAK-STAT; dual BET + JAK1/2 blockade targets both axes","approach":"Randomised pelabresib+ruxolitinib vs ruxolitinib in JAKi-naive intermediate/high-risk MF (NCT07357727) with marrow fibrosis grade and driver VAF as pre-specified disease-modification endpoints and haemoglobin trajectory as the safety signal to watch. Window/resistance: BRD4 requirement in normal HSC and gut epithelium, thrombocytopenia, MYC-independent bypass, TGF-beta reactivation","level":"LEAD","confidence":0.57,"citations":[{"kind":"NCT","id":"NCT07357727","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41761659","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40192154","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40062529","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":51,"lastVisit":2,"lastNote":"Only incremental: two NEW reviews (P3, P1) place pelabresib among the small set of agents with plausible marrow-fibrosis reversal and restate that current JAKi are anti-inflammatory with no survival/progression benefit, which is the unmet need this lead addresses. No new randomised efficacy or anaemia data, so Q2 remains open.","history":[{"visit":2,"cycle":105,"status":"STRENGTHENED","note":"Only incremental: two NEW reviews (P3, P1) place pelabresib among the small set of agents with plausible marrow-fibrosis reversal and restate that current JAKi are anti-inflammatory with no survival/progression benefit, which is the unmet need this lead addresses. No new randomised efficacy or anaemia data, so Q2 remains open."},{"visit":1,"cycle":51,"status":"NEW","note":"New: fresh phase 3 launched, and P1 pooled BET-inhibitor arm (BMS-986158) gave SVR35 90% in JAKi-naive patients. Effect size is single-arm/pooled, so treated as hypothesis-generating only."}]},{"id":"L3","title":"XPO1 inhibition (selinexor) with ruxolitinib in JAKi-naive MF","mechanism":"XPO1-mediated nuclear export sequesters p53, FOXO and IkB from the nucleus; blockade restores nuclear tumour-suppressor function and dampens NF-kB-driven inflammatory cytokine output in mutant HSPCs, complementing JAK1/2 blockade","approach":"Selinexor 60 mg weekly + ruxolitinib is the declared phase 3 dose; the randomised portion of SENTRY/XPORT-MF-034 (NCT04562389) is the test that matters. Require pre-specified anaemia/thrombocytopenia stopping rules, prophylactic antiemetics, and correlative TP53/ASXL1 sequencing plus marrow fibrosis grade at week 24. Normal-tissue risk high (XPO1 essential in proliferating tissue: nausea, thrombocytopenia, anaemia, weight loss); resistance via XPO1 C528S [KNOWN]","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"41761659","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41785311","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40192154","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":51,"lastVisit":2,"lastNote":"Primary source now in hand: P2 phase 1 (n=24) gives SVR35 79% / TSS50 58% at 60 mg — lower than the 92% pooled figure I flagged as possibly artefactual, and still single-arm — with no DLTs and manageable but real cytopenias. Partially answers Q3 (signal is real but smaller); the TP53-dependence question is untouched by this abstract.","history":[{"visit":2,"cycle":105,"status":"STRENGTHENED","note":"Primary source now in hand: P2 phase 1 (n=24) gives SVR35 79% / TSS50 58% at 60 mg — lower than the 92% pooled figure I flagged as possibly artefactual, and still single-arm — with no DLTs and manageable but real cytopenias. Partially answers Q3 (signal is real but smaller); the TP53-dependence question is untouched by this abstract."},{"visit":1,"cycle":51,"status":"NEW","note":"New from P1: highest pooled SVR35 (92%) and TSS50 (78%) of 13 rux-combinations in JAKi-naive patients, but derived from small single-arm studies without head-to-head control; confidence deliberately held low pending randomised data."}]},{"id":"L4","title":"HO-1/BACH1-NLRP3-IL-1beta axis as anti-fibrotic stromal target","mechanism":"NLRP3 in JAK2V617F-mutant haematopoietic cells (not in JAK2-wild-type radioresistant niche cells) drives IL-1beta/IL-18 release, direct thrombopoiesis, granulocytosis and HSPC expansion despite concurrent pyroptosis, and enhances bone marrow fibrosis and splenomegaly; upstream, HO-1 loss with nuclear BACH1 in MF megakaryocytes de-represses the NLRP3/caspase-1/IL-1beta axis [SOMATIC driver-dependent, cell-intrinsic]","approach":"Repurpose IL-1beta blockade (canakinumab/anakinra) or small-molecule NLRP3 inhibitors as add-on to ruxolitinib, with marrow reticulin/collagen grade, plasma IL-1beta/IL-18/IL-8 and driver VAF as endpoints; test HO-1 induction/BACH1 inhibition preclinically as an upstream alternative. Window: NLRP3/IL-1beta are required for innate antimicrobial defence and infection is a leading cause of MF death, so pre-specify infection stopping rules; additionally pre-specify vascular monitoring because NLRP3 transcript levels were inversely associated with thrombosis in MPN patients","level":"LEAD","confidence":0.58,"citations":[{"kind":"PMID","id":"42476324","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42324204","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41298546","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42000137","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":51,"lastVisit":3,"lastNote":"P2 [NEW] moves this lead out of zebrafish: genetic Nlrp3 deletion in the haematopoietic compartment abolishes IL-1beta/IL-18 elevation and pharmacological NLRP3 blockade in fully established murine JAK2V617F MPN regresses thrombocytosis, splenomegaly AND bone marrow fibrosis - a direct answer to visit-2 Q6 in a mammalian model. Mechanism relocated from stroma to mutant HSPC-intrinsic. Countervaili","history":[{"visit":3,"cycle":184,"status":"STRENGTHENED","note":"P2 [NEW] moves this lead out of zebrafish: genetic Nlrp3 deletion in the haematopoietic compartment abolishes IL-1beta/IL-18 elevation and pharmacological NLRP3 blockade in fully established murine JAK2V617F MPN regresses thrombocytosis, splenomegaly AND bone marrow fibrosis - a direct answer to visit-2 Q6 in a mammalian model. Mechanism relocated from stroma to mutant HSPC-intrinsic. Countervaili"},{"visit":1,"cycle":51,"status":"NEW","note":"New lead from P10 (patient datasets GSE53482/GSE41812, marrow biopsies, zebrafish pharmacology); P7 notes infection as a leading cause of death, which frames the therapeutic-window risk. Model organism only, no mammalian MF efficacy shown."}]},{"id":"L5","title":"LSD1 inhibition plus oral hypomethylation in advanced/accelerated-phase MPN","mechanism":"KDM1A/LSD1 sustains aberrant megakaryocyte and stem-cell self-renewal programmes in MPN; combining with DNMT1 depletion (decitabine/cedazuridine) targets the epigenetically deregulated, JAK-inhibitor-insensitive clone at risk of AML transformation","approach":"Randomised ASTX727 +/- iadademstat in advanced MPN (NCT06661915) with VAF and blast-clearance endpoints; expect on-target thrombocytopenia and anaemia from LSD1's role in normal megakaryo/erythropoiesis, plus resistance via TP53-mutant clone selection","level":"LEAD","confidence":0.33,"citations":[{"kind":"NCT","id":"NCT06661915","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42324205","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":51,"lastVisit":1,"lastNote":"New: randomised phase 2 now recruiting addresses the accelerated/blast-phase gap that guideline therapy (P6) leaves largely unmet. No efficacy data yet.","history":[{"visit":1,"cycle":51,"status":"NEW","note":"New: randomised phase 2 now recruiting addresses the accelerated/blast-phase gap that guideline therapy (P6) leaves largely unmet. No efficacy data yet."}]},{"id":"L6","title":"GLUT1/GLUT3 glucose-transport dependency downstream of HIF-1 in JAK2V617F MPN","mechanism":"JAK2V617F stabilises HIF-1alpha in normoxia and reprograms it into a non-canonical, oxygen-desensitised regulon that diverges from classical hypoxia targets; this regulon (but not canonical HIF signatures) tracks with disease severity, progression and survival in 172 JAK2V617F-MPN patients and contains a blast-phase-transformation subsignature. Downstream, SLC2A1/GLUT1 and SLC2A3/GLUT3 are selective dependencies of JAK2V617F cells by CRISPR and pharmacology, and SLC2A1 expression is independently associated with thrombosis in PV and PMF patients [SOMATIC]","approach":"Use the JAK2V617F-HIF-1 regulon and the HIF1-MPN-BP signature as enrichment/pharmacodynamic biomarkers rather than chasing GLUT1 directly. Preclinical priorities: (i) does the regulon/GLUT dependency exist in CALR/MPL-mutant and triple-negative MF; (ii) does blockade reduce marrow fibrosis grade and driver VAF, not just cell number, in a fibrosis-competent mouse; (iii) is elevated SLC2A1 mechanistically thrombogenic, which would supply a vascular endpoint. Window remains the crux: GLUT1 is the erythrocyte and blood-brain-barrier transporter and germline GLUT1 haploinsufficiency causes encephalopathy [KNOWN], so GLUT3-biased or haematopoietically restricted delivery, or upstream HIF-1/PIM1 ta","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"42337564","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40062529","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41629621","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42000137","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":105,"lastVisit":3,"lastNote":"P9 [NEW] gives the axis a chromatin-level mechanism, a patient-outcome association in 172 JAK2V617F-MPN cases, and a blast-phase signature; P10 [NEW] provides the first human clinical correlate for SLC2A1 in PMF (independent association with thrombosis, OR 2.05). Direct GLUT1 pharmacology still has no clinical-grade selective agent, so the lead is repositioned as biomarker-plus-upstream-node rathe","history":[{"visit":3,"cycle":184,"status":"STRENGTHENED","note":"P9 [NEW] gives the axis a chromatin-level mechanism, a patient-outcome association in 172 JAK2V617F-MPN cases, and a blast-phase signature; P10 [NEW] provides the first human clinical correlate for SLC2A1 in PMF (independent association with thrombosis, OR 2.05). Direct GLUT1 pharmacology still has no clinical-grade selective agent, so the lead is repositioned as biomarker-plus-upstream-node rathe"},{"visit":2,"cycle":105,"status":"NEW","note":"New from P10 — first metabolic lead in this programme, and it addresses the JAK2V617F majority that the CALR immunotherapy lead structurally cannot. Genetic (CRISPR) plus pharmacological plus in vivo evidence in one study, but no clinical-grade selective GLUT inhibitor and a hostile normal-tissue profile keep confidence moderate."}]},{"id":"L7","title":"PIM1 kinase inhibition to collapse the JAK2V617F-HIF-1 regulon","mechanism":"JAK2V617F-induced normoxic HIF-1alpha stabilisation is mediated by PIM1 kinase; PIM1 therefore sits upstream of the disease-associated non-canonical HIF-1 regulon that correlates with severity, progression, survival and blast-phase transformation in JAK2V617F-MPN, offering a druggable node where HIF-1alpha itself and GLUT1 are not [SOMATIC]","approach":"Preclinical: PIM inhibitor (PIM447/TP-3654 class [KNOWN]) alone and with ruxolitinib in Jak2V617F knock-in and fibrosis-competent models, reading out the JAK2V617F-HIF-1 regulon and HIF1-MPN-BP signature as pharmacodynamics plus marrow fibrosis grade and VAF; test whether ruxolitinib-persistent cells are PIM1-dependent (JAK-STAT-independent HIF-1 maintenance). Enrichment strategy: HIF1-MPN-BP-signature-high patients as an accelerated/pre-blast-phase population. Window: PIM1 is broadly expressed in haematopoietic and immune cells with PIM2/PIM3 redundancy, so anaemia, thrombocytopenia and GI toxicity are the expected on-target liabilities [KNOWN]; resistance via PIM2/PIM3 compensation or MYC/","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"41629621","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42337564","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":184,"lastVisit":3,"lastNote":"Created from P9 [NEW]. Attractive because it converts an undruggable transcription factor and a toxic transporter into a kinase target, and because the associated signature is prognostic for blast-phase transformation - a population with no effective therapy. No MPN clinical data in the pack; PIM inhibitor MF trials are background knowledge only [KNOWN] and must be verified with citations next vis","history":[{"visit":3,"cycle":184,"status":"NEW","note":"Created from P9 [NEW]. Attractive because it converts an undruggable transcription factor and a toxic transporter into a kinase target, and because the associated signature is prognostic for blast-phase transformation - a population with no effective therapy. No MPN clinical data in the pack; PIM inhibitor MF trials are background knowledge only [KNOWN] and must be verified with citations next vis"}]},{"id":"L8","title":"Ropeginterferon alfa-2b for clonal interception in early / low-risk primary myelofibrosis","mechanism":"Pegylated interferon alfa preferentially depletes the mutant HSC clone and can reduce driver VAF, potentially acting before the fibrotic/inflammatory cascade is established; ruxolitinib by contrast is anti-inflammatory without demonstrated progression or survival benefit [KNOWN]","approach":"Randomised placebo-controlled phase 3 of ropeginterferon alfa-2b in early or overt PMF at low/intermediate-1 risk (NCT06468033, active, not recruiting) - the only trial in this pack testing whether treating pre-fibrotic disease alters natural history. Endpoints that matter: marrow fibrosis-grade progression, driver VAF trajectory by mutation type, and time to overt MF/blast phase rather than SVR35. Window/risk: interferon autoimmune, hepatic, thyroid and depressive toxicity in an otherwise minimally symptomatic low-risk population is the central ethical and design tension; expect non-response enriched in ASXL1/high-molecular-risk co-mutated clones [INFERRED]","level":"LEAD","confidence":0.35,"citations":[{"kind":"NCT","id":"NCT06468033","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":184,"lastVisit":3,"lastNote":"New from the trials block. Rated low pending any efficacy or correlative data; included because the whole programme otherwise tests advanced disease, and because a positive fibrosis-progression readout would reframe every other lead's target population. Flonoltinib maleate phase 3 vs ruxolitinib (NCT07317700) and phase 2 in JAKi-refractory MF (NCT07443306) noted in the notebook as another-JAK-inhi","history":[{"visit":3,"cycle":184,"status":"NEW","note":"New from the trials block. Rated low pending any efficacy or correlative data; included because the whole programme otherwise tests advanced disease, and because a positive fibrosis-progression readout would reframe every other lead's target population. Flonoltinib maleate phase 3 vs ruxolitinib (NCT07317700) and phase 2 in JAKi-refractory MF (NCT07443306) noted in the notebook as another-JAK-inhi"}]}],"retired":[],"nextQueries":["(PIM1 OR PIM447 OR TP-3654 OR \"PIM kinase\") AND (myelofibrosis OR \"myeloproliferative\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(NLRP3 OR \"IL-1beta\" OR canakinumab OR anakinra OR dapansutrile) AND (myelofibrosis OR \"myeloproliferative neoplasm\") AND (fibrosis OR trial OR CALR) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"bispecific\" OR \"T cell engager\" OR \"CAR T\" OR \"antibody-drug conjugate\") AND (mutCALR OR \"mutant calreticulin\") AND (\"phase 1\" OR \"first-in-human\" OR \"clinical trial\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-20T00:48:41.602Z"},{"key":"systemic mastocytosis","name":"systemic mastocytosis","mondo":{"id":"MONDO:0016586","name":"systemic mastocytosis"},"genes":[{"label":"KIT","kind":"correlated"},{"label":"RUNX1","kind":"correlated"},{"label":"SRSF2","kind":"correlated"},{"label":"ASXL1","kind":"correlated"},{"label":"TET2","kind":"correlated"},{"label":"CBL","kind":"correlated"}],"visits":3,"openQuestions":["In HARBOR (NCT04910685) and Summit (NCT05186753), do elenestinib and bezuclastinib match avapritinib on KIT D816V VAF and tryptase reduction while eliminating the 34% cognitive-effect and 4% intracranial-bleed signals, and do they reproduce","Is dose-attenuated avapritinib plus corticosteroid reproducible as a cytopenia-sparing regimen in thrombocytopenic SM-AHN beyond the single CMML case, and how does its AHN-progression-free survival compare with TKI plus azacitidine?","When KIT inhibition clears an AHN clone (non-D816V SM-AML with RUNX1::RUNX1T1), is that because KIT is the shared founder lesion, and do serial per-mutation VAF/single-cell data show SRSF2/ASXL1/RUNX1/TET2/CBL clones unchanged in D816V dise","What are the documented acquired resistance lesions at progression on avapritinib or bezuclastinib in SM — secondary KIT substitutions, RAS-MAPK reactivation, or BCL2/MCL1 dependence — and is any pharmacologically addressable?","Why do neoplastic mast cells resist graft-versus-leukaemia while the associated AML does not, and does that immune-evasion mechanism (antigen loss, checkpoint ligand expression) suggest a tractable target?","How frequent are non-KIT kinase fusions (FGFR1, PDGFRA/B, JAK2) in KIT D816V-negative SM/mast cell leukaemia, and does fusion-directed therapy outperform ven/aza in that subset?"],"leads":[{"id":"L1","title":"D816V-selective, CNS-restricted KIT inhibition to extend targeted therapy into indolent SM","mechanism":"KIT D816V [SOMATIC] drives ligand-independent KIT autophosphorylation, clonal MC expansion and apoptosis resistance in >95% of SM (PMID:42512272); sustained blockade gives durable AdvSM control (ORR 73%, DOR 58 mo; PMID:41604606) and suppresses both KIT- and FcepsilonRI-dependent activation signalling (PMID:41701410). New: KIT inhibition is disease-modifying at the tissue level in bone, reversing SM osteoporosis and even osteosclerosis (PMID:41677670), which matters most in indolent SM where bone disease is the dominant morbidity in young men. CNS-penetrant blockade carries 34% cognitive-effect and 4% intracranial-bleed liability (PMID:41604606), motivating peripheral restriction in ISM, whi","approach":"Read out HARBOR (NCT04910685) and Summit (NCT05186753) against NCT07264959 ISM natural history for KIT D816V VAF depth and tryptase normalisation; add as co-primary-adjacent endpoints (i) mediator/anaphylaxis event rate per PMID:41701410 and (ii) DXA BMD, fracture incidence and quantitative osteosclerosis regression per PMID:41677670. Pre-specify neurocognitive testing plus CSF/CNS-exposure PK to test whether peripheral restriction eliminates the avapritinib cognitive/ICH signal. Mandate paired biopsies at progression to separate secondary KIT substitutions from RAS-MAPK reactivation or BCL2/MCL1 dependence [SPECULATIVE]. Discontinuation question stays open on the CML template (PMID:42174092","level":"CANDIDATE","confidence":0.86,"citations":[{"kind":"PMID","id":"42512272","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04910685","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05186753","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04996875","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07264959","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41604606","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41961082","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41701410","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42174092","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41677670","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":52,"lastVisit":3,"lastNote":"No HARBOR/Summit data this visit, so deliberately not promoted; strengthened only by PMID:41677670 which supplies a hard, non-VAF organ endpoint (osteoporosis and osteosclerosis reversal) directly in the indolent population the peripherally restricted agents target.","history":[{"visit":3,"cycle":185,"status":"STRENGTHENED","note":"No HARBOR/Summit data this visit, so deliberately not promoted; strengthened only by PMID:41677670 which supplies a hard, non-VAF organ endpoint (osteoporosis and osteosclerosis reversal) directly in the indolent population the peripherally restricted agents target."},{"visit":2,"cycle":106,"status":"STRENGTHENED","note":"Second evidence-bearing visit: mature PATHFINDER efficacy/toxicity quantifies both benefit and the CNS liability that motivates peripheral restriction; PMID:41961082 supplies the counter-argument that CNS penetration matters when disease is intracranial; PMID:41701410 supplies a new anaphylaxis endpoint."},{"visit":1,"cycle":52,"status":"NEW","note":"New lead from this visit's only on-target review plus four SM trials; level capped at LEAD (single evidence-bearing visit)."}]},{"id":"L2","title":"Co-mutant myeloid clone (SRSF2/ASXL1/RUNX1/TET2/CBL) as a KIT-independent compartment in advanced SM and SM-AHN","mechanism":"Spliceosome/epigenetic/TF lesions [SOMATIC] arise on a CHIP background and drive adverse phenotype (PMID:42512272), independently corroborated in a joint allergy-haematology cohort with TET2, SRSF2 P95, DNMT3A R882H clustering (PMID:42004892); PATHFINDER progression was predominantly SM-AHN and AHN-driven (PMID:41604606), and these loss-of-function lesions are not directly druggable (PMID:41378161). New nuance: separability is real but bidirectional — AML relapsed 5 y post allo-HSCT without SM relapse, implying MCs evade GVL while the AHN does not (PMID:41624689); yet in non-D816V KIT SM-AML, avapritinib drove both MC clearance (14.06% to 0.3%) and RUNX1::RUNX1T1 to undetectable (PMID:414734","approach":"Stratify AdvSM trials (Apex NCT04996875, PATHFINDER follow-on) by co-mutation number/VAF with per-mutation serial VAF and single-cell clonal architecture to test whether response is confined to the KIT-mutant MC fraction. Formal-review combination hypothesis shifts from TKI+HMA to dose-attenuated D816V inhibitor plus short-course corticosteroid in thrombocytopenic SM-AHN (PMID:41458267), with TKI+azacitidine reserved and cytopenia burden pre-specified. Endpoint: AHN-progression-free survival. Record as negatives: venetoclax-azacitidine ineffective in KIT-negative MCL (PMID:42180116) and previously in KIT-negative SM-AHN/AML without haematologic recovery (PMID:40950415); do not assume GVL cle","level":"CANDIDATE","confidence":0.75,"citations":[{"kind":"PMID","id":"42512272","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04996875","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41604606","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42004892","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40950415","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41378161","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41458267","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41473436","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41624689","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42180116","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":52,"lastVisit":3,"lastNote":"Three new SM-AHN datapoints: a cytopenia-sparing dose-attenuated avapritinib+dexamethasone case answering my OQ2, an immunological dissociation (AML relapse without SM relapse) supporting compartment separability, and a counter-case where KIT inhibition cleared the AHN fusion clone — the model is now conditional on which driver is shared, not absolute.","history":[{"visit":3,"cycle":185,"status":"STRENGTHENED","note":"Three new SM-AHN datapoints: a cytopenia-sparing dose-attenuated avapritinib+dexamethasone case answering my OQ2, an immunological dissociation (AML relapse without SM relapse) supporting compartment separability, and a counter-case where KIT inhibition cleared the AHN fusion clone — the model is now conditional on which driver is shared, not absolute."},{"visit":2,"cycle":106,"status":"STRENGTHENED","note":"Promoted: PATHFINDER attributes progression predominantly to the AHN, converting an inference into an observation; PMID:42004892 independently corroborates the co-mutation anchor and adds DNMT3A R882H; PMID:41378161 constrains the druggability expectation."},{"visit":1,"cycle":52,"status":"NEW","note":"New; converts the Monarch correlated-gene anchor into an explicit somatic-compartment hypothesis. No pack evidence yet for any combination — flagged speculative."}]},{"id":"L5","title":"Mast-cell-driven bone remodelling as a treatable axis: KIT inhibitor plus approved antiresorptive in indolent SM osteopathy","mechanism":"Neoplastic mast cells promote osteoclastogenesis and suppress osteoblast function, producing osteoporosis and fragility fractures in indolent SM, and in advanced disease drive osteosclerosis; KIT-directed TKIs, avapritinib in particular, reverse both (PMID:41677670). Mechanistically this predicts additive benefit from removing the MC source (KIT blockade) plus blocking the effector arm with approved antiresorptives (bisphosphonate, denosumab) [INFERRED]. Normal-tissue window: RANKL/osteoclast inhibition causes osteonecrosis of the jaw and, for denosumab, rebound resorption on discontinuation [KNOWN]; antiresorptives cannot treat osteosclerosis, so they are complementary rather than substitut","approach":"Repurposing-first pilot: in ISM/SSM with prevalent vertebral fracture or T-score <= -2.5, randomise antiresorptive alone versus antiresorptive plus a peripherally restricted KIT D816V inhibitor (elenestinib, bezuclastinib; NCT04910685, NCT05186753) with DXA/trabecular bone score, quantitative CT osteosclerosis burden, CTX/P1NP turnover markers, and serial tryptase/KIT D816V VAF as correlatives; benchmark natural-history fracture rates against NCT07264959. Test the machine-learning fracture-risk stratification proposed in PMID:41677670 as an enrichment tool. Failure mode: bone benefit tracks MC debulking only, making the antiresorptive redundant once VAF falls [SPECULATIVE].","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"41677670","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT04910685","verified":true,"isNew":false,"addedVisit":3},{"kind":"NCT","id":"NCT05186753","verified":true,"isNew":false,"addedVisit":3},{"kind":"NCT","id":"NCT07264959","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":185,"lastVisit":3,"lastNote":"New this visit from PMID:41677670: bone disease is reframed from a symptom to a measurable, reversible disease-modification endpoint, and it is the morbidity that justifies treating indolent disease at all.","history":[{"visit":3,"cycle":185,"status":"NEW","note":"New this visit from PMID:41677670: bone disease is reframed from a symptom to a measurable, reversible disease-modification endpoint, and it is the morbidity that justifies treating indolent disease at all."}]},{"id":"L6","title":"Driver-agnostic molecular triage of KIT-negative mast cell neoplasms: FGFR1 rearrangement and other kinase fusions","mechanism":"A minority of mast cell neoplasms lack KIT mutation; one primary acute mast cell leukaemia with intractable shock and extensive bone destruction carried an FGFR1 rearrangement, failed venetoclax-azacitidine, and was switched to an FGFR1 inhibitor (PMID:42180116). FGFR1 fusions [SOMATIC] generate constitutive ligand-independent kinase activity in a stem/progenitor clone, the 8p11 myeloid/lymphoid neoplasm paradigm [KNOWN], which would place the driver upstream of the MC compartment and explain both KIT-inhibitor irrelevance and HMA/BCL2 failure. MCL overall remains ~1.5 y median OS with only midostaurin and avapritinib approved (PMID:40904938). Normal-tissue window for FGFR inhibition: FGF23-","approach":"Mandate RNA-based fusion panel plus myeloid NGS in every KIT D816V-negative SM/MCL before committing to ven/aza; where FGFR1 rearrangement is found, treat with an FGFR inhibitor as a bridge to allo-HSCT and report tryptase, MC percentage and fusion transcript kinetics. Predicted resistance: FGFR1 gatekeeper/kinase-domain substitutions and RAS-MAPK bypass [SPECULATIVE]. Note as negatives: ven/aza ineffective here (PMID:42180116) and previously in KIT-negative SM-AHN/AML (PMID:40950415); and non-D816V KIT mutations can still be avapritinib-responsive (PMID:41473436), so KIT-negative must mean fusion/panel-negative, not D816V-negative.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42180116","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40904938","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41473436","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40950415","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":185,"lastVisit":3,"lastNote":"New from a single first-in-literature case; kept low-confidence and framed as a diagnostic-triage hypothesis rather than a drug claim, but it is actionable because the fusion classes involved already have approved inhibitors.","history":[{"visit":3,"cycle":185,"status":"NEW","note":"New from a single first-in-literature case; kept low-confidence and framed as a diagnostic-triage hypothesis rather than a drug claim, but it is actionable because the fusion classes involved already have approved inhibitors."}]}],"retired":[{"title":"BTK inhibition as an FcEpsilonRI-axis-directed strategy in mast cell neoplasms, starting with SM plus lymphoid AHN","note":"Killed as pre-committed at visit 2: two fresh reviews in exactly the relevant space (BTK indications; MC activation signalling) provide no SM or mast cell support, so the single confounded case cannot carry the lead.","cycle":185,"ts":"2026-08-20T00:52:30.900Z"},{"title":"Surface-antigen (CD30 / CD123) targeting of neoplastic mast cells","note":"Killed as pre-committed at visit 1: no cited evidence of SM eligibility or activity; recorded as a negative so the desk stops re-proposing it.","cycle":106,"ts":"2026-08-19T20:16:37.433Z"}],"nextQueries":["(\"systemic mastocytosis\") AND (avapritinib OR elenestinib OR bezuclastinib) AND (\"bone mineral density\" OR osteoporosis OR osteosclerosis OR fracture) AND SRC:MED","(\"systemic mastocytosis\" OR \"mast cell leukemia\") AND (\"KIT D816V\" ) AND (\"resistance\" OR \"progression\" OR \"variant allele frequency\" OR \"single-cell\") AND (avapritinib OR bezuclastinib OR midostaurin) AND SRC:MED","(\"mast cell leukemia\" OR \"systemic mastocytosis\") AND (\"FGFR1\" OR \"8p11\" OR \"PDGFRA\" OR \"JAK2\" OR \"fusion\") AND SRC:MED"],"updatedAt":"2026-08-20T00:52:30.900Z"},{"key":"li-fraumeni syndrome","name":"Li-Fraumeni syndrome","mondo":{"id":"MONDO:0018875","name":"Li-Fraumeni syndrome"},"genes":[{"label":"TP53","kind":"causal"},{"label":"CDKN2A","kind":"correlated"},{"label":"MDM2","kind":"correlated"},{"label":"CHEK2","kind":"correlated"}],"visits":3,"openQuestions":["Are FH-inactivating events in LFS uterine smooth muscle tumours somatic second hits or co-inherited germline HLRCC alleles — resolvable only by paired tumour/germline FH sequencing across the PMID:42312930 and PMID:42328258 cases and regist","Among germline-TP53 tumours with high p53 IHC (67% in PMID:39629784), what fraction have allele-level-confirmed stable missense protein versus cryptic splice/PTC alleles that IHC misclassifies as reactivator-eligible?","Is p.R337H a genuinely distinct therapeutic subclass (HER2-negative, later onset) requiring a different backbone from canonical hotspot-missense LFS breast cancer?","Do germline-TP53 tumours respond to PD-1/PD-L1 blockade at rates comparable to TP53-wild-type matched controls, or does the uncoupled apoptotic programme blunt T-cell-mediated killing as it appears to for CD19 CAR-T?","What fraction of LFS pedigrees carry splice-class alleles (including functional-assay-normal 'missense' calls) once RNA-level testing is applied to registry VUS?","Does short-amplicon/CIN burden predict PLK1/TTK/MPS1 versus ATR/WEE1 sensitivity better than TP53 status alone in germline-TP53 models — still no LFS-specific drug-sensitivity data?"],"leads":[{"id":"L1","title":"ERBB2 amplification as the only recurrent actionable co-driver in germline TP53 breast cancer","mechanism":"LFS breast cancers show near-universal biallelic TP53 loss with HER2 amplification as the main recurrent oncogenic event (PMID:42168203); an independent 82-patient/100-tumour cohort now finds ~50% HER2 positivity, ~half of those ER co-expressing, with no germline-variant-type/histology correlation, and p.R337H carriers uniquely HER2-negative with later onset (PMID:39629784). ERBB2 is low in adult epithelium/cardiomyocytes, giving the familiar cardiac-toxicity-limited window [KNOWN]. Radiation-sparing rationale rests on clinical second-malignancy incidence rather than a generic carrier chromosomal-fragility phenotype, since ex vivo lymphocyte radiosensitivity in breast risk-gene carriers is o","approach":"Reflex HER2 testing (FISH/NGS/HER2-low IHC) on every germline-TP53 breast tumour including pure DCIS (30% of tumours in PMID:39629784); prioritise trastuzumab/pertuzumab, T-DM1, T-DXd, tucatinib and endocrine therapy for the ER+/HER2+ half over anthracycline/taxane-plus-radiotherapy. Stratify by allele: test prospectively whether R337H carriers are truly HER2-null (PMID:39629784) and therefore need a different backbone. Pair with breaks-per-metaphase radiosensitivity assay (>=0.55 B/M) to decide assay-directed vs universal radiation avoidance (PMID:42289459). Resistance: PIK3CA/PTEN loss, p95-HER2 truncation, NRG1-HER3 bypass [KNOWN].","level":"CANDIDATE","confidence":0.68,"citations":[{"kind":"PMID","id":"42168203","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42546295","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41652616","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42289459","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39629784","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":53,"lastVisit":3,"lastNote":"Promoted: second, larger independent cohort reproduces the HER2-enriched phenotype and adds an allele-specific exception (R337H HER2-negative) plus a DCIS-stage testing rationale.","history":[{"visit":3,"cycle":186,"status":"STRENGTHENED","note":"Promoted: second, larger independent cohort reproduces the HER2-enriched phenotype and adds an allele-specific exception (R337H HER2-negative) plus a DCIS-stage testing rationale."},{"visit":2,"cycle":107,"status":"WEAKENED","note":"Radiosensitivity paper undercuts the assumed biological hypersensitivity of carriers (no TP53 arm, effect small, controls overlap); rationale narrowed to clinical second-cancer risk plus an explicit assay-based test. Oncogene-addiction core unchanged."},{"visit":1,"cycle":53,"status":"NEW","note":"New lead created from the multimodal LFS-BC vs sporadic BC comparison; radiation-sparing rationale supplied by the cutaneous ALCL case where radiotherapy was deferred for LFS."}]},{"id":"L2","title":"Short-amplicon chromosomal instability as a synthetic-lethal handle (ATR/WEE1/PKMYT1/KIF18A) in TP53-null LFS tumours","mechanism":"LFS breast cancers carry high short-amplified-segment burden already in situ, escalating with invasion — a replication-stress/breakage-fusion-bridge signature in cells lacking the p53-dependent G1 checkpoint (PMID:42168203), which forces dependence on S/M checkpoints and mitotic error tolerance [KNOWN]. Independent 2025-2026 reviews now nominate the same node set for TP53-mutant breast cancer, explicitly adding the mitotic kinases PLK1 and TTK/MPS1 alongside WEE1/ATR (PMID:41516322), within a broader SL resistance framework (PMID:41537447, PMID:42098732). Tissue support inside LFS: one biallelic-TP53 uterine STUMP with LMS features showed chromosome instability with ATRX and RB1 alterations ","approach":"Screen ceralasertib/camonsertib (ATR), adavosertib (WEE1), lunresertib (PKMYT1), KIF18A inhibitors and now PLK1 (onvansertib) and MPS1 inhibitors in isogenic germline-TP53 breast/osteosarcoma/LMS models stratified by short-amplicon burden; read out micronuclei, cGAS-STING output, single-agent non-genotoxic activity. Test whether amplicon signature outperforms TP53 status as a response biomarker. Resistance: checkpoint cross-adaptation, drug-tolerant persisters [SPECULATIVE].","level":"LEAD","confidence":0.47,"citations":[{"kind":"PMID","id":"42168203","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41917811","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41652616","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41516322","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41537447","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42098732","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42312930","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":53,"lastVisit":2,"lastNote":"Node panel widened to PLK1/TTK on independent review-level nomination for TP53-mutant breast cancer; first LFS-tissue CIN corroboration (ATRX/RB1 STUMP). Still no LFS-specific drug-sensitivity data — remains the weakness to attack.","history":[{"visit":2,"cycle":107,"status":"STRENGTHENED","note":"Node panel widened to PLK1/TTK on independent review-level nomination for TP53-mutant breast cancer; first LFS-tissue CIN corroboration (ATRX/RB1 STUMP). Still no LFS-specific drug-sensitivity data — remains the weakness to attack."},{"visit":1,"cycle":53,"status":"NEW","note":"New lead; node choice is inference from the amplicon phenotype, not demonstrated in LFS tissue — flagged as the main weakness to attack next visit."}]},{"id":"L3","title":"Allele-specific vulnerability of germline TP53 variants: P47S-PIN1 axis and colchicine-site tubulin agents","mechanism":"The African-centric P47S variant [GERMLINE] binds PIN1 more avidly, depleting PIN1-cyclin D1 complexes and sensitising to colchicine-pocket tubulin agents (PMID:41854379), proving that individual germline alleles carry private, non-reactivation vulnerabilities within the mutation-class taxonomy of PMID:41917811. The allele landscape to test is now empirically defined: 77% missense with hotspots at codons 175, 181, 245, 248, 273, 334, 337, plus 12% large rearrangements, 6% truncating, 5% splice-site (PMID:39629784), and R337H already shows a distinct clinical phenotype (later onset, HER2-negative).","approach":"Build the isogenic allele-to-drug map on the empirically prevalent alleles (R175H, R248Q, R273H, R337H, Y220C, plus a null/LGR arm) rather than an arbitrary panel; test colchicine, clinical-stage combretastatin analogues and PIN1 inhibitors (ATRA, KPT-6566) [KNOWN]. Use NCT04541654/NCT01443468 biospecimens for genotype prevalence and to confirm whether R337H segregates a distinct vulnerability set. Normal-tissue risk: tubulin agents hit gut crypts, marrow, neurons — window depends entirely on the PIN1-dependent differential.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"41854379","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41917811","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04541654","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT01443468","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"39629784","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":53,"lastVisit":3,"lastNote":"Modest bump only: the new cohort supplies the real-world allele frequency spectrum and an allele-linked clinical phenotype (R337H), which redefines the panel; no new pharmacology, and P47S remains a low-penetrance hypomorph.","history":[{"visit":3,"cycle":186,"status":"STRENGTHENED","note":"Modest bump only: the new cohort supplies the real-world allele frequency spectrum and an allele-linked clinical phenotype (R337H), which redefines the panel; no new pharmacology, and P47S remains a low-penetrance hypomorph."},{"visit":1,"cycle":53,"status":"NEW","note":"New lead; note P47S is a low-penetrance hypomorph rather than classic LFS, so generalisation to canonical LFS alleles is untested [INFERRED]."}]},{"id":"L4","title":"Restoring apoptotic priming p53-independently: BH3 mimetics and thioredoxin-system collapse in LFS tumours","mechanism":"In LFS breast cancer the pro-apoptotic p53 targets BAX and TP53I3 fail to be upregulated relative to normal breast, unlike sporadic BC (PMID:42168203) — the intrinsic death programme is transcriptionally uncoupled, so death must be forced downstream of p53. The thioredoxin/TrxR1 system is a dual-role redox node whose inhibition triggers apoptosis, ferroptosis and disulfidptosis in tumour cells with high oxidative load (PMID:42155152), and redox depletion is a known mechanism for mutant-p53-directed agents such as APR-246/eprenetapopt [KNOWN].","approach":"Test BCL-2/BCL-xL and MCL-1 inhibitors (venetoclax, navitoclax, MCL-1i) and SMAC mimetics for single-agent and combinatorial activity in germline-TP53 breast/osteosarcoma models; pair with TrxR1 inhibition (auranofin, repurposed) or APR-246 to strip GSH/Trx buffering. Assays: BH3 profiling for dynamic priming, TXNRD1 dependency by CRISPR, lipid-peroxidation readouts. Resistance: MCL-1/BCL-xL reciprocal upregulation, NRF2-driven antioxidant rebound [KNOWN].","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42168203","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42155152","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41917811","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":53,"lastVisit":1,"lastNote":"New lead; the priming defect is measured in LFS tissue but the drug-class link is inference plus a general redox review, so this is the weakest of the four and needs LFS-specific BH3-profiling data.","history":[{"visit":1,"cycle":53,"status":"NEW","note":"New lead; the priming defect is measured in LFS tissue but the drug-class link is inference plus a general redox review, so this is the weakest of the four and needs LFS-specific BH3-profiling data."}]},{"id":"L5","title":"FH-deficient, fumarate-driven metabolic vulnerability in germline-TP53 mesenchymal tumours","mechanism":"FH loss by IHC with inactivating FH variants occurred in 3/8 LFS uterine smooth muscle lesions alongside p53-aberrant/biallelic TP53 inactivation (PMID:42312930), and an independent LFS case carried a large FH-deficient uterine fibroid (PMID:42328258) — germline vs somatic origin unresolved in both abstracts. Fumarate accumulation succinates glutathione and KEAP1, driving constitutive NRF2 antioxidant signalling, pseudohypoxic HIF stabilisation and obligate glycolysis [KNOWN]; oncometabolite-driven transformation from FH and SDH deficiency is also documented in glioma (PMID:41637165). This is a p53-independent, IHC-detectable death route in a disease where the intrinsic apoptotic programme i","approach":"FH plus 2SC succination IHC and FH sequencing (tumour AND germline) on every LFS mesenchymal tumour and registry biospecimen (NCT01443468, NCT04541654) to fix prevalence and origin; FH IHC is already routine in smooth-muscle workup, so this is near-zero-cost (PMID:42466435). Extend FH/SDH/2SC staining to LFS gliomas and choroid plexus tumours (PMID:41637165). Preclinically: FH-null vs FH-proficient TP53-mutant LMS/STUMP models against glycolysis blockade, glutathione/TrxR1 depletion (auranofin, BSO), GPX4 inhibition/system-xc- blockade for ferroptosis (PMID:42318797), HMOX1 inhibition, and HIF-suppressing agents including noncanonical translation-directed ones (PMID:42202639). Window: wild-t","level":"CANDIDATE","confidence":0.52,"citations":[{"kind":"PMID","id":"42312930","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42168203","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42155152","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT01443468","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT04541654","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42328258","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42466435","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42202639","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42318797","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41637165","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":107,"lastVisit":3,"lastNote":"Promoted: second independent LFS patient with an FH-deficient uterine smooth muscle tumour, plus current pharmacology for the pseudohypoxia (HIF) and ferroptosis arms; germline/somatic question still open.","history":[{"visit":3,"cycle":186,"status":"STRENGTHENED","note":"Promoted: second independent LFS patient with an FH-deficient uterine smooth muscle tumour, plus current pharmacology for the pseudohypoxia (HIF) and ferroptosis arms; germline/somatic question still open."},{"visit":2,"cycle":107,"status":"NEW","note":"New lead from the first molecular series of LFS uterine smooth muscle tumours; gives an in-tissue, IHC-detectable metabolic co-lesion and a concrete biomarker for the redox-collapse strategy previously carried only as inference in L4."}]},{"id":"L6","title":"Splice-switching restoration of hypomorphic germline TP53 splice-region alleles","mechanism":"Two independent germline alleles now act by mis-splicing rather than by amino-acid substitution: a homozygous synonymous exon-4 last-nucleotide variant (c.375G>A) causing partial p53 loss and lethal infantile choroid plexus carcinoma (PMID:42283896), and c.671A>C (predicted p.E224A) at the penultimate nucleotide of exon 6, which is wild-type-like in yeast/human functional assays yet skips exon 6 in minigene, generating a frameshift/PTC (PMID:42463867). Coding sequence is intact in the first class, so restoring exon definition should regenerate full-length wild-type p53 — mechanistically distinct from reactivators/degraders (PMID:41917811) [INFERRED]. Consequence for the whole programme: p53 ","approach":"RNA-seq/minigene mapping in patient fibroblasts or iPSC; tile antisense splice-switching oligonucleotides and small-molecule splice modulators across the exon4/intron4 and exon6/intron6 junctions, reading out full-length TP53 mRNA and p21/MDM2 induction after nutlin or irradiation. Near-term deliverable: run RNA-level assays on all VUS/'missense' germline alleles in NCT01443468 and NCT04541654 to quantify the splice-class fraction. Tumour-cell delivery remains the principal obstacle [SPECULATIVE].","level":"CANDIDATE","confidence":0.33,"citations":[{"kind":"PMID","id":"42283896","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41917811","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT01443468","verified":true,"isNew":false,"addedVisit":2},{"kind":"NCT","id":"NCT04541654","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42463867","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"39629784","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":107,"lastVisit":3,"lastNote":"Promoted on genetic, not therapeutic, corroboration: a second splice-defective germline allele with minigene proof, and evidence that functional-assay-normal 'missense' calls can be splicing lesions. Confidence stays low — still no drug data.","history":[{"visit":3,"cycle":186,"status":"STRENGTHENED","note":"Promoted on genetic, not therapeutic, corroboration: a second splice-defective germline allele with minigene proof, and evidence that functional-assay-normal 'missense' calls can be splicing lesions. Confidence stays low — still no drug data."},{"visit":2,"cycle":107,"status":"NEW","note":"New, deliberately low-confidence lead: no drug evidence, single case report, but it names a variant class that p53 reactivators and degraders cannot address and is testable cheaply in patient fibroblasts."}]},{"id":"L7","title":"Chemotherapy-sparing backbone in LFS: oncogene-directed TKIs plus PD-L1-selected checkpoint blockade","mechanism":"LFS tumours must be killed by routes that do not require the p53-dependent apoptotic transcriptional programme, which is uncoupled in LFS breast tissue (BAX/TP53I3 not induced; PMID:42168203). A five-patient germline-TP53 series reports limited conventional chemotherapy benefit with concern for therapy-associated second tumours, and unexpected ICI activity in PD-L1-high tumours (PMID:41498535); an LFS patient with EGFR-mutant NSCLC had durable disease control on osimertinib for 36 months with normal AMH and antral follicle count, i.e. no measurable gonadotoxicity (PMID:42328258). Granzyme/perforin-mediated and receptor-blockade-driven killing are largely p53-independent [INFERRED]; HER2 addi","approach":"Mandate broad NGS plus PD-L1 IHC and TMB on every LFS tumour and test a genotype-directed-first algorithm (EGFR, ERBB2, ALK/ROS1, BRAF) with ICI for PD-L1-high/immune-inflamed tumours, reserving genotoxic chemotherapy and radiotherapy for salvage; embed in registry cohorts NCT01443468, NCT04541654, NCT03050268. Prespecified counter-test: because somatic TP53 alteration predicts poor CD19 CAR-T outcomes, formally compare ICI response rates in germline-TP53 versus TP53-wild-type matched tumours — if impaired apoptotic execution blunts T-cell killing, this lead should be retired. Also quantify gonadotoxicity/fertility endpoints prospectively (PMID:42328258). Resistance: antigen/HLA loss, MDM2 a","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"41498535","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42328258","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"39629784","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42168203","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":186,"lastVisit":3,"lastNote":"New lead from two anecdotal-grade clinical reports; deliberately low confidence, but it names a falsifiable claim (p53-independent immune/targeted killing) and a fertility-preservation advantage that matters in a young-onset syndrome.","history":[{"visit":3,"cycle":186,"status":"NEW","note":"New lead from two anecdotal-grade clinical reports; deliberately low confidence, but it names a falsifiable claim (p53-independent immune/targeted killing) and a fertility-preservation advantage that matters in a young-onset syndrome."}]}],"retired":[],"nextQueries":["(\"germline TP53\" OR \"Li-Fraumeni\") AND (\"immune checkpoint\" OR pembrolizumab OR \"PD-L1\" OR \"CAR-T\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(TP53 OR \"p53\") AND (\"splice-switching\" OR \"antisense oligonucleotide\" OR minigene OR \"exon skipping\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"TP53-mutant\" OR \"p53-null\") AND (PLK1 OR MPS1 OR TTK OR KIF18A OR PKMYT1) AND (sarcoma OR osteosarcoma OR leiomyosarcoma OR \"breast\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-20T00:56:19.585Z"},{"key":"lynch syndrome","name":"Lynch syndrome","mondo":{"id":"MONDO:0005835","name":"Lynch syndrome"},"genes":[{"label":"PMS2","kind":"causal"},{"label":"MLH1","kind":"causal"},{"label":"MSH6","kind":"causal"},{"label":"MSH2","kind":"causal"},{"label":"EPCAM","kind":"causal"},{"label":"TGFBR2","kind":"correlated"},{"label":"KRAS","kind":"correlated"},{"label":"PIK3CA","kind":"correlated"},{"label":"PMS1","kind":"correlated"}],"visits":3,"openQuestions":["From the CaPP3 primary publication: per-dose incidence of new dMMR cancers, the pre-specified non-inferiority margin, and GI-bleed rates at 100/300/600 mg, with MMR-gene and BMI interaction tests.","Is aspirin chemoprevention benefit in Lynch carriers modified by somatic PIK3CA or PTGS2 status of incident lesions, or is the PIK3CA signal confined to sporadic CRC?","What is the prevalence of protein-level MHC-I loss versus allele-resolved B2M/JAK1/JAK2 truncation and HLA LOH in Lynch-associated versus sporadic MSI-H tumours, before and after ICI exposure, and does JAK1 zygosity behave as in endometrial","How often do synchronous or metachronous dMMR adenomas fail to regress in patients achieving complete tumour response to PD-1 blockade, and are non-regressing lesions characterised by WNT/CTNNB1 activation and myeloid dominance rather than ","Beyond 3 years, what are local regrowth and metachronous-cancer rates under watch-and-wait specifically in germline carriers, and does ctDNA/stool testing (NCT05410977) precede endoscopic detection?","Is there primary literature that tumour TGFBR2 A10 frameshift status predicts benefit from TGF-beta-pathway-edited effector cells in MSI-H disease?"],"leads":[{"id":"L1","title":"Low-dose aspirin (100-300 mg) for chemoprevention of dMMR cancers in germline MMR carriers","mechanism":"COX-1/COX-2 inhibition lowers PGE2-EP2/EP4 signalling and WNT-beta-catenin output in colonic crypt stem cells, restraining clonal expansion of MMR-deficient [GERMLINE MLH1/MSH2/MSH6/PMS2/EPCAM] crypts; benefit may concentrate in lesions with PIK3CA [SOMATIC] activation via PGE2-PI3K crosstalk (PMID:42357259) [INFERRED], and PTGS2 mutation was observed in an immune-excluded dMMR adenoma (PMID:42026473).","approach":"Repurposing-first. Still required: CaPP3 per-dose dMMR-cancer incidence, the pre-specified non-inferiority margin, and GI-bleed rates at 100/300/600 mg, with interaction tests by MMR gene and BMI. Add a prospective correlative arm genotyping incident adenomas/cancers for PIK3CA and PTGS2 to test whether aspirin benefit is somatic-genotype-restricted; harmonise with the guideline divergence documented in PMID:42206489 (initiation age 20-35, intervals 1-3 y).","level":"CANDIDATE","confidence":0.7,"citations":[{"kind":"PMID","id":"42425127","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42553833","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42425128","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42556070","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42357259","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42206489","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":54,"lastVisit":3,"lastNote":"Three NEW independent 2026 sources this visit: a Lancet Gastro Hep commentary asserting efficacy of low-dose aspirin in Lynch syndrome (title only, no data), a second-primary-prevention review ranking Lynch aspirin among the strongest evidence, and a NSAID review localising benefit to PIK3CA-mutant CRC. Promoted to CANDIDATE, but the per-dose non-inferiority numbers remain unverified from abstract","history":[{"visit":3,"cycle":187,"status":"STRENGTHENED","note":"Three NEW independent 2026 sources this visit: a Lancet Gastro Hep commentary asserting efficacy of low-dose aspirin in Lynch syndrome (title only, no data), a second-primary-prevention review ranking Lynch aspirin among the strongest evidence, and a NSAID review localising benefit to PIK3CA-mutant CRC. Promoted to CANDIDATE, but the per-dose non-inferiority numbers remain unverified from abstract"},{"visit":1,"cycle":54,"status":"NEW","note":"New this visit from CaPP3 first results; abstract in pack is truncated before the results section, so non-inferiority of 100 mg is NOT established here and must be verified next visit."}]},{"id":"L2","title":"Genotype-agnostic neoadjuvant / immuno-ablative PD-1 blockade as an organ-sparing strategy in Lynch-associated MSI-H tumours","mechanism":"Dense shared frameshift-neoantigen load (TGFBR2 A10, ACVR2A, SLC35F5) drives TIL infiltration and high pCR without resection (PMID:41196394). PMID:42026473 shows the effect is lesion-autonomous: a complete carcinoma response coexisted with a non-responding synchronous dMMR adenoma, so ICI does not sterilise the metachronous field in a carrier.","approach":"Unchanged regimens (nivo+ipi for stage II-III dMMR colon; single-agent PD-1 for locally advanced dMMR rectum) with multimodal response adjudication (PMID:41097680) and ctDNA/stool surveillance (NCT05410977). Explicit amendment: complete responders in germline carriers stay on full-intensity colonoscopic surveillance with polypectomy indefinitely; organ preservation is not field protection. Do not stratify by germline MMR gene (PMID:42001099). Resistance: B2M/JAK1-2 truncation, HLA LOH, immune-excluded WNT-high lesions.","level":"CANDIDATE","confidence":0.72,"citations":[{"kind":"PMID","id":"41460162","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42001099","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42553833","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT02912559","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05410977","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41343101","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41097680","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41710674","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41196394","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":54,"lastVisit":3,"lastNote":"Scope narrowed by NEW PMID:42026473: intra-patient discordance between a fully responding recurrence and a resistant dMMR adenoma caps the 'immuno-ablative' claim to the index lesion. Level held at CANDIDATE; confidence trimmed 0.74 to 0.72.","history":[{"visit":3,"cycle":187,"status":"WEAKENED","note":"Scope narrowed by NEW PMID:42026473: intra-patient discordance between a fully responding recurrence and a resistant dMMR adenoma caps the 'immuno-ablative' claim to the index lesion. Level held at CANDIDATE; confidence trimmed 0.74 to 0.72."},{"visit":2,"cycle":109,"status":"STRENGTHENED","note":"Four NEW independent 2025-26 syntheses this visit: systematic review of 8 prospective trials n=352 (pCR 41-90%), 100% DFS at 2-3y in complete responders, ICI+chemo DFS gain in node-positive dMMR colon. All are reviews, not new primary data; no Lynch-vs-sporadic subgroup; follow-up only 2-3y against Lynch metachronous risk. Promoted to CANDIDATE."},{"visit":1,"cycle":54,"status":"NEW","note":"New; PMID:42001099 closes the door on germline-genotype-stratified ICI selection (n=93, single centre, only excludes large effects)."}]},{"id":"L3","title":"Frameshift-peptide neoantigen vaccination for primary/secondary prevention in MMR carriers","mechanism":"Recurrent coding-microsatellite frameshifts create a shared neoantigen repertoire scaling with MSI, not MMR status (PMID:42108525: 15-57 Nous-209 targets in dMMR/MSI-H, 6-19 in dMMR/MSI-low, 0-2 in MSS). PMID:42026473 now shows antigen supply is not the only bottleneck: a dMMR adenoma with CTNNB1 activation was CD8-poor and ICI-refractory, consistent with beta-catenin-driven dendritic-cell exclusion [KNOWN mechanism, SPECULATIVE here].","approach":"Multivalent FSP vaccine in unaffected carriers with adenoma incidence, dMMR-crypt clearance and ELISPOT endpoints; now add a mandatory lesion-level infiltration readout (CD8/CD68 multiplex IF on all resected adenomas) and CTNNB1/WNT genotyping, so immune-excluded lesions are counted separately from antigen-poor ones. Retain a low-dose aspirin arm for the MSI-low/antigen-poor compartment. Assay MMR-deficient normal crypts for colitis.","level":"CANDIDATE","confidence":0.45,"citations":[{"kind":"PMID","id":"42553833","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41460162","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42108525","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42213481","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41912995","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42026473","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":54,"lastVisit":3,"lastNote":"Weakened by NEW case-level evidence that a premalignant dMMR adenoma can be immune-excluded (myeloid-high, CD8-low, CTNNB1-mutant) and refractory to PD-1 in a patient whose carcinoma responded completely; immunoprevention therefore needs an infiltration endpoint, not only immunogenicity. Still zero human immunogenicity/adenoma-incidence data in carriers.","history":[{"visit":3,"cycle":187,"status":"WEAKENED","note":"Weakened by NEW case-level evidence that a premalignant dMMR adenoma can be immune-excluded (myeloid-high, CD8-low, CTNNB1-mutant) and refractory to PD-1 in a patient whose carcinoma responded completely; immunoprevention therefore needs an infiltration endpoint, not only immunogenicity. Still zero human immunogenicity/adenoma-incidence data in carriers."},{"visit":2,"cycle":109,"status":"STRENGTHENED","note":"NEW primary data (PMID:42108525, 62 lesions from 26 MLH1/MSH2 carriers) supplies the missing antigen-timing biology and defines the coverage gap in MSI-low/MSS lesions. Still zero human immunogenicity or adenoma-incidence endpoint data in carriers, hence CANDIDATE not DOSSIER."},{"visit":1,"cycle":54,"status":"NEW","note":"New but thin: P6 only flags vaccines as promising; no trial data in this pack. Needs dedicated retrieval next visit."}]},{"id":"L4","title":"Exploit the TGFBR2-frameshift asymmetry: TGFBR2-knockout effector cell therapy in MSI-H/dMMR colorectal disease","mechanism":"TGFBR2 (Monarch [SOMATIC] correlate) carries an A10 coding microsatellite biallelically inactivated in most MSI-H colorectal tumours [KNOWN], so tumour cells are already TGF-beta-insensitive while infiltrating NK/T cells remain suppressed by stromal TGF-beta; deleting TGFBR2 in the effector product removes that one-sided brake [INFERRED].","approach":"TROP2-directed CAR-NK with TGFBR2 KO, dual intraperitoneal + intravenous dosing in colorectal peritoneal carcinomatosis (NCT07411599); stratify/biomark by tumour TGFBR2 frameshift and MSI status. Normal tissue: TGFBR2 maintains lymphoid homeostasis and epithelial growth arrest, so germline-like loss risks lymphoproliferation - argues for transient allogeneic NK products over persistent T cells. Resistance: TROP2 antigen loss, TGF-beta-independent stromal suppression (IL-10, adenosine).","level":"LEAD","confidence":0.3,"citations":[{"kind":"NCT","id":"NCT07411599","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42553833","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":54,"lastVisit":1,"lastNote":"New; trial-only evidence, phase 1/2 recruiting, no efficacy data. Mechanistic rationale is mine [INFERRED] and needs literature corroboration.","history":[{"visit":1,"cycle":54,"status":"NEW","note":"New; trial-only evidence, phase 1/2 recruiting, no efficacy data. Mechanistic rationale is mine [INFERRED] and needs literature corroboration."}]},{"id":"L5","title":"MHC-I-independent salvage for ICI-refractory dMMR/MSI-H disease (B2M/JAK-null escape)","mechanism":"Loss of antigen presentation defeats CD8 recognition of frameshift neoantigens and would equally defeat FSP vaccination [KNOWN]. PMID:41071311 shows in 84 ICI-treated endometrial cancers that MHC-I expression predicts PFS while JAK1 loss is zygosity-dependent (heterozygous loss = better survival, homozygous loss = worse), so mutation presence alone misclassifies. PMID:42026473 shows a second, non-genetic escape route in Lynch disease: a CD68-high/CD8-low, NK- and B-poor dMMR adenoma with CTNNB1/NRAS/HLA class II mutations resisted PD-1 blockade while the index carcinoma achieved CR.","approach":"At ICI progression, mandate paired biopsy with MHC-I/HLA class I IHC plus allele-resolved B2M/JAK1/JAK2 and HLA LOH calling; report zygosity, not just variant presence. MHC-I-null: allogeneic NK/CAR-NK (PMID:42082461) or intralesional oncolytic HSV + PD-1 (platform precedent NCT02978625). MHC-I-intact, CD8-excluded, myeloid-high: macrophage/WNT-directed combinations rather than more checkpoint blockade. Normal tissue: NK missing-self spares HLA-intact epithelium; attenuated HSV is locally delivered. Resistance: MICA/B shedding, HLA-E upregulation, adenosine/TGF-beta.","level":"CANDIDATE","confidence":0.42,"citations":[{"kind":"NCT","id":"NCT02978625","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"41710674","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42082461","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41740058","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41071311","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42026473","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":109,"lastVisit":3,"lastNote":"First dMMR/Lynch-specific escape data in the programme (case report, n=1) plus a translational endometrial cohort that overturns the simple 'JAK1 mutant = refractory' assumption. Promoted to CANDIDATE; confidence stays modest because salvage efficacy in dMMR remains entirely untested.","history":[{"visit":3,"cycle":187,"status":"STRENGTHENED","note":"First dMMR/Lynch-specific escape data in the programme (case report, n=1) plus a translational endometrial cohort that overturns the simple 'JAK1 mutant = refractory' assumption. Promoted to CANDIDATE; confidence stays modest because salvage efficacy in dMMR remains entirely untested."},{"visit":2,"cycle":109,"status":"NEW","note":"New this visit to stop the desk assuming universal ICI benefit in dMMR. Evidence is a platform trial in unrelated histologies plus reviews - no dMMR-specific salvage data exists in this pack; deliberately low confidence."}]},{"id":"L6","title":"PGE2-EP2/EP4 blockade as an infiltration-restoring adjunct to immunoprevention in dMMR adenomas","mechanism":"The ICI-resistant Lynch dMMR adenoma in PMID:42026473 carried CTNNB1 and PTGS2 mutations with a CD68-high/CD8-low phenotype; tumour-intrinsic beta-catenin activation and COX-2/PGE2-EP2/EP4 signalling both exclude conventional dendritic cells and polarise myeloid cells [KNOWN mechanisms, SPECULATIVE for this compartment]. Aspirin's documented CRC benefit, enriched in PIK3CA-mutant disease (PMID:42357259), may therefore act partly by reopening antigen presentation rather than purely by anti-proliferative COX inhibition.","approach":"Preclinical first: Lynch-carrier adenoma organoids and Msh2/Mlh1-conditional mouse adenomas treated with aspirin or a selective EP4 antagonist, reading out cDC1 recruitment, CD8 density and clearance of dMMR crypts, with and without FSP vaccination. If positive, this converts the aspirin arm of L3 from an antigen-gap patch into a mechanistic combination partner, testable as a factorial vaccine x aspirin prevention trial with lesion-level immune endpoints. Normal-tissue window: EP2/EP4 loss impairs gastric/renal prostaglandin homeostasis and platelet function - argues for intermittent or luminally restricted dosing.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42026473","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42357259","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42108525","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":187,"lastVisit":3,"lastNote":"New this visit, generated by juxtaposing the PTGS2/CTNNB1-mutant immune-excluded dMMR adenoma with the PIK3CA-restricted aspirin benefit signal. Purely mechanistic inference so far - no direct evidence that aspirin or EP4 blockade alters immune infiltration in human dMMR adenomas.","history":[{"visit":3,"cycle":187,"status":"NEW","note":"New this visit, generated by juxtaposing the PTGS2/CTNNB1-mutant immune-excluded dMMR adenoma with the PIK3CA-restricted aspirin benefit signal. Purely mechanistic inference so far - no direct evidence that aspirin or EP4 blockade alters immune infiltration in human dMMR adenomas."}]}],"retired":[],"nextQueries":["(\"Lynch syndrome\" OR \"mismatch repair\") AND aspirin AND (CAPP3 OR \"dose\") AND (incidence OR \"non-inferiority\" OR bleeding) AND SRC:MED AND PUB_YEAR:[2025 TO 2026]","(dMMR OR \"MSI-H\") AND (adenoma OR \"precancerous\" OR crypt) AND (CTNNB1 OR \"beta-catenin\" OR \"EP4\" OR PTGS2) AND (\"immune evasion\" OR \"T cell exclusion\" OR infiltration) AND SRC:MED","(\"Lynch syndrome\" OR \"MSI-H\") AND (\"frameshift peptide\" OR Nous-209 OR \"neoantigen vaccine\") AND (immunogenicity OR ELISPOT OR \"phase 1\" OR prevention) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-20T00:59:59.149Z"},{"key":"familial adenomatous polyposis","name":"familial adenomatous polyposis","mondo":{"id":"MONDO:0021055","name":"classic familial adenomatous polyposis"},"genes":[{"label":"APC","kind":"causal"}],"visits":3,"openQuestions":["Within FAP-restricted intra-abdominal desmoid, does an active-surveillance-first strategy (as supported by ALTITUDES, PMID:42173035) yield equivalent obstruction-free survival and transplant-listing rates to immediate nirogacestat, and whic","Does the IPAA-associated 1.58-fold desmoid excess (PMID:42594997) hold within APC-genotype and desmoid-family-history strata, and should anticipated desmoid risk change the IRA-versus-IPAA recommendation given IPAA's 0.22 RR for rectal/pouc","In APC-null adenoma epithelium, is JAG1 cleavage ADAM17/ERK-dependent, and does nuclear Jag1-ICD accumulate as an escape mechanism under gamma-secretase inhibition - i.e. is MEKi+GSI non-redundant in Apc-mutant organoids?","In FAP patients already on nirogacestat for desmoid, what happens to duodenal Spigelman stage and pouch polyp burden, and does crypt IHC show secretory differentiation (MUC2/CHGA up, HES1/OLFM4 down)?","Is the C1q/CCL2-macrophage programme seen in APC1311/+ pigs present in human FAP adenomas, and does its magnitude track adenoma proliferation rather than polyp number?","Does the eRapa duodenal signal replicate in NCT06950385, and does REC-4881 (NCT05552755) show epithelial (adenoma-crypt) pERK suppression with any interim polyp-burden data?"],"leads":[{"id":"L1","title":"Intermittent-schedule mTORC1 inhibition (eRapa) targeted at duodenal rather than colorectal polyp burden in FAP","mechanism":"Biallelic APC loss stabilises beta-catenin and drives mTORC1/4E-BP1-dependent translational output in adenomatous epithelium [KNOWN]; rapamycin suppresses this, but continuous low-dose exposure permits feedback AKT/S6K reactivation, which may explain why intermittent cohorts outperformed daily dosing [INFERRED]","approach":"Encapsulated rapamycin 0.5 mg every-other-day or daily-every-other-week; primary endpoint duodenal polyp burden/Spigelman stage in post-colectomy FAP; correlative crypt phospho-4E-BP1/pS6 and pAKT(S473) on paired biopsies to test feedback rebound; phase 3 NCT06950385 as the read-out to watch","level":"LEAD","confidence":0.6,"citations":[{"kind":"PMID","id":"42048421","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06950385","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42101961","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":55,"lastVisit":1,"lastNote":"New this visit. Honest reading of the abstract: primary colorectal endpoint P=0.28 (not significant); only duodenal polyp burden at 6 months reached P=0.04 in pooled intermittent cohorts. Duodenal/pancreatic cancer dominates post-colectomy mortality (PMID:42101961), so the surviving signal is arguably the clinically important one.","history":[{"visit":1,"cycle":55,"status":"NEW","note":"New this visit. Honest reading of the abstract: primary colorectal endpoint P=0.28 (not significant); only duodenal polyp burden at 6 months reached P=0.04 in pooled intermittent cohorts. Duodenal/pancreatic cancer dominates post-colectomy mortality (PMID:42101961), so the surviving signal is arguably the clinically important one."}]},{"id":"L2","title":"Direct beta-catenin:TCF interface blockade (FOG-001) as node-matched therapy for APC-null neoplasia","mechanism":"APC loss removes the destruction-complex brake on beta-catenin; FOG-001 blocks the beta-catenin/TCF interface at the exact lesion [KNOWN]; effector-level data show individual TCF targets can be hit selectively to avoid global Wnt-inhibition toxicity (PMID:42283915).","approach":"Continue passive tracking of NCT05919264 for first tolerated exposure and crypt/bone safety; do not allocate further programme effort until human PD appears. Effector-level strategies (L7, and now the JAG1 arm in L3/L6) carry the prevention-setting hypothesis in the meantime.","level":"LEAD","confidence":0.3,"citations":[{"kind":"NCT","id":"NCT05919264","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42283915","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":55,"lastVisit":3,"lastNote":"Third consecutive visit with registry-only evidence and no safety/PD readout. Target validity unchanged; deprioritised again rather than retired because the node is the disease lesion itself.","history":[{"visit":3,"cycle":188,"status":"WEAKENED","note":"Third consecutive visit with registry-only evidence and no safety/PD readout. Target validity unchanged; deprioritised again rather than retired because the node is the disease lesion itself."},{"visit":2,"cycle":110,"status":"WEAKENED","note":"Second consecutive visit with registry-only evidence and no human safety/PD readout, while an effector-level alternative with Apc-mutant organoid data appeared in the same pack. Target validity unchanged; relative priority and window plausibility down."},{"visit":1,"cycle":55,"status":"NEW","note":"New this visit; registry-only evidence, no human efficacy or safety data in the pack. Therapeutic window, not target validity, is the limiting question."}]},{"id":"L3","title":"MEK1/2 inhibition (REC-4881) in FAP polyposis","mechanism":"MAPK cooperates with deregulated Wnt in Apc-mutant adenoma progression [KNOWN]. A specific, testable node: KRAS/ERK/ADAM17 cleaves the Wnt-target ligand JAG1 to nuclear Jag1-ICD, which drives non-canonical reverse signalling and chemoresistance in the adenoma-to-carcinoma sequence (PMID:41294868). MEK1/2 blockade should collapse this ADAM17-dependent arm, which gamma-secretase inhibition cannot reach [INFERRED].","approach":"Placebo-controlled NCT05552755 with polyp-burden endpoints; correlatives should now include pERK plus ADAM17 and nuclear JAG1-ICD in adenoma versus adjacent normal crypt, to separate epithelial from stromal engagement and to test the reverse-signalling model. If both arms are active, a low-dose MEKi + GSI combination is the node-complete proposal [SPECULATIVE]. Resistance via RAF dimerisation/MEK reactivation; window set by rash and ocular toxicity, compounded by GSI diarrhoea if combined.","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT05552755","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41294868","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":1,"createdCycle":55,"lastVisit":3,"lastNote":"First pack-cited mechanism for this lead (previously background knowledge only) and it is APC/CRC-specific; yields a concrete biomarker pair and a combination hypothesis with L6. Still zero interim clinical data.","history":[{"visit":3,"cycle":188,"status":"STRENGTHENED","note":"First pack-cited mechanism for this lead (previously background knowledge only) and it is APC/CRC-specific; yields a concrete biomarker pair and a combination hypothesis with L6. Still zero interim clinical data."},{"visit":1,"cycle":55,"status":"NEW","note":"New this visit. Only FAP-dedicated randomised trial of a targeted kinase inhibitor in the pack; no interim results available, mechanism-of-action detail is background knowledge not pack-cited."}]},{"id":"L4","title":"ONC201/dordaviprone as a mechanistically orthogonal colorectal adenoma prevention agent","mechanism":"ClpP agonism/DRD2 antagonism triggers mitochondrial proteolysis and integrated stress response with ATF4/CHOP induction, proposed to selectively kill or differentiate transformed colonic epithelium [KNOWN]","approach":"Follow phase 1 NCT05630794 (biopsy and biospecimen endpoints) for evidence of adenoma-selective ISR induction; if positive, test in APC-mutant polyposis mucosa where mTORC1-driven translational load may sensitise to ClpP-mediated proteotoxic stress [SPECULATIVE]","level":"LEAD","confidence":0.25,"citations":[{"kind":"NCT","id":"NCT05630794","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":55,"lastVisit":1,"lastNote":"New, lowest-conviction entry: registry title only, no FAP-specific rationale in the pack. Retained because its mechanism is non-overlapping with Wnt/mTOR/MAPK and its biopsy endpoints will be informative either way.","history":[{"visit":1,"cycle":55,"status":"NEW","note":"New, lowest-conviction entry: registry title only, no FAP-specific rationale in the pack. Retained because its mechanism is non-overlapping with Wnt/mTOR/MAPK and its biopsy endpoints will be informative either way."}]},{"id":"L5","title":"FAP-associated intra-abdominal desmoid: pharmacological control to displace multivisceral/intestinal transplantation","mechanism":"Germline APC loss drives Wnt/beta-catenin-dependent fibroblast proliferation; nirogacestat acts via Notch blockade and Notch-Wnt crosstalk (PMID:40888418, PMID:42192882), sorafenib via multikinase/angiogenic inhibition, methotrexate/vinblastine via antiproliferative cytotoxicity. Surgical anatomy is a modifiable upstream determinant: IPAA lowers rectal/pouch-anal cancer risk (RR 0.22) but raises desmoid incidence (RR 1.58) versus IRA (PMID:42594997), so desmoid burden is partly iatrogenic and partly preventable at the operative-choice level [INFERRED].","approach":"Restrict the systemic-therapy hypothesis to radiologically progressive disease or lesions at anatomic risk (mesenteric root, ureteric encasement, mesenteric pedicle) rather than all incident desmoid, because ALTITUDES showed one third of intra-abdominal DTF managed by active surveillance with EFS comparable to other sites (PMID:42173035). Nirogacestat first-line in that restricted stratum (DeFi 71% progression-risk reduction, PMID:40888418), methotrexate/vinblastine or anthracycline for bulky obstructive disease (PMID:42211606); primary endpoints obstruction-free survival and transplant listing (PMID:42324901, PMID:42577576). Also test prospectively whether IRA-versus-IPAA choice in APC carr","level":"CANDIDATE","confidence":0.5,"citations":[{"kind":"PMID","id":"42324901","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42577576","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42192882","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40888418","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42211606","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42326221","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42173035","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42594997","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40506115","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41948661","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":55,"lastVisit":3,"lastNote":"ALTITUDES active-surveillance arm (EFS comparable to other locations) undercuts the 'treat early, treat all' framing; hypothesis narrowed to progression/anatomic-risk strata. Partially offset by PMID:42594997 showing IPAA raises desmoid risk 1.58-fold while cutting rectal cancer risk, which raises the programme-level value of desmoid pharmacology. Cohort remains non-FAP-restricted.","history":[{"visit":3,"cycle":188,"status":"WEAKENED","note":"ALTITUDES active-surveillance arm (EFS comparable to other locations) undercuts the 'treat early, treat all' framing; hypothesis narrowed to progression/anatomic-risk strata. Partially offset by PMID:42594997 showing IPAA raises desmoid risk 1.58-fold while cutting rectal cancer risk, which raises the programme-level value of desmoid pharmacology. Cohort remains non-FAP-restricted."},{"visit":2,"cycle":110,"status":"STRENGTHENED","note":"Promoted: visit 1 had zero pharmacology, visit 2 supplies phase III/regulatory-level evidence plus an FAP-specific chemotherapy response case. Agents now nominated. Weakness: DeFi was not FAP-restricted and the FAP evidence is case-level."},{"visit":1,"cycle":55,"status":"NEW","note":"New this visit as an unmet-need lead only. Deliberately drug-agnostic: the pack supports the clinical problem (transplant as consensus indication for invasive desmoid) but contains zero pharmacology, which is itself the finding driving next visit's queries."}]},{"id":"L6","title":"Nirogacestat repurposed for duodenal/colorectal adenoma burden in FAP via Notch-blockade-induced secretory differentiation","mechanism":"Notch maintains the proliferative crypt progenitor state; gamma-secretase inhibition forces goblet/secretory differentiation [KNOWN]. JAG1 is itself a Wnt/beta-catenin-TCF target gene, so APC-null epithelium should have constitutive ligand supply, and JAG1 is additionally cleaved by a KRAS/ERK/ADAM17 cascade to nuclear Jag1-ICD driving CSL-independent reverse signalling (PMID:41294868) - a route GSI cannot block [INFERRED]. Notch-Wnt crosstalk is the declared rationale for GSI in Wnt-driven neoplasia (PMID:40888418, PMID:42192882).","approach":"Observational read-out inside the FAP desmoid population already receiving approved nirogacestat - a post-proctocolectomy/IPAA FAP patient on GSI is now documented (PMID:40506115). Add paired duodenal and pouch endoscopy with polyp count and Spigelman stage, using the ENDOPOL chromoendoscopy/virtual-chromoendoscopy protocol as the pouch scoring standard (NCT07726771). Crypt IHC: HES1/OLFM4 down, MUC2/CHGA up as on-target differentiation; add ADAM17 and nuclear JAG1-ICD staining to test for reverse-signalling escape. Pre-test differentiation versus cytostasis in APC-mutant patient-derived organoids. Limits: diarrhoea, ovarian toxicity, Jag1-ICD-mediated adaptation.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"40888418","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42192882","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40506115","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41294868","verified":true,"isNew":true,"addedVisit":3},{"kind":"NCT","id":"NCT07726771","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":110,"lastVisit":3,"lastNote":"Feasibility upgraded from hypothetical to documented (FAP + IPAA patient on GSI, PMID:40506115) and a pouch-surveillance instrument now exists (NCT07726771). PMID:41294868 supplies the Wnt->JAG1 mechanistic link and names the specific resistance route. Held at LEAD, not CANDIDATE, because no adenoma-endpoint data exist in any species.","history":[{"visit":3,"cycle":188,"status":"STRENGTHENED","note":"Feasibility upgraded from hypothetical to documented (FAP + IPAA patient on GSI, PMID:40506115) and a pouch-surveillance instrument now exists (NCT07726771). PMID:41294868 supplies the Wnt->JAG1 mechanistic link and names the specific resistance route. Held at LEAD, not CANDIDATE, because no adenoma-endpoint data exist in any species."},{"visit":2,"cycle":110,"status":"NEW","note":"New this visit. Pack supports Notch-Wnt crosstalk and drug availability only; no adenoma endpoint data exist. Cheap observational read-out inside an already-treated FAP cohort is the reason it is worth carrying."}]},{"id":"L7","title":"TTI1/TTT-complex suppression as Wnt-output synthetic lethality in APC-mutant neoplasia (chemo/ATR sensitisation without global Wnt blockade)","mechanism":"TTI1 is a direct beta-catenin/TCF transcriptional target that maintains the TELO2-TTI1-TTI2 complex and stabilises ATM and ATR; its loss attenuates DNA damage signalling and double-strand break repair, sensitising to 5-FU and oxaliplatin, and piperlongumine phenocopies this pharmacologically in Apc-mutant patient-derived organoids and Apc-mutant models (PMID:42283915)","approach":"Test whether APC-null adenoma/carcinoma cells are selectively dependent on TTT-complex output relative to normal crypt (which has lower beta-catenin/TCF drive), using paired FAP adenoma versus adjacent normal organoids; benchmark piperlongumine against ATR inhibitors (a cleaner pharmacology than a reactive natural product) plus fluoropyrimidine. Node-matched alternative to L2 because it spares physiological crypt and osteoblast Wnt signalling [INFERRED]. Expected resistance: ATM/ATR-independent repair, or TTI1 restoration; expected toxicity: myelosuppression from combined DDR plus antimetabolite blockade [SPECULATIVE]","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42283915","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":110,"lastVisit":2,"lastNote":"New this visit; the pack's only mechanistic (non-review) paper and the only one using Apc-mutant organoids. Framed here as a therapy/chemo-sensitisation axis, not chemoprevention — piperlongumine is not a prevention-grade agent.","history":[{"visit":2,"cycle":110,"status":"NEW","note":"New this visit; the pack's only mechanistic (non-review) paper and the only one using Apc-mutant organoids. Framed here as a therapy/chemo-sensitisation axis, not chemoprevention — piperlongumine is not a prevention-grade agent."}]},{"id":"L8","title":"C1q/CCL2-dependent macrophage remodelling as a proliferation-supporting stromal programme in early APC-mutant polyps","mechanism":"In APC1311/+ pigs, TP53 loss did not change macroscopic polyp burden or growth but reduced polyp-crypt Ki67, stromal IBA1+ macrophage/monocyte-like infiltrate, and CCL2/C1q-family transcripts (PMID:42516388). The parsimonious reading is that a complement-C1q/CCL2-driven myeloid programme is recruited early in APC-null polyps and supports epithelial proliferation, and that TP53 is required to sustain it [INFERRED]; blocking recruitment could be proliferation-lowering chemoprevention independent of Wnt, mTOR and MAPK [SPECULATIVE].","approach":"Quantify IBA1/CD68, C1QA/C1QB, CCL2 and CCR2 in graded human FAP adenomas versus adjacent normal mucosa, stratified by TP53 status, to test whether the porcine relationship holds in human APC-germline tissue. If it does, test CCR2 antagonism or C1q blockade for polyp multiplicity and crypt Ki67 in Apc-Min mice, with normal-tissue window defined by macrophage-dependent mucosal repair and complement-mediated host defence. Caveats: single porcine study, direction of causality unresolved from an abstract, and TP53-null polyps were less proliferative yet not fewer - so the endpoint must be proliferation/progression, not polyp count.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42516388","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":188,"lastVisit":3,"lastNote":"New from the fresh pack; only mechanistic in vivo APC-germline study this visit. Also records a negative: TP53 loss does not increase early polyp burden in APC1311/+ pigs, so TP53 status should not be modelled as an early-burden driver.","history":[{"visit":3,"cycle":188,"status":"NEW","note":"New from the fresh pack; only mechanistic in vivo APC-germline study this visit. Also records a negative: TP53 loss does not increase early polyp burden in APC1311/+ pigs, so TP53 status should not be modelled as an early-burden driver."}]}],"retired":[],"nextQueries":["(\"familial adenomatous polyposis\" OR \"germline APC\" OR \"Apc(Min)\") AND (JAG1 OR Jagged1 OR ADAM17 OR \"Notch intracellular domain\" OR nirogacestat) AND SRC:MED AND PUB_YEAR:[2019 TO 2026]","(\"familial adenomatous polyposis\" OR \"Apc(Min)\" OR \"APC-mutant adenoma\") AND (macrophage OR C1q OR CCL2 OR CCR2 OR complement OR \"tumor microenvironment\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"familial adenomatous polyposis\" AND (\"desmoid\" AND (\"active surveillance\" OR \"wait and see\" OR nirogacestat OR sorafenib) )) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-20T01:03:44.597Z"},{"key":"hereditary breast and ovarian cancer syndrome","name":"hereditary breast and ovarian cancer syndrome","mondo":{"id":"MONDO:0003582","name":"hereditary breast ovarian cancer syndrome"},"genes":[{"label":"BRCA1","kind":"causal"},{"label":"BRCA2","kind":"causal"},{"label":"TP53","kind":"correlated"},{"label":"ATM","kind":"correlated"},{"label":"RAD51D","kind":"correlated"},{"label":"BARD1","kind":"correlated"},{"label":"PALB2","kind":"correlated"},{"label":"CHEK2","kind":"correlated"},{"label":"RAD51","kind":"correlated"},{"label":"PTEN","kind":"correlated"},{"label":"RAD50","kind":"correlated"},{"label":"NBN","kind":"correlated"}],"visits":3,"openQuestions":["Per-gene, zygosity-stratified PARPi ORR/PFS for PALB2, RAD51C, RAD51D, BARD1, ATM, CHEK2 in breast/ovarian cancer - does the biallelic-only benefit from NCT03601923 (PMID:41686836) replicate outside pancreatic cancer?","Any prospective ATR (ceralasertib/camonsertib) or WEE1 readout specifically in ATM- or CHEK2-altered breast/ovarian disease, and does ATM loss-of-function protein status outperform genotype as the selector?","Is there primary (non-review) data on lead time from ctDNA reversion/PARP1/PARG/ABCB1 detection to radiographic progression, and any mechanism-matched switch cohort?","Has RAD51-foci immunofluorescence in geminin+ cycling cells been analytically validated (CV, cutoff, concordance with resolved biallelic status and HRD scar) for treatment gating in non-BRCA genes?","Do POLQ, USP1 or ATR inhibitor combinations with PARPi have 2024-2026 clinical readouts in HRD or PARPi-resistant disease, and does replicative gap load outperform HRD scar as the predictor?","Does either circulating BRCAness classifier survive external held-out validation - if not, retire L2."],"leads":[{"id":"L1","title":"Functional-HRD gating, not gene label, for PARPi in non-BRCA1/2 HBOC genes","mechanism":"PALB2 (BRCA1-BRCA2 bridge) and RAD51C/RAD51D (filament loading) losses phenocopy BRCA-null strand-invasion failure and are synthetically lethal with PARP trapping/fork collapse [KNOWN]; ATM/CHEK2 act upstream in checkpoint signalling and predict PARPi response poorly [KNOWN], being better matched to ATR/WEE1 inhibition. Prospective phase II niraparib in pancreatic cancer selected on germline/somatic BRCA1/BRCA2/PALB2/ATM/CHEK2 PVs gave 6-month PFS 25% but median PFS only 2 months and ORR 14%, and every patient with >=6-month PFS and evaluable zygosity had biallelic DNA-repair inactivation (PMID:41686836, NCT03601923) - monoallelic carrier status is not the actionable unit [INFERRED from abst","approach":"Require somatic zygosity resolution (LOH/second-hit calling) plus RAD51-foci IF in geminin+ cycling tumour cells before PARPi in PALB2/RAD51C/RAD51D/BARD1 carriers; route monoallelic-only or ATM/CHEK2 carriers to ATR (ceralasertib/camonsertib) or WEE1 inhibition +/- platinum instead. Re-analyse NCT03601923 and PARPi registration cohorts with zygosity as the stratifier to estimate per-gene biallelic response rates. Extend to BRCA2 pancreatic disease with platinum induction then PARPi maintenance (PMID:41899580). Expected resistance: BRCA/PALB2/RAD51C reversion alleles, 53BP1/SHLD2 loss, ABCB1 efflux, PARP1 trapping-deficient mutations.","level":"CANDIDATE","confidence":0.72,"citations":[{"kind":"PMID","id":"41528496","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41899580","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41686836","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42589411","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41520277","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT03601923","verified":false,"isNew":false,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":56,"lastVisit":2,"lastNote":"Promoted: two new independent evidence-bearing sources this visit. P3 is the first prospective test of the panel-label-vs-biallelic question and supports the biallelic gate; P10 independently isolates PALB2 as the reliable non-BRCA predictor. ATM-specific failure remains inferred (no per-gene breakdown in abstract).","history":[{"visit":2,"cycle":111,"status":"STRENGTHENED","note":"Promoted: two new independent evidence-bearing sources this visit. P3 is the first prospective test of the panel-label-vs-biallelic question and supports the biallelic gate; P10 independently isolates PALB2 as the reliable non-BRCA predictor. ATM-specific failure remains inferred (no per-gene breakdown in abstract)."},{"visit":1,"cycle":56,"status":"NEW","note":"Opened on P6's formalisation of HBOC as a multigene HRR syndrome with therapy-relevant germline status, plus P5's organ extension to BRCA2 pancreatic risk. P8 (PMID:42272637) would nominally support HRD prostate biology but its 47.5%/55% BRCA1/2 mutation rates with ~65% homozygosity in 40 FFPE blocks are not credible pathogenic burden — weighted near zero, abstract-only."}]},{"id":"L2","title":"Circulating BRCAness signatures (metabolome + miRNA) to enrich and time interception in HBOC carriers","mechanism":"Monoallelic HRR loss is proposed to produce a systemic metabolic/miRNA phenotype separating healthy carriers from non-carriers (PMID:41620477, PMID:41876608), implying haploinsufficiency-driven rewiring [INFERRED]; if causal (one-carbon/NAD+/redox support of replication under reduced HR capacity) it would itself be a chemoprevention target [SPECULATIVE].","approach":"Terminal test only: strict held-out external-cohort revalidation of both classifiers, or identification of the discriminating metabolite classes with a proliferation readout in carrier-derived fallopian-tube/breast organoids. If neither appears next visit, retire. Downstream use (timing RRSO vs salpingectomy-first, NCT02760849) is on hold until validation exists.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"41620477","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41876608","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT02760849","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":56,"lastVisit":3,"lastNote":"Second consecutive evidence-bearing visit with no independent validation; the AUC 0.98 leakage concern is unresolved and this visit's pack contained only registry/cascade-testing trials (NCT04494945, NCT04009148), none biomarker-validating. Confidence cut 0.35 -> 0.25 with an explicit retirement condition.","history":[{"visit":3,"cycle":189,"status":"WEAKENED","note":"Second consecutive evidence-bearing visit with no independent validation; the AUC 0.98 leakage concern is unresolved and this visit's pack contained only registry/cascade-testing trials (NCT04494945, NCT04009148), none biomarker-validating. Confidence cut 0.35 -> 0.25 with an explicit retirement condition."},{"visit":1,"cycle":56,"status":"NEW","note":"New this visit. Deliberately low confidence: P3's AUC 0.98 (95% CI 0.94-1.0) in a 1831-subject biobank smells of overfitting/leakage; the independent 1044-subject correlation (R=0.93) is the part worth chasing. P2 is single-cohort, n small, abstract-only."}]},{"id":"L3","title":"MINAS: tumour-deficiency-matched rather than germline-list-matched therapy","mechanism":"Multilocus inherited neoplasia alleles syndrome (~1.37% of hereditary cancer patients) co-occurs HBOC with Lynch/other syndromes; each primary tumour manifests the deficiency of whichever allele it inactivated biallelically. A BRCA2/MLH1 dual carrier developed an MLH1/PMS2-deficient colonic primary and a luminal A breast cancer that responded completely to ribociclib+letrozole (PMID:42016816) — i.e. the breast lesion behaved as ER-driven, not as HRD, and germline BRCA2 status did not dictate the effective agent.","approach":"Per-lesion molecular triage in MINAS: MMR IHC/MSI and HRD scar on every primary; anti-PD1 for MMRd lesions, PARPi for HR-deficient lesions, CDK4/6+AI for ER+/HR-proficient lesions. Prospectively register MINAS cases to test whether germline-directed single-agent choices underperform lesion-directed choices. Expected resistance: RB1 loss and CDK6/cyclin E1 amplification for CDK4/6i; JAK1/B2M loss for checkpoint blockade.","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"42016816","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":56,"lastVisit":1,"lastNote":"New; single case report (n=1), hypothesis-generating only. Recorded chiefly to stop the desk assuming germline BRCA2 status alone should drive first-line choice in dual-syndrome carriers.","history":[{"visit":1,"cycle":56,"status":"NEW","note":"New; single case report (n=1), hypothesis-generating only. Recorded chiefly to stop the desk assuming germline BRCA2 status alone should drive first-line choice in dual-syndrome carriers."}]},{"id":"L5","title":"Longitudinal ctDNA resistance-mechanism triage on PARPi: reversion vs trapping loss vs efflux vs fork protection","mechanism":"Acquired PARPi resistance partitions into HR restoration (reversion alleles, 53BP1/shieldin loss), reduced PARP trapping (PARP1 mutation, PARG loss), efflux, and fork stabilisation (PMID:40442774, PMID:41772736, PMID:41900841); these routes are not therapeutically interchangeable [INFERRED]. Evidence base remains review-only.","approach":"Unchanged design (8-weekly plasma panel covering BRCA1/2/PALB2/RAD51C reversion breakpoints, TP53BP1/SHLD2/DYNLL1, PARP1, PARG, ABCB1; primary endpoint lead time to radiographic progression; paired RAD51-foci biopsies), but survival now conditional on locating at least one primary cohort reporting reversion-detection lead time or mechanism-matched switching outcomes.","level":"LEAD","confidence":0.32,"citations":[{"kind":"PMID","id":"40442774","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41772736","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41900841","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":111,"lastVisit":3,"lastNote":"Stated visit-2 survival condition (primary ctDNA surveillance cohorts) not met; pack delivered no papers. Weakened 0.40 -> 0.32 to prevent a review stack accruing confidence by repetition.","history":[{"visit":3,"cycle":189,"status":"WEAKENED","note":"Stated visit-2 survival condition (primary ctDNA surveillance cohorts) not met; pack delivered no papers. Weakened 0.40 -> 0.32 to prevent a review stack accruing confidence by repetition."},{"visit":2,"cycle":111,"status":"NEW","note":"New this visit from four convergent resistance reviews. Review-only evidence, so confidence capped; needs primary ctDNA reversion-surveillance cohorts next visit to survive."}]},{"id":"L6","title":"Replicative-gap load, not HRD scar, as the functional PARPi biomarker - and sequence-dependence of platinum/PARPi","mechanism":"A unifying model of PARPi sensitivity centres on unrepaired replicative ssDNA gaps rather than HR status per se, explaining sensitivity in some BRCA-wild-type tumours and resistance in scar-positive ones (PMID:39927794) [INFERRED as clinically untested]. This predicts that agents increasing gap load (POLQ/Pol-theta, USP1, ATR, WEE1 inhibitors) should synergise with PARPi independently of gene label, and that PARP-trapping capacity is co-limiting. Critically, in patient-ascites-derived HGSC lines cultured as organoids and spheroids with RAD51-IF HRD classification, direct concurrent carboplatin+olaparib or +niraparib killed no better than carboplatin alone, while sequential exposures were ord","approach":"Benchmark a gap-load assay (S1-nuclease/EdU comet or fibre-based ssDNA gap quantification) against RAD51 foci and genomic HRD scar in matched HBOC-genotype organoids for prediction of PARPi IC50; test PARPi with POLQ, USP1 and ATR inhibitors in gap-high vs gap-low, HR-proficient lines. For platinum combinations, test induction-then-maintenance ordering only; do not re-propose concurrent full-dose carboplatin+PARPi. Window argument: gap-directed partners spare non-cycling normal tissue but overlap PARPi marrow toxicity - dose-fractionated or intermittent schedules required.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"39927794","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41520277","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41395847","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":111,"lastVisit":2,"lastNote":"New. Records the concurrent carboplatin+PARPi negative from PMID:41520277 so the desk never re-proposes it, and opens the gap-load hypothesis as a testable alternative to HRD scars. Preclinical only.","history":[{"visit":2,"cycle":111,"status":"NEW","note":"New. Records the concurrent carboplatin+PARPi negative from PMID:41520277 so the desk never re-proposes it, and opens the gap-load hypothesis as a testable alternative to HRD scars. Preclinical only."}]}],"retired":[{"title":"Founder-allele cohorts as ready-made, genotype-uniform interception and pharmacodynamic populations","note":"Retired against its own pre-registered kill criterion: this visit's pack delivered no functional or pharmacodynamic data attached to any founder cohort. Infrastructural, not mechanistic; re-open only if PD endpoints (RAD51 foci, gammaH2AX) or reversion surveillance data appear in a founder registry.","cycle":111,"ts":"2026-08-19T20:33:49.288Z"}],"nextQueries":["(PALB2 OR RAD51C OR RAD51D OR BARD1) AND (biallelic OR \"loss of heterozygosity\") AND (olaparib OR niraparib OR talazoparib OR rucaparib)","(ceralasertib OR camonsertib OR adavosertib OR \"ATR inhibitor\") AND (ATM OR CHEK2) AND (breast OR ovarian)","(\"reversion mutation\" OR \"reversion allele\") AND (ctDNA OR \"circulating tumor DNA\") AND (BRCA1 OR BRCA2 OR PALB2)"],"updatedAt":"2026-08-20T01:06:45.591Z"},{"key":"hereditary diffuse gastric cancer","name":"hereditary diffuse gastric cancer","mondo":{"id":"MONDO:0007648","name":"hereditary diffuse gastric adenocarcinoma"},"genes":[{"label":"CDH1","kind":"causal"},{"label":"MAP3K6","kind":"correlated"},{"label":"CTNNA1","kind":"correlated"}],"visits":3,"openQuestions":["Applying the PMID:40033056 buffering framework, which druggable genes are hyperexpressed in CDH1-null/E-cadherin-low DGC and lobular breast and also score as synthetic-lethal partners, and do CDH1- and CTNNA1-null genotypes converge on any ","What fraction of HDGC second hits (and specifically of pT1a SRCC foci) are reversible promoter methylation with an intact retained allele, versus LOH or truncating somatic mutation?","Do CDH1-KO or CDH1/TP53 gastric organoids without KRAS activation remain WNT-niche dependent and Porcupine-inhibitor sensitive, or is diffuse gastric cancer WNT-independent?","What is the membranous alphavbeta6/ITGB6 prevalence and heterogeneity in HDGC prophylactic-gastrectomy pT1a SRCC and advanced poorly cohesive gastric cancer, and is ITGB6 induced by CDH1 or CTNNA1 loss in isogenic epithelium?","Does the STC1-ITGB6-PI3K/AKT-JAK2/STAT3/IL-10 axis operate in diffuse/signet-ring histology, and would ITGB6 blockade reduce M2 polarisation enough to matter for the L3 immunotherapy combination?","Does CTNNA1 loss, like CDH1 loss, act mainly as an invasion/metastasis event with no fitness cost, meaning viability-based dependency screens should be abandoned in favour of invasion and orthotopic readouts?"],"leads":[{"id":"L1","title":"Spindle-orientation dependency as synthetic lethal partner of adherens-junction loss in CDH1/CTNNA1-null gastric epithelium","mechanism":"Germline CDH1/CTNNA1 [GERMLINE] plus a somatic second hit abolishes E-cadherin/alphaE-catenin. PMID:40033056 shows TSG loss is commonly buffered by hyperexpression of synthetic-lethal partners across >9,000 tumours, and that buffered partners give the more robust synthetic-lethal effects, so the tractable query is which genes are hyperexpressed in CDH1/CTNNA1-null DGC and LBC. PMID:41218116 shows CTNNA1 is a metastasis-specific suppressor in engineered colorectal organoids, promoting invasion/migration without any primary-tumour fitness advantage; combined with spindle misorientation on E-cadherin loss (PMID:41517846), this predicts that proliferation-based CRISPR screens are structurally bl","approach":"Step 1: apply the buffering framework (PMID:40033056) plus DepMine (PMID:42203685; DOI:10.5281/zenodo.19570601) to rank genes hyperexpressed in CDH1-mutant/E-cadherin-low and CTNNA1-low gastric and lobular breast tumours that also score as synthetic-lethal partners; require druggability. Step 2: test top hits in isogenic CDH1-KO and CTNNA1-KO gastric lines (PMID:40998418) using invasion/migration and multipolar-division readouts, not viability. Step 3: in vivo orthotopic organoid CRISPR screening in the format of PMID:41218116, and pT1a SRCC organoid intraperitoneal xenografts (PMID:42190666). Kill criterion: if no druggable buffered partner is shared between the two genotypes, retire.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"41517846","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40998418","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42203685","verified":true,"isNew":true,"addedVisit":2},{"kind":"DOI","id":"10.5281/zenodo.19570601","verified":false,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42190666","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40033056","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41218116","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":57,"lastVisit":3,"lastNote":"Reframed on two new papers: buffering (PMID:40033056) supplies a concrete in-silico test to replace the failed dependency query, and PMID:41218116 explains the prior null results by showing CTNNA1 loss is an invasion/metastasis phenotype with no fitness cost. Confidence held, not raised, because still zero CDH1/CTNNA1-specific dependency data.","history":[{"visit":3,"cycle":190,"status":"STRENGTHENED","note":"Reframed on two new papers: buffering (PMID:40033056) supplies a concrete in-silico test to replace the failed dependency query, and PMID:41218116 explains the prior null results by showing CTNNA1 loss is an invasion/metastasis phenotype with no fitness cost. Confidence held, not raised, because still zero CDH1/CTNNA1-specific dependency data."},{"visit":2,"cycle":112,"status":"WEAKENED","note":"Weakened: a query designed to find CDH1/CTNNA1 synthetic-lethal or spindle data in gastric cancer returned none, so two visits have produced no biological support. Retained only because a low-cost computational test (DepMine) now exists; if that returns no convergent dependency next visit, retire."},{"visit":1,"cycle":57,"status":"NEW","note":"New this visit; only mechanistic route in the pack to a directly druggable dependency downstream of tumour-suppressor loss. Explicitly speculative on the drug side - no agent has been tested in HDGC in this pack."}]},{"id":"L2","title":"NMD-based functional classification of CTNNA1 variants as the gate for risk-reducing decisions","mechanism":"CTNNA1-truncating transcripts are degraded by nonsense-mediated decay and tumours lose alphaE-catenin protein, whereas non-truncating transcripts retain function in CTNNA1-humanised Drosophila; DGC risk is 8-fold higher in truncating carriers, and GC/LBC risk is ~5-8-fold lower than in CDH1 carriers (PMID:40998418).","approach":"Deploy a two-tier companion assay - allele-specific transcript/NMD quantification in carrier-derived cells plus Drosophila complementation - to reclassify CTNNA1 VUS, and prospectively link classification to endoscopic-surveillance versus gastrectomy pathways within the CAFE carrier cohort (NCT05126290).","level":"LEAD","confidence":0.6,"citations":[{"kind":"PMID","id":"40998418","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05126290","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41517846","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":57,"lastVisit":1,"lastNote":"New; strongest-evidence lead in the pack but preventive/diagnostic rather than therapeutic. Distinguishes germline predisposition from tumour maintenance explicitly.","history":[{"visit":1,"cycle":57,"status":"NEW","note":"New; strongest-evidence lead in the pack but preventive/diagnostic rather than therapeutic. Distinguishes germline predisposition from tumour maintenance explicitly."}]},{"id":"L3","title":"TLS-induction / Treg-depletion combination required for any immunotherapy in diffuse and signet-ring gastric cancer","mechanism":"SRCC has a quiescent, Treg-enriched, CD8-effector-poor microenvironment with CXCL13-depleted exhausted CD8 cells and no mature tertiary lymphoid structures (PMID:41902313); independently, GSRCC is described as stromal-rich and immunosuppressive with CAF activation, ECM remodelling and complement-cascade dysfunction driving checkpoint-inhibitor resistance (PMID:41250973). Dense stroma additionally raises interstitial pressure and restricts drug penetration (PMID:42125068), so immune-agonist monotherapy is likely to fail on delivery grounds as well as immunological ones [INFERRED].","approach":"No PD-1/PD-L1 monotherapy. Combination arms: CCR8-directed or Fc-engineered anti-CTLA-4 Treg depletion + LTbetaR/STING agonism to nucleate TLS + CXCL13 restoration, layered on CAF/ECM-modulating or vascular-normalising agents. Primary pharmacodynamic endpoints: TLS maturity score, CD8-Tex CXCL13, CAF state, complement deposition; test in poorly cohesive/SRCC and HDGC-derived DGC models.","level":"CANDIDATE","confidence":0.5,"citations":[{"kind":"PMID","id":"41902313","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41250973","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42125068","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":57,"lastVisit":2,"lastNote":"Strengthened by a second, independent SRCC-specific characterisation (PMID:41250973) reaching the same conclusion about immunotherapy resistance from a different dataset, and by addition of a physical drug-delivery axis. Two evidence-bearing visits, three citations.","history":[{"visit":2,"cycle":112,"status":"STRENGTHENED","note":"Strengthened by a second, independent SRCC-specific characterisation (PMID:41250973) reaching the same conclusion about immunotherapy resistance from a different dataset, and by addition of a physical drug-delivery axis. Two evidence-bearing visits, three citations."},{"visit":1,"cycle":57,"status":"NEW","note":"New. Recorded chiefly as a negative-evidence guardrail: single-agent checkpoint blockade in SRCC/DGC is now off the table for this desk unless a fresh paper overturns PMID:41902313."}]},{"id":"L4","title":"Surface-antigen payload delivery (HER2-low ADC, CLDN18.2) as genotype-agnostic systemic option in diffuse gastric cancer","mechanism":"CLDN18.2 is named among the actionable biomarkers of gastric signet-ring cell carcinoma alongside MSMB, AGR2 and GRIN2D (PMID:41250973), consistent with its [KNOWN] enrichment in genomically stable/diffuse GC. Conversely, actionable targets including HER2 are reported absent, heterogeneous or lost in high-grade diffuse, poorly cohesive and signet-ring carcinomas (PMID:42512297), which argues against a HER2-low ADC strategy in this histology. Open variable: whether loss of E-cadherin/alphaE-catenin alters junctional CLDN18.2 localisation and antibody internalisation [INFERRED].","approach":"Quantify CLDN18.2 by IHC/RNA in HDGC-associated DGC and pT1a SRCC foci from prophylactic gastrectomy specimens; test CLDN18.2-directed antibody, ADC and CAR formats in DGC organoids/PDX with isogenic CDH1- and CTNNA1-restored controls, measuring surface density, internalisation rate and cytotoxicity. Expected resistance: antigen loss/heterogeneity, mucin-mediated steric block, low internalisation, payload efflux.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42278208","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41250973","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42512297","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":57,"lastVisit":2,"lastNote":"Reframed: HER2-low sub-arm retired on PMID:42512297 (targets lost in poorly cohesive/signet-ring histology); CLDN18.2 arm strengthened by first SRCC-specific citation. Net confidence up only modestly because no prevalence numbers for HDGC-derived tumours exist in the pack.","history":[{"visit":2,"cycle":112,"status":"STRENGTHENED","note":"Reframed: HER2-low sub-arm retired on PMID:42512297 (targets lost in poorly cohesive/signet-ring histology); CLDN18.2 arm strengthened by first SRCC-specific citation. Net confidence up only modestly because no prevalence numbers for HDGC-derived tumours exist in the pack."},{"visit":1,"cycle":57,"status":"NEW","note":"New but weakest lead: pack evidence is a general GC/GEJ review with no diffuse-type or HDGC-specific data. Flagged for early kill-testing next visit."}]},{"id":"L5","title":"Integrin alphavbeta6 as a histopathology-selectable radiotheranostic target in poorly cohesive/signet-ring and HDGC-derived gastric cancer","mechanism":"alphavbeta6 is an epithelial-restricted, TGF-beta-activating adhesion receptor near-absent in normal adult tissue and nominated for the histologies where HER2/CLDN18.2/MMR options fail (PMID:42512297). New: ITGB6 is functionally engaged in gastric cancer as the receptor for STC1, driving PI3K/AKT proliferation and JAK2/STAT3/IL-10-dependent M2 tumour-associated macrophage polarisation (PMID:42484012) — so blockade may be cytostatic and immune-modulating, linking this lead to the immunosuppressed SRCC microenvironment of L3. Radiotheranostic feasibility is now quantified in another aggressive carcinoma: 43.8% moderate-to-strong and 25% strong (>=50% cells) membranous alphavbeta6 in 48 TNBC ca","approach":"Score membranous alphavbeta6 IHC (same semi-quantitative scheme as PMID:42194054) in HDGC prophylactic-gastrectomy pT1a SRCC foci and advanced poorly cohesive DGC; test ITGB6/alphavbeta6 induction in isogenic CDH1-KO and CTNNA1-KO gastric lines (PMID:40998418); assay whether the STC1-ITGB6 axis operates in diffuse histology (STC1 blockade or ITGB6 knockdown, PI3K/AKT and macrophage IL-10 readouts). If prevalence and homogeneity suffice, evaluate alphavbeta6 peptide radioligands (imaging first) and ADC formats. Expected resistance: patchy expression and antigen-negative clones (explicit in PMID:42194054), on-target uptake in TGF-beta-high fibrotic stroma, renal/salivary radioligand toxicity.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42512297","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40998418","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42484012","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42194054","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":112,"lastVisit":3,"lastNote":"Two new citations: first gastric-specific functional role for ITGB6 (STC1 ligand, PI3K/AKT, M2/IL-10) and first quantitative alphavbeta6 radiotheranostic prevalence dataset in an aggressive carcinoma. Still no gastric/SRCC prevalence numbers, and the TNBC data are cross-histology, so the rise is bounded.","history":[{"visit":3,"cycle":190,"status":"STRENGTHENED","note":"Two new citations: first gastric-specific functional role for ITGB6 (STC1 ligand, PI3K/AKT, M2/IL-10) and first quantitative alphavbeta6 radiotheranostic prevalence dataset in an aggressive carcinoma. Still no gastric/SRCC prevalence numbers, and the TNBC data are cross-histology, so the rise is bounded."},{"visit":2,"cycle":112,"status":"NEW","note":"New this visit. Only pack item offering a target explicitly nominated for poorly cohesive/signet-ring histology; abstract is truncated so the actual prevalence across the 53 cases and any diffuse-type breakdown are unknown — must be verified before this rises."}]},{"id":"L6","title":"Epigenetic reactivation of the methylation-silenced wild-type CDH1 allele as interception in pT1a SRCC in carriers declining gastrectomy","mechanism":"In HDGC the second hit at CDH1 is most commonly promoter hypermethylation, with LOH and somatic mutation less frequent, and epigenetic drugs plus synthetic-lethal approaches are proposed to restore CDH1 function (PMID:40485214). Methylation is reversible, so in lesions where the retained allele is intact-but-silenced, DNMT inhibition could restore E-cadherin and reverse the loss-of-adhesion phenotype that underpins spindle misorientation and progenitor displacement (PMID:41517846) [INFERRED]. The clinical space is now explicit: advanced-DGC lifetime risk revised to 13-19%, about one third of CDH1 carriers decline prophylactic total gastrectomy, and nearly every gastrectomy specimen contains ","approach":"Tier 1: on endoscopic and prophylactic-gastrectomy material, genotype each pT1a SRCC focus for second-hit class (promoter methylation vs LOH vs truncating somatic mutation) and quantify the fraction that is methylation-driven with an intact second allele; correlate with E-cadherin IHC. Tier 2: ex vivo test of low-dose decitabine/azacitidine and DNMT1-selective agents in carrier-derived pT1a SRCC organoids, primary endpoints CDH1 promoter demethylation, E-cadherin membrane restoration, restored cohesion/spindle orientation. Tier 3: only methylation-positive carriers; local/oral low-dose schedules to protect the therapeutic window, since DNMT inhibition in healthy carriers risks myelosuppressi","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"40485214","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"39379994","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41517846","verified":true,"isNew":false,"addedVisit":3},{"kind":"NCT","id":"NCT06726642","verified":true,"isNew":false,"addedVisit":3},{"kind":"NCT","id":"NCT05126290","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":190,"lastVisit":3,"lastNote":"New this visit. First pack evidence that the rate-limiting somatic event in HDGC is pharmacologically reversible, arriving alongside a review that both lowers penetrance estimates and documents a third of carriers refusing gastrectomy — i.e. an unmet-need population for interception rather than cytotoxic therapy. Gated on second-hit class prevalence, which the abstract does not quantify.","history":[{"visit":3,"cycle":190,"status":"NEW","note":"New this visit. First pack evidence that the rate-limiting somatic event in HDGC is pharmacologically reversible, arriving alongside a review that both lowers penetrance estimates and documents a third of carriers refusing gastrectomy — i.e. an unmet-need population for interception rather than cytotoxic therapy. Gated on second-hit class prevalence, which the abstract does not quantify."}]},{"id":"L7","title":"WNT-niche dependence of CDH1-null early gastric lesions as a Porcupine/WNT2B-directed interception target","mechanism":"Gastric fibroblasts secrete canonical WNT2B to sustain the homeostatic epithelium; in KRAS-G12D organoids, MAPK signalling opens SMAD2/3-bound enhancers at WNT7B, letting epithelium secrete its own WNT and escape the niche, and this was tested in CDH1/TP53-mutant as well as RNF43/ZNRF3-mutant backgrounds with growth-factor withdrawal, Porcupine inhibition and WNT rescue (PMID:41398956). The abstract does not state whether CDH1/TP53 organoids lacking KRAS activation achieve WNT self-sufficiency; if they remain stroma-WNT dependent, then early CDH1-null lesions are conditionally addressable by PORCN inhibition or WNT2B/FZD blockade, and acquisition of MAPK activation would mark the escape poin","approach":"Determine niche dependence directly: CDH1-KO and CDH1/TP53 gastric organoids +/- KRAS-G12D under WNT/R-spondin withdrawal and PORCN inhibitor (LGK974-class), with WNT7B/WNT2B expression and SMAD2/3 enhancer accessibility as readouts; extend to HDGC carrier-derived pT1a SRCC organoids and to CTNNA1-KO lines (PMID:40998418) to test whether the dependency is adherens-junction-generic. If dependence holds, evaluate PORCN inhibition or fibroblast-WNT2B neutralisation as an interception arm in carriers under surveillance (PMID:39379994). Expected liabilities: PORCN-inhibitor bone/intestinal toxicity in an otherwise healthy population [KNOWN]; escape via MAPK-driven autocrine WNT7B, or by RNF43/ZNR","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"41398956","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"39379994","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"40998418","verified":true,"isNew":false,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":190,"lastVisit":3,"lastNote":"New this visit from the first gastric organoid paper in the programme that includes a CDH1-mutant genotype and a druggable niche axis. Deliberately low confidence: the key datum (WNT dependence of CDH1-mutant organoids without KRAS) is not in the abstract, so this is a conditional lead with an explicit falsification experiment.","history":[{"visit":3,"cycle":190,"status":"NEW","note":"New this visit from the first gastric organoid paper in the programme that includes a CDH1-mutant genotype and a druggable niche axis. Deliberately low confidence: the key datum (WNT dependence of CDH1-mutant organoids without KRAS) is not in the abstract, so this is a conditional lead with an explicit falsification experiment."}]}],"retired":[],"nextQueries":["(CDH1) AND (\"promoter methylation\" OR hypermethylation OR decitabine OR azacitidine OR DNMT) AND (gastric OR \"signet ring\" OR \"lobular breast\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(PORCN OR \"porcupine inhibitor\" OR WNT2B OR WNT7B OR RNF43) AND (gastric AND (organoid OR \"diffuse\" OR \"signet ring\")) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"E-cadherin\" OR CDH1) AND (\"synthetic lethal\" OR \"transcriptomic buffering\" OR \"collateral vulnerability\") AND (\"lobular breast\" OR \"diffuse gastric\" OR ROS1 OR \"synthetic lethality screen\") AND SRC:MED AND PUB_YEAR:[20"],"updatedAt":"2026-08-20T01:10:42.106Z"},{"key":"multiple endocrine neoplasia type 1","name":"multiple endocrine neoplasia type 1","mondo":{"id":"MONDO:0007540","name":"multiple endocrine neoplasia type 1"},"genes":[{"label":"MEN1","kind":"causal"},{"label":"CDKN1B","kind":"correlated"},{"label":"CDKN2B","kind":"correlated"}],"visits":3,"openQuestions":["Does any group hold MEN1-conditional-knockout or MEN1-null adult human islet/panNET organoids, and can a CDK4/6i IC50 shift with p27/p18 rescue be run in them (the decisive test L2 now depends on)?","Are MEN1-germline panNETs systematically SSTR2-higher (68Ga-DOTATATE SUVmax) than sporadic panNETs, and is there published PRRT outcome data specifically in MEN1 patients?","Does concurrent CDK4/6 or mTOR inhibition antagonise or radiosensitise 177Lu-DOTATATE cytotoxicity in neuroendocrine models?","Is there any single-cell or spatial dataset of MEN1-germline panNET/parathyroid tissue at all, published or in a repository, that can resolve CD8 topology, TAM polarisation and HLA copy number?","In MEN1 tumour archives, what is the frequency of RB1 loss, CDKN2A/p16 deletion and MTAP co-deletion — i.e. how large are the RB-intact CDK4/6-eligible and PRMT5-eligible fractions?","Can the cervical-thymectomy cure benefit be reproduced with surgeon volume and resection extent controlled, and what permanent hypoparathyroidism rate does a natural-history cohort such as NCT04969926 imply?"],"leads":[{"id":"L1","title":"MET-IHC-selected c-MET inhibition (cabozantinib +/- anti-VEGF) in MEN1-related duodenopancreatic NET","mechanism":"MET/HGF signalling drives proliferation and invasion in a minority subset of MEN1-related NETs; c-MET IHC H-score >50 in 3/43 tumours, weak in 6/43, negative in 34/43, so any benefit is confined to a biomarker-defined subset rather than the MEN1 population at large (PMID:41018051). MET in normal tissue supports hepatocyte regeneration and epithelial wound repair, giving a workable but not risk-free window; cabozantinib's anti-VEGFR activity adds hypertension/perforation risk in duodenopancreatic disease.","approach":"Retrospective MET IHC + FISH/NGS on archival MEN1 NETs to test whether H-score tracks MET amplification or HGF autocrine loops; then a MET-IHC-enriched cohort of cabozantinib (or savolitinib for selective MET) in progressive MEN1 metastatic NET, with paired biopsies for kinase-switch resistance (KRAS/HER3/FGFR bypass, MET exon 14/D1228 mutations).","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"41018051","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":58,"lastVisit":1,"lastNote":"New this visit. Opened deliberately at low confidence because the pack's own data (79% MET-negative) undercut the authors' unselected conclusion; the lead survives only in biomarker-selected form.","history":[{"visit":1,"cycle":58,"status":"NEW","note":"New this visit. Opened deliberately at low confidence because the pack's own data (79% MET-negative) undercut the authors' unselected conclusion; the lead survives only in biomarker-selected form."}]},{"id":"L2","title":"Menin-loss to p27/p18 G1 dysregulation as a CDK4/6-inhibitor dependency in MEN1 tumours","mechanism":"[KNOWN] Menin scaffolds KMT2A/H3K4me3 at CDKN1B (p27) and CDKN2C (p18); biallelic MEN1 loss ([GERMLINE] first hit, [SOMATIC] second) lowers CIP/KIP and INK4 restraint, predicting RB-intact CCND1-CDK4/6 dependence. CDKN1B is independently listed as a recurrent panNET driver alongside MEN1/DAXX/ATRX (PMID:40869136) and as a germline endocrine-predisposition gene in MEN4 (PMID:42141904); focal CDK4 amplification with a cell-cycle-altered subtype is documented in adrenocortical carcinoma carrying 8% somatic MEN1 mutation (PMID:42550593); RB protein loss in a somatotropinoma defines an intrinsically refractory subset (PMID:42245474). Normal-tissue cost is proliferating marrow and gut epithelium.","approach":"Blocking issue is reagents: PMID:41238828 documents the paucity of NEN models and argues panNETs derive from adult pancreatic endocrine cells, so build MEN1-null vs -WT adult human islet/panNET organoids rather than progenitor systems. Readouts p27/p18/pRB-S780, E2F targets, palbociclib/ribociclib/abemaciclib IC50 shift, p27/p18 re-expression rescue; pre-screen archival MEN1 parathyroid/panNET/pituitary tumours for RB1 and CDKN2A/p16 by IHC+NGS to size the RB-intact eligible fraction; pre-specify CCNE1 amplification, RB1 loss, CDK6 upregulation as resistance routes.","level":"CANDIDATE","confidence":0.32,"citations":[{"kind":"PMID","id":"42137458","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42550593","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42141904","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42245474","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40869136","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41238828","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":58,"lastVisit":3,"lastNote":"Targeted query for isogenic/organoid/xenograft MEN1 + CDK4/6i returned zero studies — an informative null, explained by the documented absence of NEN models (PMID:41238828). Mechanism unrefuted but untested; only review-level CDKN1B corroboration added (PMID:40869136), so confidence trimmed and the lead is now gated on model construction.","history":[{"visit":3,"cycle":191,"status":"WEAKENED","note":"Targeted query for isogenic/organoid/xenograft MEN1 + CDK4/6i returned zero studies — an informative null, explained by the documented absence of NEN models (PMID:41238828). Mechanism unrefuted but untested; only review-level CDKN1B corroboration added (PMID:40869136), so confidence trimmed and the lead is now gated on model construction."},{"visit":2,"cycle":113,"status":"STRENGTHENED","note":"Second evidence-bearing visit with new, independent, endocrine-tumour-specific corroboration of the cell-cycle axis and a concrete exclusion biomarker (RB loss). Held at 0.35 because the ACC data are cross-tumour and the abstract does not state whether MEN1-mutant cases fall in the CDK4/6-nominated CCA cluster; no isogenic MEN1-null CDK4/6i data exist yet."},{"visit":1,"cycle":58,"status":"NEW","note":"New. Citation supports only the panNET genomic-instability framing, not CDK4/6 specifically; the mechanistic chain is [KNOWN]/[INFERRED] and needs a dedicated literature pass next visit before this can rise."}]},{"id":"L3","title":"Stroma/immune-exclusion-directed combination rather than checkpoint monotherapy in MEN1 panNET","mechanism":"panNET is immune-excluded, CAF-rich and immunosuppressive, co-evolving with genomic instability (PMID:42137458); 40% of adrenocortical carcinomas form an immune-suppressed subtype with TCR downregulation and HLA class II deletion (PMID:42550593). Tumour-associated macrophage infiltration is highlighted as an under-modelled axis of panNET heterogeneity (PMID:40869136). [INFERRED] Antigen-presentation loss plus T-cell exclusion predicts PD-1 monotherapy failure and favours vascular/stromal normalisation.","approach":"Single-cell plus spatial transcriptomics of MEN1-germline panNET/parathyroid tumours vs sporadic panNET (the modality explicitly nominated for NEN in PMID:41238828): CAF subsets, TAM polarisation, CD8 topology, MHC-I/II retention, HLA copy number. If equally excluded and HLA-deleted, prioritise anti-VEGF+IO or CAF/TAM-directed preclinical combinations and deprioritise IO monotherapy.","level":"LEAD","confidence":0.2,"citations":[{"kind":"PMID","id":"42137458","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42550593","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40869136","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41238828","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":3,"createdVisit":1,"createdCycle":58,"lastVisit":3,"lastNote":"Dedicated MEN1 single-cell/spatial query returned no MEN1-specific TME study across 2020-2026. Two visits of searching without a primary dataset; support remains wholly lateral, so confidence drops. Remains the programme's largest empirical hole.","history":[{"visit":3,"cycle":191,"status":"WEAKENED","note":"Dedicated MEN1 single-cell/spatial query returned no MEN1-specific TME study across 2020-2026. Two visits of searching without a primary dataset; support remains wholly lateral, so confidence drops. Remains the programme's largest empirical hole."},{"visit":2,"cycle":113,"status":"STRENGTHENED","note":"Only weak lateral strengthening: the new immune-cold/HLA-deletion data are from adrenocortical carcinoma, not MEN1 tumours, and remain review/cohort-level. MEN1-specific TME data are still absent, which keeps this the programme's biggest empirical gap."},{"visit":1,"cycle":58,"status":"NEW","note":"New, review-level evidence only, and derived from sporadic panNET cohorts; MEN1-specific TME data are absent, which is itself the near-term question."}]},{"id":"L4","title":"Concomitant cervical thymectomy at parathyroidectomy to eradicate intrathymic supernumerary parathyroid tissue in MEN1 pHPT","mechanism":"MEN1 primary hyperparathyroidism is multiglandular with frequent supernumerary/ectopic intrathymic glands; resecting the cervical thymus removes the reservoir of persistent disease. In 434 MEN1 parathyroidectomies (129 with thymectomy), cure rose 96.9% vs 88.2% (P=.004) with RR 0.26 for persistent disease, at the cost of higher transient hypoparathyroidism (~38%) (PMID:42140757).","approach":"Confirm in a surgeon-matched or propensity-weighted cohort with permanent-hypoparathyroidism and thymic-NET-incidence endpoints; contrast with recent single-institution null studies to test whether the TriNetX signal is selection-driven.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42140757","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":58,"lastVisit":1,"lastNote":"New and the most immediately decision-relevant item in the pack, but retrospective claims-network data conflicting with prior single-centre null results; not promotable without independent confirmation.","history":[{"visit":1,"cycle":58,"status":"NEW","note":"New and the most immediately decision-relevant item in the pack, but retrospective claims-network data conflicting with prior single-centre null results; not promotable without independent confirmation."}]},{"id":"L5","title":"Chromatin-writer dependency created by menin loss (PRC2/EZH2, PRMT5, DOT1L) — and explicit exclusion of menin-KMT2A inhibitors","mechanism":"NETs are low-mutational-burden and substantially epigenetically driven (PMID:42252277, PMID:40869136). [INFERRED] Menin loss redistributes KMT2A-dependent H3K4me3 and may create compensatory dependence on other writers/erasers with clinical-stage inhibitors (EZH2, PRMT5, DOT1L, KDM1A) (PMID:40181550, PMID:41051795, PMID:39601374). Recorded anti-lead, now triply confirmed: KMT2A-fusion leukaemogenesis requires menin as an obligate cofactor and revumenib/ziftomenib act by disrupting that interaction, with resistance via MEN1 binding-site mutations (PMID:42122138, PMID:41704185, PMID:41899095) — in MEN1 tumours the target protein is biallelically deleted, so menin inhibition is mechanistically ","approach":"CRISPR/drug-panel screen in MEN1-null vs -WT adult islet/panNET organoids against tazemetostat, GSK126, MTA-cooperative PRMT5 inhibitors, pinometostat, KDM1A inhibitors; CUT&RUN for H3K4me3/H3K27me3 redistribution at CDKN1B/CDKN2C and neuroendocrine identity loci; genotype MTAP/CDKN2A co-deletion in MEN1 archives to size a PRMT5-eligible subset.","level":"LEAD","confidence":0.2,"citations":[{"kind":"PMID","id":"42252277","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40181550","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41051795","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39601374","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42122138","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41704185","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"41899095","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":2,"createdVisit":2,"createdCycle":113,"lastVisit":3,"lastNote":"Strengthening applies only to the exclusion clause: three new independent 2026 reviews restate menin as the obligate cofactor targeted by menin inhibitors, hardening the anti-lead in a menin-loss disease. The positive chromatin-writer arm gained no screen data, so confidence held at 0.20.","history":[{"visit":3,"cycle":191,"status":"STRENGTHENED","note":"Strengthening applies only to the exclusion clause: three new independent 2026 reviews restate menin as the obligate cofactor targeted by menin inhibitors, hardening the anti-lead in a menin-loss disease. The positive chromatin-writer arm gained no screen data, so confidence held at 0.20."},{"visit":2,"cycle":113,"status":"NEW","note":"New this visit and deliberately low confidence: all supporting material is review-level with no MEN1-null screen data. Its main immediate value is the recorded anti-lead against menin-KMT2A inhibitors in a menin-loss disease, which the desk must never propose."}]},{"id":"L6","title":"SSTR2-density-stratified PRRT with mTOR-pathway inhibition in MEN1 duodenopancreatic NET","mechanism":"SSTR2 is described as central to panNET biology and as both prognostic marker and therapeutic handle enabling 68Ga-DOTATATE PET/CT selection, somatostatin analogues and PRRT, alongside recurrent mTOR-pathway dysregulation (PMID:40869136); PI3K/AKT/mTOR activation is likewise a documented axis in parathyroid neoplasia (PMID:42196524). [INFERRED] In MEN1-germline disease, multifocal indolent SSTR2-high lesions make receptor-targeted radioligand delivery the mechanism most independent of the unresolved menin-downstream biology, while mTOR blockade (everolimus, approved in panNET) supplies a non-overlapping cytostatic pressure and may act as a radiosensitiser. Normal-tissue window: SSTR2 on pitu","approach":"Retrospective 68Ga-DOTATATE SUVmax quantification across MEN1-germline vs sporadic panNET to test whether MEN1 tumours are systematically SSTR2-high; then a biomarker-gated cohort of 177Lu-DOTATATE with sequential rather than concurrent everolimus in progressive MEN1 disease, with renal/marrow dosimetry primary safety, ctDNA and chromogranin A monitoring (PMID:40869136). Pre-specify resistance routes: SSTR2 downregulation/dedifferentiation, Ki-67 escalation, DNA-repair competence; explicitly test whether CDK4/6 arrest antagonises radioligand cytotoxicity before combining with L2.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"40869136","verified":true,"isNew":true,"addedVisit":3},{"kind":"PMID","id":"42196524","verified":true,"isNew":true,"addedVisit":3}],"corrobVisits":1,"createdVisit":3,"createdCycle":191,"lastVisit":3,"lastNote":"New this visit. Opened as the repurposing-first, reagent-independent arm of the programme while L2/L3 wait on models and tissue; deliberately capped at 0.3 because the anchor is a review and no MEN1-germline-specific PRRT outcome data were in the pack.","history":[{"visit":3,"cycle":191,"status":"NEW","note":"New this visit. Opened as the repurposing-first, reagent-independent arm of the programme while L2/L3 wait on models and tissue; deliberately capped at 0.3 because the anchor is a review and no MEN1-germline-specific PRRT outcome data were in the pack."}]}],"retired":[],"nextQueries":["(MEN1 OR menin) AND (\"conditional knockout\" OR organoid OR \"islet\" OR \"mouse model\") AND (CRISPR OR \"drug screen\" OR dependency) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]","(\"pancreatic neuroendocrine\" OR panNET) AND (\"177Lu-DOTATATE\" OR PRRT OR \"peptide receptor radionuclide\") AND (MEN1 OR \"multiple endocrine neoplasia\" OR everolimus) AND SRC:MED","(MEN1 OR \"multiple endocrine neoplasia type 1\") AND (parathyroid OR pancreatic OR pituitary) AND (\"single-cell RNA\" OR \"spatial transcriptomics\" OR \"tumor microenvironment\" OR HLA) AND SRC:MED"],"updatedAt":"2026-08-20T01:14:11.105Z"},{"key":"multiple endocrine neoplasia type 2","name":"multiple endocrine neoplasia type 2","mondo":{"id":"MONDO:0019003","name":"multiple endocrine neoplasia type 2"},"genes":[{"label":"RET","kind":"causal"},{"label":"ESR2","kind":"correlated"},{"label":"NTRK1","kind":"correlated"}],"visits":2,"openQuestions":["Are there any published human MTC biopsy or ctDNA series at selpercatinib/pralsetinib progression that report NF1 loss, RAS or MAP2K1 mutations, i.e. does the CRISPR-derived MAPK-reflux mechanism exist in patients at all?","What are the reported potencies, MTC-specific response data and trial identifiers for zeteletinib, SYHA1815, BOS172738 and SY-5007 against RET G810 solvent-front and V804 gatekeeper mutants?","Does SSTR2 expression in MEN2-associated MTC and pheochromocytoma support 177Lu-DOTATATE, and what response/biochemical endpoints have been reported for PRRT in MTC?","Are MET or EGFR bypass tracks documented in MTC (as opposed to RET-fusion lung cancer), and with what frequency relative to secondary RET mutations?","Do RET-driven MEN2 pheochromocytomas show any HIF-2alpha/EPAS1 target-gene activation that would justify belzutifan, or should they be managed purely as cluster-2 kinase-driven disease?","Is GLP-1R expressed in human MTC and C-cell hyperplasia from MEN2 carriers, and does GLP-1RA exposure alter calcitonin kinetics?"],"leads":[{"id":"L1","title":"Vertical RET+MEK blockade (selpercatinib + trametinib) for RET-inhibitor-resistant MEN2-associated MTC","mechanism":"RET [GERMLINE causal in MEN2; somatic second-hit/amplification at resistance] drives RAS-MAPK, PI3K-AKT and JAK-STAT output (PMID:41930492, PMID:41977363). In a vandetanib-selected RET-mutant MTC model, resistance arose via RET copy gain plus secondary p.G810S, and CRISPR KO identified NF1 loss with RAS/MAPK activation as sufficient for resistance, reversible by MEK inhibition (PMID:42258786). However, no human MTC biopsy or ctDNA series documenting NF1 loss or MAPK reflux at selpercatinib/pralsetinib progression exists in the pack; dedicated MTC reviews enumerate gatekeeper and solvent-front RET mutations as the dominant described resistance mechanisms (PMID:42525389, PMID:42520863), not do","approach":"Restrict the phase Ib selpercatinib + intermittent trametinib design to patients with ctDNA/biopsy-proven MAPK reactivation (NF1 loss, RAS or MAP2K1 mutation, MAPK transcriptional signature) rather than all post-RET-inhibitor progressors; pERK in tumour or surrogate skin as PD marker; enrolment gated on the somatic profiling workflow mandated for advanced disease in PMID:41837125. Solvent-front cases route to L4 instead. Window argument: adult RET dependence largely confined to C cells and enteric/renal development [KNOWN]; trametinib rash/LVEF/ocular toxicity is schedule-modifiable.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42258786","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41977363","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41930492","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42297674","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42525389","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42520863","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41837125","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":114,"lastVisit":2,"lastNote":"Fielded query for MTC/MEN2 + MEK inhibitor/trametinib/selumetinib/NF1 returned no primary human data this visit, only generic reviews (PMID:41976235) — absence of corroboration after a directed search. Simultaneously, two MTC reviews centre resistance on gatekeeper/solvent-front RET, giving a better-supported competing route for that subset. Lead survives but narrowed to a biomarker-selected subse","history":[{"visit":2,"cycle":193,"status":"WEAKENED","note":"Fielded query for MTC/MEN2 + MEK inhibitor/trametinib/selumetinib/NF1 returned no primary human data this visit, only generic reviews (PMID:41976235) — absence of corroboration after a directed search. Simultaneously, two MTC reviews centre resistance on gatekeeper/solvent-front RET, giving a better-supported competing route for that subset. Lead survives but narrowed to a biomarker-selected subse"},{"visit":1,"cycle":114,"status":"NEW","note":"Created this visit from PMID:42258786 [NEW] — first pack evidence that resistance is MAPK-reflux-dominated and pharmacologically reversible in vivo. Held at LEAD: preclinical only, single visit, no human combination data. Anticipated escape: MET/EGFR bypass, PI3K-AKT, ERK/MEK1 mutation."}]},{"id":"L2","title":"Radioligand-plus-systemic control of MEN2A metastatic pheochromocytoma, with cluster-2 vs pseudohypoxia target triage","mechanism":"MEN2 pheochromocytoma is germline RET-driven kinase-signalling disease rather than pseudohypoxic VHL/SDHx biology [GERMLINE; INFERRED from classification]. 131I-MIBG produced a normetanephrine response without tumour shrinkage in one MEN2A case (PMID:42128848), i.e. hormonal rather than cytoreductive benefit. New case evidence: metastatic recurrence of MEN2A pheochromocytoma was heralded by rising spot urine normetanephrine (biochemical phenotype shift) and cytotoxic chemotherapy was ineffective, with death 3y2m after adrenalectomy (PMID:41837230) — chemotherapy is now a recorded negative for this setting. Adrenal-sparing surgery in bilateral MEN2/VHL pheo preserves steroid independence but ","approach":"Genotype-annotated retrospective/prospective series of MEN2 metastatic pheo treated with 131I-MIBG or 177Lu-DOTATATE with catecholamine/metanephrine control as primary endpoint and metanephrine kinetics as the recurrence-detection trigger; parallel SSTR2 and NET-transporter expression mapping in MEN2 pheo and MTC to decide radioligand choice; assay HIF-2alpha/EPAS1 target-gene signature in MEN2 pheo tissue before entertaining belzutifan (NCT04924075), which remains an eligibility observation only. Exclude cytotoxic chemotherapy from future proposals.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42128848","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42297674","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04924075","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41837230","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41809780","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42525389","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":114,"lastVisit":2,"lastNote":"Two [NEW] case reports plus a [NEW] MTC review add: a documented chemotherapy failure and biochemical-phenotype-shift surveillance signal (PMID:41837230), the adrenal-sparing surgical context (PMID:41809780), and PRRT as an emerging MTC modality (PMID:42525389). Still all case-level; confidence 0.3 to 0.35, held at LEAD — no independent mechanistic corroboration of radioligand efficacy in RET-driv","history":[{"visit":2,"cycle":193,"status":"STRENGTHENED","note":"Two [NEW] case reports plus a [NEW] MTC review add: a documented chemotherapy failure and biochemical-phenotype-shift surveillance signal (PMID:41837230), the adrenal-sparing surgical context (PMID:41809780), and PRRT as an emerging MTC modality (PMID:42525389). Still all case-level; confidence 0.3 to 0.35, held at LEAD — no independent mechanistic corroboration of radioligand efficacy in RET-driv"},{"visit":1,"cycle":114,"status":"NEW","note":"New this visit. Deliberately low confidence: n=1 case report with biochemical-only response, and belzutifan's inclusion is a trial-eligibility observation, not evidence of HIF-2alpha dependence in RET-driven pheo."}]},{"id":"L3","title":"Does GLP-1R exist on human C-cell neoplasia? De-risking the MEN2/MTC GLP-1RA black box and testing GLP-1R as a ligand target","mechanism":"The MTC/MEN2 contraindication for GLP-1RAs derives from rodent C-cell proliferation; the review finds GLP-1R expression across non-neoplastic endocrine tissue and some NETs, preclinical proliferative effects in panNET/siNET lines, but conflicting-to-neutral human registry, RCT and epidemiological data (PMID:42541759). If human C-cell neoplasms lack GLP-1R, the warning is mechanistically unfounded; if they express it, GLP-1R becomes a candidate imaging/radioligand handle rather than a growth driver to fear.","approach":"IHC/RNA quantification of GLP-1R in human MTC and C-cell hyperplasia from MEN2 carriers (biospecimens plausibly available via NCT01660984); calcitonin trajectory in GLP-1RA-exposed MEN2 carriers in registry data; only if expression is confirmed, consider exendin-based radioligand imaging as a research probe [SPECULATIVE].","level":"LEAD","confidence":0.2,"citations":[{"kind":"PMID","id":"42541759","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT01660984","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":114,"lastVisit":1,"lastNote":"New this visit; a target-existence/safety question, not yet a therapy. Recorded so the desk does not treat the black box as settled biology in either direction.","history":[{"visit":1,"cycle":114,"status":"NEW","note":"New this visit; a target-existence/safety question, not yet a therapy. Recorded so the desk does not treat the black box as settled biology in either direction."}]},{"id":"L4","title":"Genotype-directed sequencing to next-generation RET inhibitors for gatekeeper/solvent-front resistant MEN2-associated MTC","mechanism":"Selective RET inhibitors (selpercatinib, pralsetinib) are first-line for RET-mutant MTC but are escaped by gatekeeper (V804) and solvent-front (G810) secondary RET mutations that sterically exclude the drug while preserving RET kinase dependence [KNOWN mechanism; described as the dominant acquired resistance class in PMID:42525389 and PMID:42520863]. Because the resistant tumour remains RET-addicted, a structurally distinct next-generation inhibitor should retain vertical target coverage where downstream MEK blockade would only partially restrain a still-active receptor. Agents named as in-development: zeteletinib and SYHA1815 (PMID:42520863), BOS172738 and SY-5007 with promising early resul","approach":"Prospective ctDNA-triaged sequencing study at progression on a selective RET inhibitor, using the universal germline RET plus somatic profiling workflow of PMID:41837125: arm A (RET solvent-front/gatekeeper) to a next-generation RET inhibitor; arm B (MAPK reactivation) to the L1 combination; arm C (no RET/MAPK lesion) to bypass-track profiling (MET, EGFR) or PRRT. Endpoints: calcitonin/CEA kinetics plus RECIST; serial ctBNA RET allele fractions. Expected escape routes: compound RET mutations, RET-independent bypass activation, and MYC/lineage plasticity [SPECULATIVE for MTC]. Window argument: greater RET selectivity should reproduce the reduced off-target VEGFR2 toxicity that distinguishes s","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42520863","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42525389","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42116529","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41837125","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT01660984","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":193,"lastVisit":2,"lastNote":"Created this visit from two independent [NEW] MTC-focused reviews naming a concrete next-generation RET pipeline plus the pralsetinib withdrawal. Held at LEAD: all agent-level evidence is review-level narrative, no primary MTC efficacy data or trial identifiers in the pack.","history":[{"visit":2,"cycle":193,"status":"NEW","note":"Created this visit from two independent [NEW] MTC-focused reviews naming a concrete next-generation RET pipeline plus the pralsetinib withdrawal. Held at LEAD: all agent-level evidence is review-level narrative, no primary MTC efficacy data or trial identifiers in the pack."}]}],"retired":[],"nextQueries":["(\"medullary thyroid\" OR \"RET\") AND (zeteletinib OR SYHA1815 OR BOS172738 OR \"SY-5007\" OR vepafestinib) AND SRC:MED","(\"medullary thyroid carcinoma\") AND (\"circulating tumor DNA\" OR ctDNA OR \"somatic profiling\") AND (progression OR resistance OR \"acquired\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"medullary thyroid carcinoma\" OR \"pheochromocytoma\") AND (\"177Lu-DOTATATE\" OR \"peptide receptor radionuclide\" OR SSTR2 OR MIBG) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-20T01:21:17.407Z"},{"key":"gorlin syndrome","name":"Gorlin syndrome","mondo":{"id":"MONDO:0007187","name":"nevoid basal cell carcinoma syndrome"},"genes":[{"label":"PTCH1","kind":"causal"},{"label":"SUFU","kind":"causal"},{"label":"PTCH2","kind":"correlated"}],"visits":2,"openQuestions":["Does NCT06050122 replicate the phase IIA signal, and why did the earlier patidegib gel 2% phase 3 fail — vehicle/follicular penetration, dosing area, or new-lesion endpoint definition?","Are there measured plasma patidegib concentrations and lesional GLI1/PTCH1 transcript changes proving true skin compartmentalisation rather than inferring it from absent toxicity?","What is the somatic genotype spectrum at HHi progression in Gorlin BCC (SMO binding-site mutants vs GLI2/CCND1 amplification vs somatic SUFU loss), and does germline PTCH1 vs SUFU status change it?","Does intermittent/pulsed oral HHi dosing preserve the 84% ORR while cutting the 90% adverse-effect burden, and does it delay or accelerate resistance?","Is there any Gorlin- or BCC-specific evidence for checkpoint blockade after HHi failure, or for GLI-direct agents (arsenic trioxide, BET/BRD4, phenformin) in PTCH1-null keratinocytes?","Can SMO or GLI inhibition permit radiotherapy avoidance in Gorlin medulloblastoma, and what is the measured growth-plate risk under intermittent or delivery-restricted dosing in children?"],"leads":[{"id":"L1","title":"Skin-compartment-restricted SMO inhibition (topical patidegib) as chemoprevention in germline PTCH1 Gorlin syndrome","mechanism":"Germline PTCH1 loss [GERMLINE] leaves follicular basal keratinocytes one somatic hit from SMO-dependent GLI1/2 derepression, driving continuous BCC field carcinogenesis; systemic SMO blockade controls this but cramps, dysgeusia, alopecia and teratogenicity are on-target consequences of Hh loss in muscle, taste bud and hair-follicle renewal [KNOWN], so benefit hinges on confining exposure to skin. A cyclopamine-derived topical gel was engineered specifically to reach tumoricidal follicular concentrations without systemic Hh-inhibitory plasma levels (PMID:39545486).","approach":"Phase 3 patidegib gel 2% vs vehicle on the face in Gorlin (NCT06050122) read out as new-lesion rate plus systemic Hh-toxicity signal; demand plasma patidegib PK and lesional GLI1/PTCH1 transcript knockdown to prove compartmentalisation rather than infer it. Pre-specify resistance routes: SMO drug-binding mutations, GLI2/CCND1 amplification, non-canonical GLI activation, and inadequate follicular penetration. Reconcile any positive result against the prior failed patidegib gel 2% phase 3 [KNOWN].","level":"CANDIDATE","confidence":0.65,"citations":[{"kind":"NCT","id":"NCT06050122","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40492880","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42462758","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"39545486","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39969481","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40262619","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39796697","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":115,"lastVisit":2,"lastNote":"Promoted on new, independent, Gorlin-specific randomised phase IIA evidence (PMID:39545486) with two review corroborations; efficacy claim is post hoc and the abstract shows no plasma PK or lesion counts, and a previous phase 3 of the same 2% gel missed its primary endpoint [KNOWN] — hence 0.65, not higher.","history":[{"visit":2,"cycle":194,"status":"STRENGTHENED","note":"Promoted on new, independent, Gorlin-specific randomised phase IIA evidence (PMID:39545486) with two review corroborations; efficacy claim is post hoc and the abstract shows no plasma PK or lesion counts, and a previous phase 3 of the same 2% gel missed its primary endpoint [KNOWN] — hence 0.65, not higher."},{"visit":1,"cycle":115,"status":"NEW","note":"New this visit. Justified by PMID:40492880 showing 90% of HHi-treated patients have QoL-limiting adverse effects despite 84% ORR — tolerability, not efficacy, is the limiting variable in a lifelong-surveillance syndrome (PMID:42462758)."}]},{"id":"L2","title":"SMO-independent modality stacking: cyclic ALA-photodynamic therapy combined with oral sonidegib","mechanism":"PDT kills via photosensitiser-derived ROS, a mechanism orthogonal to SMO/GLI signalling, so it should remain active against HHi-resistant clones; conversely PDT fails in thick, nodular or hypoxic lesions, and HHi-induced cytoreduction plausibly converts nodular BCC into PDT-tractable superficial disease [INFERRED].","approach":"Phase 1 ALA + BLU-U blue-light PDT with sonidegib in multiple BCC (NCT06623201); test whether intermittent/pulsed HHi dosing plus cyclic PDT preserves response while reducing cumulative Hh-inhibitor exposure. Failure modes: PDT light/oxygen penetration limits, photosensitiser efflux, pain-limited field treatment.","level":"LEAD","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT06623201","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42511737","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40492880","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":115,"lastVisit":1,"lastNote":"New this visit. PMID:42511737 explicitly identifies cyclic PDT as a tissue-sparing standby in Gorlin and names hypoxia/thickness as PDT's limit — the exact deficit an HHi could relieve; PMID:40492880 supplies the tolerability rationale for sparing systemic dose.","history":[{"visit":1,"cycle":115,"status":"NEW","note":"New this visit. PMID:42511737 explicitly identifies cyclic PDT as a tissue-sparing standby in Gorlin and names hypoxia/thickness as PDT's limit — the exact deficit an HHi could relieve; PMID:40492880 supplies the tolerability rationale for sparing systemic dose."}]},{"id":"L3","title":"Downstream/parallel-node salvage for SMO-inhibitor-resistant Hedgehog tumours: dual PI3K-AKT plus CDK4/6 inhibition","mechanism":"Hh-driven tumours converge on GLI-dependent CCND1/CDK4-6 activity and are sustained by non-canonical PI3K/AKT input; blocking these nodes acts distal to SMO and should therefore survive SMO mutation or GLI2 amplification [INFERRED]. In a Gorlin patient-derived neuroepithelial stem cell line versus its SHH-medulloblastoma derivative, PI3K (BYL719), AKT (AZD5363) and CDK4/6 (PD-0332991) inhibitors were selectively more active on the tumour derivative in 2D and largely in 3D, with synergistic/additive combinations — a built-in normal-cell window argument.","approach":"Extend the tNES/NES paired isogenic assay to Gorlin BCC-derived keratinocyte models and to HHi-resistant BCC explants; test alpelisib or capivasertib plus palbociclib after vismodegib/sonidegib failure. Expected resistance: RB1 loss and CDK6/CCNE1 upregulation for CDK4/6, PTEN loss/PI3K reactivation, and haematologic/hyperglycaemic toxicity limiting combination dosing [KNOWN].","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"41734992","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40492880","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":115,"lastVisit":1,"lastNote":"New this visit. PMID:41734992 is the only fresh mechanistic evidence in the pack and uses Gorlin-patient material with a normal comparator; caveat recorded — medulloblastoma lineage, viability/apoptosis endpoints only, no in vivo data, so BCC relevance is unproven.","history":[{"visit":1,"cycle":115,"status":"NEW","note":"New this visit. PMID:41734992 is the only fresh mechanistic evidence in the pack and uses Gorlin-patient material with a normal comparator; caveat recorded — medulloblastoma lineage, viability/apoptosis endpoints only, no in vivo data, so BCC relevance is unproven."}]},{"id":"L4","title":"Resistance-genotype mapping of Hedgehog-inhibitor failure in Gorlin BCC via prospective registries","mechanism":"Acquired HHi resistance is genotype-heterogeneous (SMO drug-binding mutants, GLI2/CCND1 amplification, somatic SUFU loss [SOMATIC], non-canonical bypass) [KNOWN]; salvage choice between re-dosing, downstream inhibitors and ablative modalities is arbitrary without serial tissue genotyping.","approach":"Embed paired pre-treatment/at-progression biopsy sequencing plus GLI1 transcript read-out in NCT05463757 and NCT03050268; output a stratifier assigning SMO-mutant lesions to downstream/GLI-direct agents and amplification-driven lesions to PDT, surgery or CDK4/6-directed arms.","level":"LEAD","confidence":0.35,"citations":[{"kind":"NCT","id":"NCT05463757","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03050268","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40492880","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42462758","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40262619","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":115,"lastVisit":2,"lastNote":"Weakened: a query aimed directly at BCC HHi resistance with SMO/GLI2/SUFU terms returned only narrative reviews (PMID:40262619, PMID:39796697) and no primary paired-biopsy genotyping series — the germline-PTCH1-specific resistance spectrum is an unfilled void, so the lead cannot yet be corroborated.","history":[{"visit":2,"cycle":194,"status":"WEAKENED","note":"Weakened: a query aimed directly at BCC HHi resistance with SMO/GLI2/SUFU terms returned only narrative reviews (PMID:40262619, PMID:39796697) and no primary paired-biopsy genotyping series — the germline-PTCH1-specific resistance spectrum is an unfilled void, so the lead cannot yet be corroborated."},{"visit":1,"cycle":115,"status":"NEW","note":"New this visit, driven by the 77% (10/13) acquired-resistance rate at median 13 months in PMID:40492880 — the programme cannot rank salvage strategies without knowing which bypass dominates in germline-PTCH1 skin."}]},{"id":"L5","title":"Delivery-restricted SMO/GLI inhibition as a radiotherapy-sparing strategy in Gorlin-associated SHH medulloblastoma","mechanism":"Gorlin SHH-medulloblastoma is SMO-dependent downstream of germline PTCH1/SUFU loss [GERMLINE], and craniospinal radiotherapy is both neurotoxic and BCC-inducing in these patients [KNOWN]; systemic HHi causes irreversible growth-plate fusion in children [KNOWN], so the therapeutic window must come from spatial confinement of drug rather than from pathway selectivity. A single adult metastatic medulloblastoma has sustained a 10-year complete response on first-line vismodegib without radiotherapy (PMID:42109078), and phenformin-loaded niosomes achieved preferential cerebellar tumour accumulation with reduced hepatic exposure and marked intratumoral Gli1/Ptch1 downregulation in SHH-MB models (PM","approach":"Test nanocarrier-confined GLI1-directed agents (phenformin niosomes) and intermittent SMO inhibition in PTCH1/SUFU-germline SHH-MB models, with growth-plate histomorphometry and plasma-versus-intratumoral drug ratios as co-primary endpoints; in humans, a radiotherapy-deferral arm within a predisposition cohort (NCT03050268). Resistance routes: SMO mutation, GLI2 amplification, MYCN co-amplification, and non-genetic persistence.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42109078","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42117983","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT03050268","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"42462758","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":194,"lastVisit":2,"lastNote":"New this visit; addresses open question 6. Evidence is one anecdotal adult case (not Gorlin, not paediatric) plus a preclinical nanocarrier proof-of-concept in generic SHH-MB — no germline-PTCH1 model data, hence low confidence.","history":[{"visit":2,"cycle":194,"status":"NEW","note":"New this visit; addresses open question 6. Evidence is one anecdotal adult case (not Gorlin, not paediatric) plus a preclinical nanocarrier proof-of-concept in generic SHH-MB — no germline-PTCH1 model data, hence low confidence."}]},{"id":"L6","title":"Immune-checkpoint blockade as post-HHi salvage and Hh/checkpoint combination in Gorlin BCC","mechanism":"UV-driven BCC carries a high tumour mutational burden [KNOWN]; HHi exposure and GLI-dependent immune-evasion programmes may condition the microenvironment such that sequential or combined PD-1 blockade retains activity after SMO-mutant or GLI2-amplified escape, i.e. a mechanism entirely orthogonal to the Hh axis. Neoadjuvant and combined Hh-plus-checkpoint approaches are the current frontier in advanced BCC (PMID:39796697).","approach":"Gorlin-restricted cohort of cemiplimab after documented HHi progression, with paired biopsies for SMO/GLI2 genotype and PD-L1/T-cell infiltrate; test whether HHi-induced cytoreduction raises response. Explicit risk to pre-specify: syndromic patients face lifelong repeated dosing and cumulative immune-related toxicity, and immunotherapy response in field-carcinogenesis skin is unproven.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"39796697","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40492880","verified":true,"isNew":false,"addedVisit":2},{"kind":"PMID","id":"40262619","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":194,"lastVisit":2,"lastNote":"New this visit from review-level evidence only (no Gorlin-specific checkpoint data in the pack); opened because open question 5 had no prior lead and HHi resistance at 77%/13 months (PMID:40492880) demands an Hh-independent salvage option.","history":[{"visit":2,"cycle":194,"status":"NEW","note":"New this visit from review-level evidence only (no Gorlin-specific checkpoint data in the pack); opened because open question 5 had no prior lead and HHi resistance at 77%/13 months (PMID:40492880) demands an Hh-independent salvage option."}]}],"retired":[],"nextQueries":["(patidegib) AND (\"basal cell carcinoma\" OR Gorlin) AND (pharmacokinetic* OR plasma OR \"phase 3\" OR \"phase III\") AND SRC:MED","(\"basal cell carcinoma\") AND (vismodegib OR sonidegib) AND (\"paired biops*\" OR \"whole exome\" OR sequencing) AND (progression OR resistance) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"basal cell carcinoma\") AND (cemiplimab OR pembrolizumab OR \"immune checkpoint\") AND (\"hedgehog inhibitor\" OR vismodegib OR sonidegib OR Gorlin) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-20T01:24:43.201Z"},{"key":"birt-hogg-dube syndrome","name":"Birt-Hogg-Dube syndrome","mondo":{"id":"MONDO:0800444","name":"Birt-Hogg-Dube syndrome"},"genes":[{"label":"PRDM10","kind":"causal"},{"label":"FLCN","kind":"causal"}],"visits":2,"openQuestions":["In FLCN-mutant renal tumours treated with ICI+TKI, can VEGFR-TKI effect be separated from checkpoint effect — is there any case of response to single-agent PD-1/CTLA-4 blockade, and what are TMB/PD-L1/CD8 values?","Does TFEB amplification in a germline-FLCN clear cell RCC (PMID:42000053) behave as a dependency, i.e. does TFEB degradation or knockdown kill FLCN-null renal cells more than WT?","What is the quantitative dynamic range of GPNMB IHC/transcript between FLCN-null and FLCN-WT oncocytic tumours, and can it move measurably on drug to serve as a trial endpoint?","Do FLCN-null renal and thyroid oncocytic cells show a measurable complex I / OXPHOS dependency, and is any approved agent (biguanide) active in isogenic models?","What is the natural history of the newly defined histiocyte-rich and unclassified FLCN-mutant morphologies — metastatic rate versus classic HOCT — since only aggressive subsets can justify systemic toxicity?","Is stromal senescence in fibrofolliculoma (L2) reproducible in genetically confirmed BHD carriers only, and do senolytics clear PAS+ dermal glycogenosis ex vivo?"],"leads":[{"id":"L1","title":"Dual immune checkpoint blockade (ipilimumab + nivolumab) in FLCN-null renal neoplasia, including epithelioid angiomyolipoma","mechanism":"Germline FLCN loss [GERMLINE] plus somatic second hit [SOMATIC] de-represses TFE3/TFEB and activates mTORC1 [KNOWN]. The prior rationale rested on one epithelioid AML with a shared expanded TCR clone and durable complete response (PMID:42527032). New this visit: a BHD-associated sarcomatoid RCC progressed on first-line axitinib + toripalimab and responded only after switching the TKI to anlotinib while continuing the same PD-1 antibody (PMID:40707936) — PD-1 exposure was constant across failure and response, so the anti-angiogenic backbone is the more parsimonious driver [INFERRED].","approach":"Do not open a single-agent or ipilimumab/nivolumab-first basket on this evidence. Reframe as a retrospective multi-institutional audit of FLCN-mutant renal tumours already treated with ICI or ICI+TKI (available cohorts: PMID:42000053, PMID:42379850, NCT00033137), scoring TMB, PD-L1, CD8 spatial density and GPNMB, and separating VEGFR-TKI from checkpoint contribution. Pre-specify sarcomatoid dedifferentiation as the only subgroup with an aggressive natural history worth systemic exposure. Resistance/toxicity routes unchanged: B2M/HLA-I loss, JAK1/2 truncation, sarcoidosis-like irAE.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42527032","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41823029","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40707936","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42000053","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT00033137","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":116,"lastVisit":2,"lastNote":"Weakened: the only new ICI datum in the pack is effectively a PD-1 failure with response attributable to the TKI switch. Recorded in the notebook so the desk does not re-propose ICI monotherapy as the lead hypothesis.","history":[{"visit":2,"cycle":195,"status":"WEAKENED","note":"Weakened: the only new ICI datum in the pack is effectively a PD-1 failure with response attributable to the TKI switch. Recorded in the notebook so the desk does not re-propose ICI monotherapy as the lead hypothesis."},{"visit":1,"cycle":116,"status":"NEW","note":"New this visit from a single case report — n=1, no TMB/PD-L1 in the abstract, and E-AML biology may be driven by TSC-pathway convergence rather than FLCN itself. Cited as hypothesis-generating only."}]},{"id":"L2","title":"Senescent-stroma-directed therapy for BHD fibrofolliculoma, not epithelial mTOR monotherapy","mechanism":"All 13 fibrofolliculomas showed dermal interstitial glycogenosis (diastase-sensitive PAS+) with stromal GLB1, p53 and phospho-S6 positivity and absent CD68, i.e. non-histiocytic stromal senescence plus mTORC1 activation in the mesenchymal compartment (PMID:42357990). [KNOWN] Randomised topical rapamycin for BHD fibrofolliculomas was negative; compartmental mislocalisation of the drug target plus a senescence-associated secretory program sustaining perifollicular proliferation is a candidate explanation [INFERRED].","approach":"Ex vivo/organotypic test of senolytics (dasatinib+quercetin, navitoclax) and senomorphics (JAK inhibitor) on fibrofolliculoma-derived stromal fibroblasts from FLCN carriers; then intra-lesional or penetration-enhanced topical sirolimus + senolytic combination, randomised split-body design. Pharmacodynamic endpoints: stromal phospho-S6, GLB1/SA-beta-gal, p16/p21, PAS+ glycogen clearance on serial punch biopsy. Window: senolytics spare quiescent normal dermal fibroblasts at intermittent dosing [KNOWN]; platelet toxicity limits navitoclax.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42357990","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":116,"lastVisit":1,"lastNote":"New; small descriptive IHC series (n=13 vs 3 controls), BHD genetically confirmed in only part of the cohort, so sporadic and syndromic lesions are pooled. Notebook records topical rapalog monotherapy as a settled negative — do not re-propose.","history":[{"visit":1,"cycle":116,"status":"NEW","note":"New; small descriptive IHC series (n=13 vs 3 controls), BHD genetically confirmed in only part of the cohort, so sporadic and syndromic lesions are pooled. Notebook records topical rapalog monotherapy as a settled negative — do not re-propose."}]},{"id":"L3","title":"Two-hit FLCN inactivation as the maintenance state to attack by synthetic lethality","mechanism":"Biallelic FLCN loss (germline variant/17p deletion plus somatic hit; PMID:41823029, PMID:42278264) removes the RagC/D GAP and drives a constitutive TFEB/TFE3 lysosomal-biogenesis program [KNOWN]. New: FLCN-mutant renal tumours are morphologically promiscuous (unclassified, translocation-like, papillary, ESC-like, histiocyte-rich, ChRCC-like, SDH-like) yet share diffuse TFE3 and GPNMB positivity and recurrent 1p/15q/17p/14q loss with 17q gain (PMID:42000053, PMID:42423092, PMID:42379850); one germline-FLCN clear cell RCC reached the same node through TFEB locus amplification (PMID:42000053) — independent genetic convergence on TFEB dosage [INFERRED].","approach":"Isogenic FLCN-null vs FLCN-WT CRISPR screens in renal epithelial and oncocytic backgrounds, now explicitly benchmarked against a TFEB-amplified line as a positive-control genotype: query V-ATPase/Ragulator subunits, TFEB/TFE3 coactivators (MITF family partners, EP300/CREBBP), glutamine anaplerosis and complex I. Read out GPNMB transcript/protein as on-target PD marker. Germline/somatic annotation mandatory; tissue via NCT00033137.","level":"CANDIDATE","confidence":0.42,"citations":[{"kind":"PMID","id":"41823029","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42278264","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41939121","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42000053","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42423092","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42379850","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":116,"lastVisit":2,"lastNote":"Strengthened by three new independent series (n=7, 11, 18) confirming the two-hit state and, critically, by TFEB amplification as an alternative route to the same axis — that is a druggable node rather than an undruggable tumour suppressor.","history":[{"visit":2,"cycle":195,"status":"STRENGTHENED","note":"Strengthened by three new independent series (n=7, 11, 18) confirming the two-hit state and, critically, by TFEB amplification as an alternative route to the same axis — that is a druggable node rather than an undruggable tumour suppressor."},{"visit":1,"cycle":116,"status":"NEW","note":"New; framing lead with no drug attached yet. Deliberately stated as a screen-to-target plan rather than a therapeutic claim, since the pack contains no FLCN-null dependency data."}]},{"id":"L4","title":"GPNMB as pharmacodynamic biomarker — and conditional surface target — of the FLCN/TFEB program","mechanism":"GPNMB is a direct TFEB transcriptional target [KNOWN]. It is diffusely expressed in every FLCN-mutant renal neoplasm across two new series, spanning oncocytic, histiocyte-rich and unclassified morphology (PMID:42000053: 5/5 with material; PMID:42423092: all FLCN-mutant cases), making it a protein-level readout of pathway output usable on a punch or core biopsy [INFERRED]. Specificity is limited: 3/6 morphologically similar FLCN-wild-type tumours were also GPNMB-positive (PMID:42423092), so it reports pathway state, not genotype.","approach":"Primary use: qualify GPNMB IHC (H-score) alongside TFE3 nuclear localisation and phospho-S6 as the PD endpoint for any FLCN-axis trial, calibrated on archival FLCN-mutant vs FLCN-WT mimics from the existing series and NCT00033137. Secondary, lower priority: GPNMB-directed ADC or CAR. Window argument against it — GPNMB is expressed on melanocytes, osteoclasts and macrophages, glembatumumab vedotin gave dose-limiting rash and failed its phase II endpoint in TNBC [KNOWN], and BHD renal disease is largely indolent and surgically managed, so cytotoxic ADC exposure is hard to justify outside sarcomatoid or metastatic FLCN-RCC.","level":"LEAD","confidence":0.38,"citations":[{"kind":"PMID","id":"42000053","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42423092","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42379850","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT00033137","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":195,"lastVisit":2,"lastNote":"New this visit; directly addresses open question 6. Framed biomarker-first because the therapeutic window for a GPNMB ADC in an indolent syndrome is poor.","history":[{"visit":2,"cycle":195,"status":"NEW","note":"New this visit; directly addresses open question 6. Framed biomarker-first because the therapeutic window for a GPNMB ADC in an indolent syndrome is poor."}]},{"id":"L5","title":"Pan-organ oncocytic phenotype of FLCN loss (kidney and thyroid) as a shared mitochondrial/OXPHOS vulnerability","mechanism":"FLCN alterations occur in 1.1% of thyroid carcinomas, are enriched in oncocytic morphology, and rise from 2% of sporadic to 23% of anaplastic TC, with homozygous deletion clustering in genomically unstable tumours (PMID:40277780); three BHD patients developed thyroid carcinoma including a dedifferentiated oncocytic TC with FLCN/DAXX/TP53 pathogenic variants (PMID:40658617). The same eosinophilic/oncocytic morphology dominates FLCN-mutant renal tumours (PMID:42379850, PMID:42000053). Oncocytic change reflects mitochondrial mass expansion downstream of TFEB/PGC-1-family activation when FLCN is lost [KNOWN for the FLCN-PGC1A link; SPECULATIVE that it creates a complex I dependency].","approach":"Test complex I / OXPHOS dependency in FLCN-null renal and thyroid oncocytic models (Seahorse, galactose-forced respiration, metformin/phenformin and a research-grade complex I inhibitor) against isogenic FLCN-WT controls; if a window exists, the repurposing candidate is biguanide, not IACS-class inhibitors, given prior lactic acidosis and neurotoxicity signals [KNOWN]. Separately, ask whether BHD surveillance should include thyroid ultrasound — FLCN appears to co-operate with TP53/RB1 rather than drive alone (PMID:40277780, PMID:40658617), so absolute risk is likely low.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"40277780","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40658617","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42379850","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42000053","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":195,"lastVisit":2,"lastNote":"New extra-renal axis from this pack. Deliberately low confidence: the metabolic dependency is inferred from morphology, not measured, and the thyroid data are two case reports plus a 1.1% prevalence scan.","history":[{"visit":2,"cycle":195,"status":"NEW","note":"New extra-renal axis from this pack. Deliberately low confidence: the metabolic dependency is inferred from morphology, not measured, and the thyroid data are two case reports plus a 1.1% prevalence scan."}]}],"retired":[],"nextQueries":["(FLCN OR folliculin) AND (\"synthetic lethal\" OR \"CRISPR screen\" OR dependency OR \"complex I\" OR OXPHOS OR mitochondrial) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]","(TFEB OR TFE3) AND (amplification OR degrader OR \"transcription factor inhibitor\") AND (\"renal cell carcinoma\" OR kidney) AND SRC:MED","(GPNMB OR \"glycoprotein nonmetastatic B\" OR glembatumumab) AND (biomarker OR immunohistochemistry OR \"antibody-drug conjugate\") AND SRC:MED"],"updatedAt":"2026-08-20T01:28:12.481Z"},{"key":"peutz-jeghers syndrome","name":"Peutz-Jeghers syndrome","mondo":{"id":"MONDO:0008280","name":"Peutz-Jeghers syndrome"},"genes":[{"label":"STK11","kind":"causal"}],"visits":2,"openQuestions":["Does NCT05887492 (TNG260 + pembrolizumab) enrol or permit germline STK11 carriers, and what were the objective response and PD data in the STK11-deficient cohort beyond acetylation/PD-L1 changes?","Is there any Lkb1+/- murine or human PJS evidence for rapalog (rapamycin/everolimus) effects on polyp burden, and does it outperform celecoxib — the visit-2 query found none?","Can AMPK-T172 phosphorylation be induced by metformin or phenformin in STK11-null intestinal epithelium/hamartoma organoids, or is the AMPK arm truly uncoupled?","Do PJS hamartomas versus PJS-associated carcinomas differ in HDAC1/CoREST-dependent immunomodulatory gene programmes and T-cell exclusion, i.e. is epigenetic priming carcinoma-restricted?","What inter-operator reproducibility and paediatric bleeding rates have been published for size-stratified small-bowel polyp burden, and can a PJS registry replicate the Danish FAP model?","In STK11-mutant gynaecologic mucinous and SMMN-FGT lesions, what fraction of STK11 mutations are germline versus somatic, and does KRAS co-mutation stratify outcome or immune contexture?"],"leads":[{"id":"L1","title":"COX-2 inhibition (celecoxib) as pharmacologic chemoprevention of STK11-germline hamartomatous polyposis","mechanism":"Germline STK11/LKB1 loss [GERMLINE] disables AMPK-mediated mTORC1 restraint and de-represses COX-2/PGE2 in hamartomatous stroma-epithelium [KNOWN]; PGE2 blockade should slow polyp growth and the metaplasia-to-dysplasia field effect [INFERRED]. COX-2 is inducible with low constitutive expression in normal gut epithelium, giving a window, offset by cardiorenal risk during multi-year dosing in children/young adults [KNOWN].","approach":"Track NCT06722534 (celecoxib 400 mg vs placebo) for polyp-burden and PD readouts; propose companion urinary PGE-M / tissue COX-2 PD sampling and intermittent-dosing schedules; anticipated resistance routes: COX-2-independent mTORC1 drive, EP2/EP4 receptor autocrine bypass, sporadic KRAS acquisition.","level":"LEAD","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT06722534","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42544942","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":117,"lastVisit":1,"lastNote":"New lead: first interventional pharmacologic prevention trial in PJS found in this pack; mechanism itself is [KNOWN] background, not pack-derived, so level held at LEAD.","history":[{"visit":1,"cycle":117,"status":"NEW","note":"New lead: first interventional pharmacologic prevention trial in PJS found in this pack; mechanism itself is [KNOWN] background, not pack-derived, so level held at LEAD."}]},{"id":"L2","title":"Size-stratified endoscopic polyp burden as the primary efficacy endpoint for PJS drug trials","mechanism":"PJS morbidity in the polyp phase is mechanical/haemorrhagic (intussusception, gastric outlet obstruction, melena), so polyp number/size trajectory is the proximal variable a preventive agent must move [INFERRED]. Five decades of the Danish Polyposis Register in FAP demonstrate that nationwide registry linkage plus lifelong protocolised endoscopy can resolve lesion-burden phenotypes (classical vs attenuated) and translate surveillance into life-expectancy gains (PMID:42101961) — the closest available template for a PJS endpoint infrastructure [INFERRED].","approach":"Adopt double-balloon-enteroscopy cold-snare metrics as the control-arm benchmark (median 6 mm targets, 66 s/polyp, 5.9% immediate bleeding, bleeding polyps larger at 8 vs 6 mm; PMID:42544942) with obstructive events (PMID:41843399) secondary; embed in a PJS register modelled on PMID:42101961 with central image adjudication and pre-specified inter-operator reproducibility before randomisation; use low-dose aspirin (PMID:41017554) as the cross-syndrome comparator arm for L1's celecoxib.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42544942","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41843399","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42101961","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41017554","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":117,"lastVisit":2,"lastNote":"Strengthened modestly by a new hereditary-polyposis registry precedent (PMID:42101961) and an aspirin comparator (PMID:41017554); the reproducibility question that blocks promotion is still unaddressed by any pack item.","history":[{"visit":2,"cycle":196,"status":"STRENGTHENED","note":"Strengthened modestly by a new hereditary-polyposis registry precedent (PMID:42101961) and an aspirin comparator (PMID:41017554); the reproducibility question that blocks promotion is still unaddressed by any pack item."},{"visit":1,"cycle":117,"status":"NEW","note":"New lead from prospective CSP trial plus paediatric GOO case; supplies the measurable endpoint that lead 1 requires."}]},{"id":"L3","title":"LKB1-null / KRAS co-mutant PJS-spectrum tumours: avoid PD-1 monotherapy, prioritise MEK-plus-immune-priming combinations","mechanism":"In vivo CRISPR screening identifies HDAC1 as the node whose inhibition reverses STK11-loss-driven anti-PD-1 resistance; TNG260, a selective CoREST-complex inhibitor, upregulates immunomodulatory genes in STK11-deficient cells and induces immune-mediated stasis/regression with anti-PD-1 in syngeneic and autochthonous NSCLC models, with human PD confirmation of increased intratumoral histone acetylation, PD-L1 TPS and T-cell infiltration (PMID:40882030). PJS carcinomas arise on a germline STK11 background with somatic second hit, so the same cold-tumour immune-evasion state is expected [INFERRED]; a shared clonal STK11 field event with site-divergent KRAS is documented in SMMN-FGT (PMID:409002","approach":"Ask whether germline STK11 carriers with advanced carcinoma are eligible for NCT05887492; propose a genotype-stratified expansion cohort (germline STK11 PJS colorectal/pancreatic/gynaecologic carcinoma) with paired biopsies for H3K27ac/H3K9ac, PD-L1 TPS and multiplex T-cell infiltration as PD. Retain the negative-design constraint: no PD-1 monotherapy proposals in LKB1-null disease. Drop MEK+STING as the default partner (unsupported by this pack); keep KRAS genotyping for stratification. Resistance routes: antigen-presentation loss (B2M/JAK1-2), MYC/serine-glycine metabolic immune suppression, HDAC-class compensation (HDAC2/LSD1), and MAPK reactivation in KRAS co-mutants.","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"PMID","id":"40900228","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40882030","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT05887492","verified":false,"isNew":false,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":117,"lastVisit":2,"lastNote":"Promoted: independent new evidence (PMID:40882030, in vivo screen + clinical PD in NCT05887492) confirms the visit-1 negative-design claim and supplies a validated priming partner, replacing the speculative MEK/STING arm. Scope explicitly narrowed to carcinomas, not hamartomas.","history":[{"visit":2,"cycle":196,"status":"STRENGTHENED","note":"Promoted: independent new evidence (PMID:40882030, in vivo screen + clinical PD in NCT05887492) confirms the visit-1 negative-design claim and supplies a validated priming partner, replacing the speculative MEK/STING arm. Scope explicitly narrowed to carcinomas, not hamartomas."},{"visit":1,"cycle":117,"status":"NEW","note":"New lead; single case report only. Recorded as a negative-design constraint (no PD-1 monotherapy proposals) so the desk never re-proposes it."}]},{"id":"L4","title":"STK11 loss-of-function as a synthetic-lethal drug-response biomarker","mechanism":"PMID:42286854 (cervical lines, abstract truncated) still names no partner gene, drug or effect size. The only STK11-LoF dependency validated in this pack is HDAC1/CoREST and it is immune-contextual, requiring an intact host immune system (PMID:40882030) — suggesting cell-line pharmacoprofiling is a poorly powered assay for this genotype [INFERRED].","approach":"Single kill-or-confirm attempt: obtain the full pharmacoprofiling report for a named gene/drug pair and require isogenic STK11-null vs -restored validation plus an in vivo arm. This pack's CRISPR-screen query returned only an influenza-attachment role for STK11 in porcine trachea cells (PMID:41061927) and a generic KRAS review (PMID:38275900) — record so 'STK11 AND CRISPR screen' is not re-run unfielded.","level":"LEAD","confidence":0.12,"citations":[{"kind":"PMID","id":"42286854","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40882030","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41061927","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":117,"lastVisit":2,"lastNote":"Weakened: targeted search for a replicating cell-intrinsic partner failed; the one real dependency found is immune-mediated, undercutting the premise. Retire next visit absent a named partner.","history":[{"visit":2,"cycle":196,"status":"WEAKENED","note":"Weakened: targeted search for a replicating cell-intrinsic partner failed; the one real dependency found is immune-mediated, undercutting the premise. Retire next visit absent a named partner."},{"visit":1,"cycle":117,"status":"NEW","note":"New but deliberately low-confidence: abstract-only, cervical-cancer context, cell lines not PJS tissue; flagged for kill-or-confirm next visit."}]},{"id":"L5","title":"Metformin/AMPK-axis chemoprevention in PJS is mechanistically self-defeating — test complex-I-dependent, AMPK-independent readouts before any PJS trial","mechanism":"Drug-target Mendelian randomisation finds PRKAG1 (AMPK gamma-1) genetic proxies associated with reduced colorectal cancer risk (OR 0.74 per mmol/mol HbA1c reduction, HbA1c-independent) (PMID:41755790); observational meta-analysis favours metformin over sulfonylureas/AGIs/insulin for pancreatic cancer risk reduction (PMID:42196179); endometrial-cancer reviews attribute benefit to AMPK/mTOR plus insulin sensitisation (PMID:42384117). But LKB1 is the obligate upstream activating kinase of AMPK [KNOWN], so germline STK11 loss [GERMLINE] should blunt exactly the arm these data implicate — predicting attenuated metformin benefit in PJS tissue relative to the general population, and favouring direc","approach":"Falsification-first: in Lkb1+/- murine polyposis and PJS-patient-derived hamartoma organoids, compare metformin/phenformin with a rapalog on p-AMPK-T172, p-S6/p-4E-BP1 and polyp burden; if AMPK phosphorylation is uninducible, treat metformin as PJS-inactive and record it as a closed avenue. Note that the pack's rapamycin/everolimus/polyposis query returned zero PJS or Lkb1+/- interventional data, so open question 1 is still unanswered. Confounders in PMID:42196179 (observational, immortal-time/prevalent-user bias) preclude any preventive claim; no germline STK11 carriers were studied.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"41755790","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42196179","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42384117","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":196,"lastVisit":2,"lastNote":"New lead framed as a mechanistic contradiction, not a repurposing endorsement: genetic validation of metformin's cancer benefit runs through PRKAG1/AMPK, the node LKB1 loss disables.","history":[{"visit":2,"cycle":196,"status":"NEW","note":"New lead framed as a mechanistic contradiction, not a repurposing endorsement: genetic validation of metformin's cancer benefit runs through PRKAG1/AMPK, the node LKB1 loss disables."}]}],"retired":[],"nextQueries":["(TNG260 OR \"CoREST\" OR \"HDAC1\") AND (STK11 OR LKB1) AND (immunotherapy OR \"PD-1\") AND SRC:MED","(\"Peutz-Jeghers\" OR \"Lkb1+/-\" OR \"Stk11 heterozygous\") AND (rapamycin OR sirolimus OR everolimus OR \"mTORC1\") AND (polyp OR hamartoma) AND SRC:MED","(STK11 OR LKB1) AND (AMPK OR PRKAA1 OR \"complex I\") AND (metformin OR phenformin) AND (organoid OR intestin*) AND PUB_YEAR:[2020 TO 2026] AND SRC:MED"],"updatedAt":"2026-08-20T01:31:49.845Z"},{"key":"juvenile polyposis syndrome","name":"juvenile polyposis syndrome","mondo":{"id":"MONDO:0017380","name":"juvenile polyposis syndrome"},"genes":[{"label":"SMAD4","kind":"causal"},{"label":"BMPR1A","kind":"causal"},{"label":"PTEN","kind":"correlated"},{"label":"ENG","kind":"correlated"}],"visits":2,"openQuestions":["Does any human cohort or case series report polyp burden change on sirolimus/everolimus in a hamartomatous polyposis syndrome (PHTS, Peutz-Jeghers, Cowden) that could serve as the phenocopy benchmark for JPS?","In JPS polyps that progress to dysplasia, is the second hit (SMAD4/BMPR1A LOH, KRAS, APC, TGFBR2) in the epithelium or the stroma, and is there compartment-resolved sequencing anywhere in the literature?","Is SMAD4-JPS gastric polyposis (and prophylactic gastrectomy series) a better-documented endpoint substrate than colonic polyp count for a within-patient pre/post trial design?","Can any Ipsl1-3 candidate (STAM2, PSMD6, NAMPT, CACNB4) be tied to polyp burden in genotype-matched human SMAD4 carriers?","Does BMP9/10-ALK1-ENG-SMAD4 endothelial pharmacology (pazopanib, bevacizumab, thalidomide) have transfusion-requirement data in SMAD4-JPS/HHT overlap specifically, as opposed to HHT1/HHT2?"],"leads":[{"id":"L1","title":"Rapalog (sirolimus/everolimus) suppression of hamartomatous polyp burden in SMAD4/BMPR1A-germline JPS","mechanism":"Germline LOF of SMAD4 [GERMLINE] or BMPR1A [GERMLINE] removes BMP/SMAD restraint on PI3K-AKT-mTORC1 in polyp epithelium and stroma [INFERRED]; convergence with PTEN [GERMLINE] hamartoma biology, where rapalogs reduce hamartoma burden [KNOWN], predicts mTORC1 dependence of polyp growth and of the bleeding/protein-losing phenotype.","approach":"Registry-embedded (NCT03050268-type cohorts) single-arm sirolimus or everolimus; primary endpoint polyp number/size per segment at paired surveillance endoscopy, secondary haemoglobin/ferritin/albumin; paired biopsies for phospho-S6 and 4E-BP1 pharmacodynamics. Before any trial design work, must first establish whether ANY human polyp-burden data exist in a rapalog-treated hamartomatous polyposis cohort (PHTS or Peutz-Jeghers as phenocopy). Expected resistance: S6K-IRS1 feedback loss with AKT reactivation, 4E-BP1-independent eIF4E activity, mTORC1-independent stromal drive. Window: chronic immunosuppression, stomatitis, growth suppression in paediatric carriers.","level":"LEAD","confidence":0.29,"citations":[{"kind":"PMID","id":"42110114","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03050268","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":118,"lastVisit":2,"lastNote":"A query purpose-built to find rapalog evidence in JPS ('juvenile polyposis' OR SMAD4 OR BMPR1A AND sirolimus/everolimus/rapamycin/mTOR) returned zero on-topic records; the entire pack was off-target (renal fibrosis, IBD circRNA, PDAC, carp nutrition). Directed search failure shifts the prior against existence of indexed cohort evidence, so confidence drops 0.35 to 0.29. Lead retained because the s","history":[{"visit":2,"cycle":197,"status":"WEAKENED","note":"A query purpose-built to find rapalog evidence in JPS ('juvenile polyposis' OR SMAD4 OR BMPR1A AND sirolimus/everolimus/rapamycin/mTOR) returned zero on-topic records; the entire pack was off-target (renal fibrosis, IBD circRNA, PDAC, carp nutrition). Directed search failure shifts the prior against existence of indexed cohort evidence, so confidence drops 0.35 to 0.29. Lead retained because the s"},{"visit":1,"cycle":118,"status":"NEW","note":"Created this visit. Only drug-named therapeutic hypothesis in the pack; evidence is one sentence in a paediatric SMAD4 c.1549_1550del case report (abstract only, no dose, no burden metric, no outcome) — deliberately entered at low confidence and must be corroborated by independent cohort data before promotion."}]},{"id":"L2","title":"Modifier-locus-directed chemoprevention in Smad4-deficient polyposis (Ipsl1-3: immune, ubiquitin-proteasome, NAD-metabolic nodes)","mechanism":"Phenotypic variability among identical SMAD4 [GERMLINE] carriers is modifier-driven; Collaborative Cross x Smad4-KO QTL mapping localises polyp number/size to Ipsl1 (chr16), Ipsl2 (chr14), Ipsl3 (chr12) plus sex-specific loci, enriched for immune signalling, ubiquitin-proteasome degradation and metabolic regulation, with STAM2, PSMD6, NAMPT, CACNB4 as candidates. [SPECULATIVE] NAD salvage (NAMPT) and proteasome subunit nodes are already pharmacologically addressable, so a validated modifier becomes a chemoprevention target that spares the undruggable tumour-suppressor loss itself.","approach":"Fine-map Ipsl intervals and test candidate causality by allele-specific knock-in or CC-line-stratified pharmacology in Smad4+/- mice (NAMPT inhibitor e.g. FK866 [KNOWN]; proteasome modulation) with polyp count per segment as endpoint; require human replication of modifier orthologues in genotype-matched SMAD4 carriers with discordant polyp burden before any target claim.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42193864","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":118,"lastVisit":1,"lastNote":"Created this visit from the pack's only mechanistic study. QTL intervals are wide and candidate assignment is enrichment-based, so this is a prioritisation substrate, not yet a target; role in normal tissue (NAMPT in NAD homeostasis, PSMD6 in global proteostasis) makes therapeutic window the main risk.","history":[{"visit":1,"cycle":118,"status":"NEW","note":"Created this visit from the pack's only mechanistic study. QTL intervals are wide and candidate assignment is enrichment-based, so this is a prioritisation substrate, not yet a target; role in normal tissue (NAMPT in NAD homeostasis, PSMD6 in global proteostasis) makes therapeutic window the main risk."}]},{"id":"L3","title":"Anti-angiogenic control of the SMAD4-JPS/HHT overlap bleeding and anaemia phenotype","mechanism":"SMAD4 [GERMLINE] and ENG [GERMLINE, miscalled correlated/somatic by the KG] act in the same BMP9/10-ALK1-ENG-SMAD4 endothelial pathway; LOF de-represses VEGF-driven vascular remodelling, producing mucocutaneous/GI telangiectasia and AVMs, and in SMAD4 carriers this overlaps with hamartomatous polyposis to drive the dominant morbidity of chronic GI blood loss.","approach":"Morbidity-control (not anticancer) hypothesis: evaluate VEGF-directed therapy in SMAD4-JPS/HHT overlap with endpoints of transfusion/iron requirement and haemoglobin, benchmarked against embolisation for PAVMs which is already standard of care; stratify by SMAD4 vs ENG/ACVRL1 genotype since HHT1 is pulmonary/cerebral-predominant while SMAD4-overlap is hepatic/GI-predominant. Expected resistance: VEGF-independent ANGPT2/TIE2 remodelling; window: hypertension, impaired mucosal healing, contraindication around polypectomy.","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"42209023","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42110114","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":118,"lastVisit":1,"lastNote":"Created this visit; both citations are case reports establishing the shared axis and the SMAD4 overlap phenotype, not efficacy data. Explicitly framed as symptom/morbidity control so it is not mistaken for a cancer-prevention claim.","history":[{"visit":1,"cycle":118,"status":"NEW","note":"Created this visit; both citations are case reports establishing the shared axis and the SMAD4 overlap phenotype, not efficacy data. Explicitly framed as symptom/morbidity control so it is not mistaken for a cancer-prevention claim."}]},{"id":"L4","title":"SMAD4-loss-associated stromal/CAF and immune-exclusion programme as the polyp-to-carcinoma engine in JPS (scaffolding lead)","mechanism":"SMAD4 [GERMLINE in JPS; SOMATIC in sporadic GI cancer] is the common node of TGF-beta/BMP transcriptional output; its loss is [KNOWN] a frequent somatic event in pancreatic and colorectal carcinoma where it associates with desmoplastic, immunosuppressive stroma. [SPECULATIVE] The stromal compartment of JPS polyps, not the epithelium, may carry the SMAD4-null growth advantage, in which case CAF-directed pharmacology (ECM modulation, disruption of CAF-epithelial crosstalk) rather than epithelial-targeted agents would be the correct axis for progression prevention. Cited reviews describe CAF-targeting strategies generically (PMID:41902481) and the immunosuppressive PDAC microenvironment with IC","approach":"Before any drug claim: laser-capture or single-cell separation of epithelium vs stroma from JPS polyps genotyped for germline SMAD4/BMPR1A, testing for second-hit LOH compartment-by-compartment and for a CAF signature; only if the stroma is the SMAD4-null compartment does CAF-directed or TGF-beta-axis pharmacology become rational. Note the PDAC precedent that checkpoint blockade fails outside MSI-high tumours (PMID:42082461) argues against naive ICI in SMAD4-driven GI neoplasia. Normal-tissue window: fibroblast and TGF-beta signalling are required for mucosal repair, so anti-stromal agents risk impaired healing after polypectomy.","level":"LEAD","confidence":0.15,"citations":[{"kind":"PMID","id":"41902481","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42082461","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":197,"lastVisit":2,"lastNote":"Created only to give open question 4 a docket entry. Both citations are generic 2026 reviews with no SMAD4 content in the abstract, so this is hypothesis scaffolding and is explicitly barred from promotion on these citations; it must be either fed real SMAD4-genotype stromal data next visit or retired.","history":[{"visit":2,"cycle":197,"status":"NEW","note":"Created only to give open question 4 a docket entry. Both citations are generic 2026 reviews with no SMAD4 content in the abstract, so this is hypothesis scaffolding and is explicitly barred from promotion on these citations; it must be either fed real SMAD4-genotype stromal data next visit or retired."}]}],"retired":[],"nextQueries":["(\"juvenile polyposis\" OR \"hamartomatous polyp*\" OR \"BMPR1A\") AND (sirolimus OR everolimus OR rapamycin) AND SRC:MED","(\"juvenile polyposis\" OR \"BMPR1A\") AND (\"loss of heterozygosity\" OR \"second hit\" OR somatic OR dysplasia OR carcinoma) AND SRC:MED","(\"SMAD4\" AND \"hereditary hemorrhagic telangiectasia\") AND (bevacizumab OR pazopanib OR thalidomide OR transfusion) AND SRC:MED"],"updatedAt":"2026-08-20T01:34:52.296Z"},{"key":"hereditary pheochromocytoma-paraganglioma","name":"hereditary pheochromocytoma-paraganglioma","mondo":{"id":"MONDO:0017366","name":"hereditary pheochromocytoma-paraganglioma"},"genes":[{"label":"SDHAF2","kind":"causal"},{"label":"SLC25A11","kind":"causal"},{"label":"DLST","kind":"causal"},{"label":"SDHB","kind":"causal"},{"label":"SDHC","kind":"causal"},{"label":"SDHD","kind":"causal"},{"label":"SDHA","kind":"causal"},{"label":"RET","kind":"correlated"},{"label":"NF1","kind":"correlated"},{"label":"VHL","kind":"correlated"},{"label":"MDH2","kind":"correlated"},{"label":"KIF1B","kind":"correlated"}],"visits":2,"openQuestions":["Do SDHx-mutant PPGL show the same insulator-loss-driven FGF3/FGF4 derepression and FGFR1 phosphorylation as SDH-deficient GIST, and what fraction carry MGMT promoter methylation?","Within LITESPARK-015 / NCT04924075, does belzutifan response (ORR, PFS) segregate by SDHx vs VHL vs FH vs sporadic genotype, and what genomic correlates emerge in response to PMID:42481355?","What acquired-resistance mechanisms occur on belzutifan in PPGL specifically (HIF2A PAS-B/dimerisation mutations, HIF1A switching, EGLN1 or VHL restoration), and are ctDNA assays able to detect them?","Is the UBE2F/neddylation dependency reproducible in human SDHB-mutant PPGL cells or PDX in vivo, and which CRL5 substrate mediates it?","Is there any 177Lu-DOTATATE response or SSTR2 expression data restricted to SDHx-mutant metastatic PPGL, as opposed to imaging avidity alone?","Does SDH/FH loss cause a bona fide homologous-recombination defect, or is alkylator sensitivity purely MGMT-methylation-driven?"],"leads":[{"id":"L1","title":"HIF-2α inhibition (belzutifan) in cluster-1 pseudohypoxic hereditary PPGL","mechanism":"Germline SDHA/B/C/D, SDHAF2, SLC25A11, DLST loss [GERMLINE] causes succinate accumulation and competitive PHD2 inhibition; VHL and FH loss converge on the same node, stabilising HIF-2α and driving VEGFA/PDGFB/EPO/LOX output (PMID:42573142). Belzutifan blocks HIF-2α/ARNT dimerisation at the point of convergence; anaemia is the on-target normal-tissue cost via renal EPO suppression [KNOWN].","approach":"Genotype-stratified analysis and expansion within NCT04924075 (SDHx vs VHL vs FH vs sporadic), directly answering the biomarker call in PMID:42481355; paired pre/post biopsy for HIF-2α target-gene signature and succinate/2-OG ratios; HIF2A/HIF1A/EGLN1 resequencing at progression for P-loop/PAS-B dimerisation-domain mutations and HIF1A switching; test belzutifan + VEGFR-TKI or + 177Lu-DOTATATE in metastatic SDHB disease; capture perioperative interactions (PMID:42468809).","level":"CANDIDATE","confidence":0.72,"citations":[{"kind":"NCT","id":"NCT04924075","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07167329","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT00001238","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42573142","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42481355","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42503916","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42468809","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":119,"lastVisit":2,"lastNote":"Promoted on NEW independent phase 2 efficacy data (LITESPARK-015: DCR 85%, ORR 26%) plus FDA approval; however PMID:42481355 confirms genotype/genomic correlates of response are still absent, so the SDHx-vs-VHL dependence question that defines this lead remains open rather than answered.","history":[{"visit":2,"cycle":198,"status":"STRENGTHENED","note":"Promoted on NEW independent phase 2 efficacy data (LITESPARK-015: DCR 85%, ORR 26%) plus FDA approval; however PMID:42481355 confirms genotype/genomic correlates of response are still absent, so the SDHx-vs-VHL dependence question that defines this lead remains open rather than answered."},{"visit":1,"cycle":119,"status":"NEW","note":"New programme. Two active belzutifan trials in the pack, one enrolling advanced PPGL explicitly; anchors directly onto the causal SDHx germline anchor set via the succinate-PHD2-HIF2A axis. Resistance routes named (HIF1A compensation, HIF2A dimerisation-domain mutations); window limited by normal renal EPO and carotid-body HIF-2α function."}]},{"id":"L2","title":"SSTR2-directed radioligand therapy, with HIF-2α blockade as radiosensitising partner","mechanism":"Cluster-1 PPGL/PGL overexpress somatostatin receptor 2; the pack's DOTATATE-avid cases (including a VHL child with multifocal primaries and an ACTH-cosecreting pheochromocytoma) confirm target presence in situ. SSTR2 internalisation delivers 177Lu to chromaffin tumour cells; HIF-2α blockade may reduce hypoxia-mediated radioresistance [SPECULATIVE].","approach":"Quantify SSTR2 IHC/DOTATATE SUVmax against germline genotype in banked HPPGL cohorts; design a 177Lu-DOTATATE ± belzutifan window-of-opportunity study in unresectable SDHB-mutant metastatic disease; monitor renal and marrow dosimetry and post-treatment SSTR2 downregulation as the anticipated resistance route.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"39253568","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42221407","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":119,"lastVisit":1,"lastNote":"New. Evidence is imaging-only (target presence, not efficacy) — explicitly a hypothesis-generating lead, not corroboration of benefit.","history":[{"visit":1,"cycle":119,"status":"NEW","note":"New. Evidence is imaging-only (target presence, not efficacy) — explicitly a hypothesis-generating lead, not corroboration of benefit."}]},{"id":"L4","title":"Integrated germline+tumour interpretation (including splice-altering VUS) to define the trial-eligible cluster-1 population","mechanism":"SDHx tumorigenesis follows two-hit inactivation, so somatic loss of the wild-type allele plus SDHB IHC loss is corroborating evidence for germline pathogenicity; conversely, single-nucleotide 'VUS' can create cryptic splice donors and be functionally null, as shown by RT-PCR for an SDHB variant reported as VUS.","approach":"Route HPPGL VUS through INT2GRATE-style integrated germline/somatic assessment plus RNA/RT-PCR splice confirmation before declaring patients genotype-negative; use reclassified cases as the enrolment funnel for HIF-2α-directed trials; prospectively re-test panel-negative bilateral/recurrent cases (as in the MAX case found only on repeat testing).","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"38473309","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41030646","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42005593","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41446467","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":119,"lastVisit":1,"lastNote":"New. Enabling rather than therapeutic, but it directly gates every genotype-stratified hypothesis above; three independent pack items show the eligible population is undercounted.","history":[{"visit":1,"cycle":119,"status":"NEW","note":"New. Enabling rather than therapeutic, but it directly gates every genotype-stratified hypothesis above; three independent pack items show the eligible population is undercounted."}]},{"id":"L5","title":"Neddylation (UBE2F/NAE) inhibition as an SDHB-selective vulnerability in PPGL","mechanism":"Unbiased CRISPR-Cas9 screening in immortalised mouse chromaffin cells ± Sdhb loss identified the neddylation pathway as differentially essential: loss of UBE2F suppressed Sdhb-deficient growth while loss of UBE2M increased proliferation, and pevonedistat/HA-9104 reduced UBE2F activity and selectively inhibited Sdhb-deficient cells (PMID:42181244). [INFERRED] SDHB loss likely creates dependence on CRL5/UBE2F-mediated degradation of a stress- or redox-regulated substrate, plausibly linked to the reductive-stress/PTM rewiring state described in PMID:42150423.","approach":"Validate in human SDHB-mutant PPGL models and PDX (noted as scarce in PMID:42503916): CRL5 substrate profiling, UBE2F vs UBE2M dependency arms, pevonedistat dose-response with succinate rescue; then a genotype-restricted phase 1/2 of pevonedistat in SDHx metastatic PPGL, possibly with belzutifan. Window argument: pan-NAE1 inhibition is myelosuppressive/hepatotoxic [KNOWN], so UBE2F/CRL5 selectivity is the therapeutic-window claim to test. Resistance routes: NAE1 gatekeeper mutations, UBE2M compensation.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42181244","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42150423","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":198,"lastVisit":2,"lastNote":"New: first functional synthetic-lethal screen in an SDH-loss chromaffin model in this programme; mouse imCC only, no human tumour or in vivo data, hence LEAD not higher.","history":[{"visit":2,"cycle":198,"status":"NEW","note":"New: first functional synthetic-lethal screen in an SDH-loss chromaffin model in this programme; mouse imCC only, no human tumour or in vivo data, hence LEAD not higher."}]},{"id":"L6","title":"FGFR1 autocrine loop from succinate-driven hypermethylation: rogaratinib repurposing in SDHx PPGL","mechanism":"In SDH-deficient GIST, genome-wide DNA hypermethylation disrupts genomic insulators and derepresses FGF3/FGF4, creating an autocrine FGFR1 loop; pan-FGFR inhibition with rogaratinib gave ORR 41.7% and median PFS 31.0 months in a phase 2 cohort (PMID:42191879). Methylation profiling confirms SDH-deficient GIST as an epigenomically distinct hypermethylator class (PMID:40629847). [INFERRED] SDHx PPGL shares the same succinate→TET/2-OG-dioxygenase inhibition→hypermethylation state [KNOWN], so the same insulator-loss/FGF ligand mechanism may operate in chromaffin tumours; the ETC-limitation→dioxygenase framework in PMID:42150423 supports transferability.","approach":"First, biomarker triage, not a trial: FGF3/FGF4/FGFR1 RNA and protein plus insulator-region methylation (WGBS/EPIC) in banked SDHB/SDHD PPGL versus cluster-2 and sporadic tumours; serum FGF3/FGF4 as PD readout as done in PMID:42191879. If ligand derepression is confirmed, a genotype-restricted rogaratinib (or erdafitinib/pemigatinib) basket arm in metastatic SDHx PPGL. Expected toxicity/window: hyperphosphatemia, nail and retinal effects from normal FGFR-dependent phosphate and epithelial homeostasis [KNOWN]. Resistance: FGFR1 gatekeeper mutations, FGF ligand switching, MAPK reactivation.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42191879","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40629847","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42150423","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":198,"lastVisit":2,"lastNote":"New and explicitly cross-tumour: strong clinical efficacy in SDH-deficient GIST, zero PPGL data. Entered at moderate confidence contingent on measuring FGF3/FGF4 in SDHx chromaffin tumours; will be retired if PPGL lacks the ligand derepression.","history":[{"visit":2,"cycle":198,"status":"NEW","note":"New and explicitly cross-tumour: strong clinical efficacy in SDH-deficient GIST, zero PPGL data. Entered at moderate confidence contingent on measuring FGF3/FGF4 in SDHx chromaffin tumours; will be retired if PPGL lacks the ligand derepression."}]},{"id":"L7","title":"MGMT-methylation-stratified alkylator therapy (and MDM4-p53 axis) in SDHx metastatic PPGL","mechanism":"Methylation profiling of SDH-deficient GIST found MGMT promoter methylation in 6 primary and 5 metastatic tumours and MDM4 gain/low-level amplification in 7, activating the MDM4-p53 axis (PMID:40629847). [INFERRED] Succinate-driven global hypermethylation can silence MGMT, providing a mechanistic biomarker for the empirical temozolomide/dacarbazine sensitivity long observed in SDHB-mutant metastatic PPGL [KNOWN]; CVD-type regimens are still the guideline comparator for aggressive disease (PMID:42454639).","approach":"Retrospective MGMT promoter methylation and MGMT IHC on archival SDHB/SDHD metastatic PPGL with documented temozolomide or CVD outcomes; prospectively use MGMT methylation as the enrolment biomarker for single-agent temozolomide (or TMZ + PARP inhibitor, testing the 2-OG-dioxygenase/BRCAness question) versus CVD. Separately, test MDM4/MDM2 inhibitor sensitivity in TP53-wild-type SDHx models. Window: alkylator myelosuppression and secondary malignancy risk in young germline carriers is the limiting argument. Resistance: MGMT re-expression by promoter demethylation, MMR loss with hypermutation.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"40629847","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42454639","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42150423","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":198,"lastVisit":2,"lastNote":"New; partially addresses open question 3 by supplying an epigenetic rather than homologous-recombination rationale for alkylator sensitivity. Evidence is from SDH-deficient GIST, not PPGL, and is biomarker-prevalence only with no response correlation.","history":[{"visit":2,"cycle":198,"status":"NEW","note":"New; partially addresses open question 3 by supplying an epigenetic rather than homologous-recombination rationale for alkylator sensitivity. Evidence is from SDH-deficient GIST, not PPGL, and is biomarker-prevalence only with no response correlation."}]}],"retired":[{"title":"MAX-null (MEN5) PPGL: synthetic-lethal dependencies downstream of lost MXD repression","note":"Retired as pre-committed at visit 1: the chromaffin CRISPR screen that arrived this visit (PMID:42181244) was Sdhb-focused and yielded no MAX arm, no MYC-network or MGA/MNT paralogue dependency, and no drug data for MAX-null tumours. No functional dependency evidence exists in the pack; carrying it further would be unfunded speculation.","cycle":198,"ts":"2026-08-20T01:38:18.358Z"}],"nextQueries":["(pheochromocytoma OR paraganglioma OR SDHB OR SDHD) AND (FGF3 OR FGF4 OR FGFR1 OR insulator OR \"methylation classifier\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(pheochromocytoma OR paraganglioma) AND (belzutifan OR \"HIF-2alpha\") AND (resistance OR biomarker OR genotype OR ctDNA OR \"LITESPARK-015\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(SDHB OR SDHx OR paraganglioma) AND (MGMT OR temozolomide OR \"177Lu-DOTATATE\" OR neddylation OR pevonedistat OR UBE2F) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-20T01:38:18.358Z"},{"key":"von hippel-lindau disease","name":"von Hippel-Lindau disease","mondo":{"id":"MONDO:0008667","name":"von Hippel-Lindau disease"},"genes":[{"label":"VHL","kind":"causal"},{"label":"CCND1","kind":"correlated"}],"visits":2,"openQuestions":["What is the published frequency and spectrum of acquired belzutifan resistance mechanisms (EPAS1 gatekeeper substitutions, ARNT alterations, HIF-1α or ETS1-dependent persistence) in VHL disease and sporadic ccRCC — still unanswered after tw","Which HIF-independent pVHL functions are named in the recent literature (non-canonical substrates, ubiquitin-ligase-independent activities), and are any lesion-type specific and druggable?","Can ETS1 be degraded with a therapeutic window — i.e. does any CRBN glue/PROTAC degrade ETS1 without GSPT1 co-degradation, and does ETS1 loss spare T/NK and endothelial compartments in vivo?","Is systemic belzutifan or cabozantinib activity in retinal and CNS/spinal hemangioblastoma durable and cyst-penetrating enough to defer resection — what quantitative lesion- and cyst-volume data exist?","Do belzutifan PPGL/pNET responses segregate by genotype or SSTR expression, and how should 177Lu-DOTATATE be sequenced against HIF-2α blockade under renal dosimetric constraint?","Is the FAM120A/SREBP1 lipogenic axis a VHL-genotype-selective dependency in ccRCC, or a general lipid phenotype of the histology?"],"leads":[{"id":"L1","title":"HIF-2α–ARNT dimerization blockade (belzutifan) as systemic backbone across the VHL lesion spectrum","mechanism":"Germline VHL loss plus somatic second hit abolishes CUL2/ELOB/ELOC/RBX1-dependent HIF-α degradation; hardwired HIF-2α output (VEGFA, EPO, CXCR4) drives ccRCC, hemangioblastoma, pNET and PPGL. Belzutifan blocks the HIF-2α–ARNT interface. PMID:42313274 confirms regulatory breadth (FDA and EMA) across VHL lesion types and flags HIF-independent pVHL functions as an unaddressed residual driver.","approach":"Belzutifan monotherapy with organ-preservation endpoints (NCT04924075, NCT07405164, registries NCT00001238/NCT00005902); ICI/TKI-sequenced and earlier-line combinations per PMID:42406187; monitor anaemia and hypoxaemia. Named resistance routes: EPAS1 gatekeeper substitutions, ARNT alterations, HIF-1α compensation, VEGF-independent angiogenic switch, cofactor-mediated (ETS1) persistence. Normal tissue: HIF-2α drives renal EPO and carotid-body O2 sensing — defines the window [KNOWN].","level":"CANDIDATE","confidence":0.82,"citations":[{"kind":"PMID","id":"41569310","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42604778","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42593521","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04924075","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07405164","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42313274","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42406187","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT00001238","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":121,"lastVisit":2,"lastNote":"New independent 2026 VHL pathophysiology review (PMID:42313274) plus a checkpoint-combination review positioning belzutifan post-ICI/TKI and earlier-line (PMID:42406187) corroborate the backbone on a second evidence-bearing visit. Still no published EPAS1 gatekeeper frequency data in the pack.","history":[{"visit":2,"cycle":199,"status":"STRENGTHENED","note":"New independent 2026 VHL pathophysiology review (PMID:42313274) plus a checkpoint-combination review positioning belzutifan post-ICI/TKI and earlier-line (PMID:42406187) corroborate the backbone on a second evidence-bearing visit. Still no published EPAS1 gatekeeper frequency data in the pack."},{"visit":1,"cycle":121,"status":"NEW","note":"Opened this visit: 2026 reviews document phase III ccRCC validation, cabozantinib combination durability, PPGL/pediatric approval, and Japanese reimbursement specifically for VHL hemangioblastoma; two live Merck protocols cover the VHL spectrum."}]},{"id":"L2","title":"Dual-axis HIF suppression: reduce HIF-α abundance (translation/mTOR-eIF2α) on top of dimerization blockade to pre-empt belzutifan escape","mechanism":"Chemically diverse HIF inhibitors converge on translation-centred mechanisms — mTORC1 inhibition, eIF2α-dependent stress response, reduced HIF-α synthesis — acting independently of oxygen-dependent degradation (PMID:42202639). Lowering HIF-α protein pool is orthogonal to blocking HIF-2α–ARNT interface, so it should retain activity against gatekeeper EPAS1 mutants and against HIF-1α compensation [INFERRED].","approach":"Preclinical VHL-null ccRCC/hemangioblastoma models: belzutifan plus mTOR inhibitor (everolimus) or eIF2α-stress inducers; readouts HIF-2α protein, ARNT ChIP occupancy, VEGFA/CCND1 transcript output; engineer EPAS1 gatekeeper alleles to test cross-resistance. Window caveat: additive anaemia and immunosuppression with mTOR blockade [SPECULATIVE].","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"42202639","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42593521","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":121,"lastVisit":1,"lastNote":"New axis derived from the Redox Biology HIF-inhibition review; positioned as resistance pre-emption rather than a standalone claim, since no VHL-specific in vivo data are in the pack.","history":[{"visit":1,"cycle":121,"status":"NEW","note":"New axis derived from the Redox Biology HIF-inhibition review; positioned as resistance pre-emption rather than a standalone claim, since no VHL-specific in vivo data are in the pack."}]},{"id":"L3","title":"Compartment-directed therapy for retinal capillary hemangioblastoma: intravitreal anti-VEGF plus focal laser as adjunct or alternative to systemic HIF-2α blocka","mechanism":"RCH is driven by HIF-2α-dependent VEGFA/angiogenic output after biallelic VHL loss. Contrary to the drug-sequestered-eye premise, systemic HIF-2α blockade produced RCH size reduction with decreased perfusion and vascularity at 4 months (PMID:42494590), and systemic VEGFR/MET inhibition (cabozantinib) produced complete, 3-year-durable regression of a juxtapapillary lesion refractory to intravitreal anti-VEGF, corticosteroid, vitrectomy and laser (PMID:42111285). Systemic exposure therefore suffices for retinal lesion control in at least some patients.","approach":"Prospective ocular-endpoint substudy within belzutifan protocols (NCT04924075/NCT07405164) using OCT-A perfusion and lesion volume; ask whether systemic therapy reduces intravitreal injection burden, and whether cabozantinib rescues RCH progressing on belzutifan (and vice versa). Reserve focal laser/intravitreal anti-VEGF for exudative salvage. Use NCI/NEI/MDACC registries (NCT01496625, NCT05955014, NCT00001238) for baseline ocular natural history. Window: belzutifan anaemia/hypoxaemia vs cabozantinib hypertension and wound-healing risk in an eye already surgically manipulated [KNOWN].","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42254309","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT01496625","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05955014","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42494590","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42111285","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT04924075","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":121,"lastVisit":2,"lastNote":"Direction reversed: two independent 2026 case reports show systemic agents reach and regress retinal lesions, one of them in a lesion explicitly refractory to intravitreal anti-VEGF — so local-compartment primacy is weakened while the lead itself gains support. Held at LEAD despite two new citations because the evidence is n=2 uncontrolled case reports; promotion awaits prospective ocular endpoint","history":[{"visit":2,"cycle":199,"status":"STRENGTHENED","note":"Direction reversed: two independent 2026 case reports show systemic agents reach and regress retinal lesions, one of them in a lesion explicitly refractory to intravitreal anti-VEGF — so local-compartment primacy is weakened while the lead itself gains support. Held at LEAD despite two new citations because the evidence is n=2 uncontrolled case reports; promotion awaits prospective ocular endpoint"},{"visit":1,"cycle":121,"status":"NEW","note":"Single pediatric case, confounded by co-inherited NR2E3 enhanced S-cone syndrome — low-weight evidence, kept as a compartment-pharmacology question rather than an efficacy claim."}]},{"id":"L4","title":"SSTR-directed theranostics for VHL pseudohypoxic pNET and pheochromocytoma/paraganglioma","mechanism":"Cluster-1 pseudohypoxic VHL-mutant neuroendocrine lesions are 68Ga-DOTATATE-avid [KNOWN], enabling 177Lu-DOTATATE for unresectable multifocal disease. PMID:42481355 shows belzutifan's PPGL approval currently lacks published genomic correlates or subgroup outcome data, so the choice between HIF-2α blockade and PRRT in a molecularly heterogeneous population is unguided.","approach":"Genotype- and tracer-directed algorithm (68Ga-DOTATATE vs 18F-FDG vs 18F-DOPA) to allocate VHL patients to PRRT vs belzutifan; embed germline/somatic genomic correlates and SSTR2 expression in belzutifan PPGL cohorts as the multistakeholder call demands; renal dosimetry mandatory given lifelong nephron-sparing surgery burden.","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"42274298","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41569310","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41948715","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42481355","verified":true,"isNew":true,"addedVisit":2},{"kind":"NCT","id":"NCT04924075","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":121,"lastVisit":2,"lastNote":"New multistakeholder call (PMID:42481355) confirms the biomarker vacuum behind the PPGL approval, which is exactly the gap this lead exploits; still no VHL-specific PRRT outcome data in any pack, so confidence rises only marginally.","history":[{"visit":2,"cycle":199,"status":"STRENGTHENED","note":"New multistakeholder call (PMID:42481355) confirms the biomarker vacuum behind the PPGL approval, which is exactly the gap this lead exploits; still no VHL-specific PRRT outcome data in any pack, so confidence rises only marginally."},{"visit":1,"cycle":121,"status":"NEW","note":"New: functional-imaging review makes genotype-directed theranostics explicit; a VHL gastric NET case shows the neuroendocrine spectrum is broader than adrenal/pancreatic. No VHL-specific PRRT outcome data in pack."}]},{"id":"L6","title":"ETS1 degradation as a cofactor-directed adjunct to HIF-2α blockade in VHL-null ccRCC","mechanism":"ETS1 (p51/p42 isoforms) cooperates with EPAS1/HIF-2α to drive VHL-deficient ccRCC transcriptional output; the CRBN molecular glue cc-885 ubiquitinates and degrades ETS1, disrupts the ETS1–EPAS1 complex and selectively suppresses VHL-null cells, with enhanced efficacy when combined with belzutifan (PMID:42089431). Removing a required cofactor is orthogonal to blocking the HIF-2α–ARNT interface, so it should retain activity against EPAS1 gatekeeper mutants and possibly against HIF-1α switching [INFERRED].","approach":"Reconstitute isogenic VHL-null vs VHL-restored ccRCC and hemangioblastoma-like lines; engineer EPAS1 gatekeeper alleles and test cc-885 (and cleaner, non-GSPT1-degrading ETS1 glues/PROTACs) ± belzutifan; readouts ETS1 protein, ETS1/HIF-2α co-occupancy ChIP, VEGFA output, xenograft regression. Window: cc-885 also degrades GSPT1 and is broadly cytotoxic [KNOWN]; ETS1 is required for T/NK lineage development and endothelial function, so selectivity engineering and CRBN-neosubstrate profiling are prerequisites, not afterthoughts.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42089431","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42313274","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":199,"lastVisit":2,"lastNote":"Opened this visit on a single primary paper with in vitro plus xenograft data and an explicit belzutifan combination — the first pack evidence for a cofactor-directed, interface-independent escape-proofing strategy. Single study, tool-compound toxicity unresolved.","history":[{"visit":2,"cycle":199,"status":"NEW","note":"Opened this visit on a single primary paper with in vitro plus xenograft data and an explicit belzutifan combination — the first pack evidence for a cofactor-directed, interface-independent escape-proofing strategy. Single study, tool-compound toxicity unresolved."}]}],"retired":[{"title":"CCND1/CDK4-6 as a downstream node after HIF-2α escape","note":"Retired as pre-committed at visit 1: two consecutive packs, including a targeted resistance/biomarker query, returned no independent literature connecting CCND1 to HIF-2α-inhibitor resistance. The ETS1–EPAS1 cofactor axis (PMID:42089431) is the better-evidenced downstream node and inherits this slot.","cycle":199,"ts":"2026-08-20T01:41:54.229Z"}],"nextQueries":["(\"ETS1\" OR \"molecular glue\" OR \"cereblon\") AND (\"renal cell carcinoma\" OR \"VHL\" OR \"HIF-2\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"von Hippel-Lindau\" OR pVHL) AND (\"HIF-independent\" OR \"non-canonical substrate\" OR \"ubiquitin ligase independent\" OR \"genotype-phenotype\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(belzutifan OR \"MK-6482\" OR cabozantinib) AND (hemangioblastoma OR \"retinal capillary\" OR \"spinal cord\" OR cyst) AND (volume OR response OR durability) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-20T01:41:54.229Z"},{"key":"neurofibromatosis type 1","name":"neurofibromatosis type 1","mondo":{"id":"MONDO:0018975","name":"neurofibromatosis type 1"},"genes":[{"label":"NF1","kind":"causal"},{"label":"RNF135","kind":"correlated"}],"visits":2,"openQuestions":["Is H3K27me3-negative (SUZ12/EED-null) MPNST actually BET-inhibitor sensitive in NF1 PDX, and is that sensitivity separable from generic MYC dependence?","Do chr8 gain and PTK2 expression/amplification track independently within the 'significant aneuploidy' MPNST class, and does either predict FAKi+MEKi synergy?","In NCT04750928, does abemaciclib response track with biallelic CDKN2A/B loss, and does it reduce conversion to MPNST rather than only stabilise volume?","How does the proposed reclassification of 'low-grade MPNST' to ANNUBP-with-in-situ-transformation change eligibility and endpoint definitions for interception trials?","Are the brigatinib, bevacizumab and TbR1-RKIP claims in PMID:41898726 NF1-specific or NF2-SWN-specific? Still unresolved and still blocking any lead built on them.","Do MEK inhibitors help or harm NF1 skeletal outcomes (BMD, pseudarthrosis healing) in children on chronic therapy?"],"leads":[{"id":"L1","title":"FAK/PTK2 + RAF-MEK co-inhibition in chr8-gain MPNST","mechanism":"Chr8 gain creates dosage dependence on PTK2/FAK; FAK sustains STAT3/AKT signalling that rebounds adaptively under MEK inhibition in NF1-null, ERK-hyperactive MPNST, so co-targeting collapses both arms with caspase-3/PARP-1 cleavage. Significant aneuploidy is now a formal MPNST-defining molecular criterion (PMID:39500722), raising the expected prevalence of chr8-gain strata, though the consensus names neither chr8 nor PTK2.","approach":"Defactinib or GSK2256098 [KNOWN] plus selumetinib or a pan-RAF agent in chr8-gain-selected MPNST PDX; score chr8 copy number and PTK2 expression/amplification separately in archival cohorts now being profiled under the consensus workflow, then a biomarker-stratified phase 1b. Monitor CRAF/ERK reactivation, YAP/TAZ, PDGFRA/EGFR switching; overlapping cardiac/ocular/dermatologic toxicity.","level":"LEAD","confidence":0.58,"citations":[{"kind":"PMID","id":"42579369","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41898726","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"39500722","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":122,"lastVisit":2,"lastNote":"Prior-raising only: aneuploidy is now diagnostic doctrine, but a targeted MPNST/FAK/PTK2/chr8 query 2022-2026 returned no new mechanistic corroboration. Held at LEAD, not promoted; hypothesis still rests on a single functional paper.","history":[{"visit":2,"cycle":200,"status":"STRENGTHENED","note":"Prior-raising only: aneuploidy is now diagnostic doctrine, but a targeted MPNST/FAK/PTK2/chr8 query 2022-2026 returned no new mechanistic corroboration. Held at LEAD, not promoted; hypothesis still rests on a single functional paper."},{"visit":1,"cycle":122,"status":"NEW","note":"New this visit from PMID:42579369 (genetic + pharmacologic FAK validation, PDX combination superiority in chr8-gain). Aneuploidy-defined vulnerability, not an oncogene — unusually actionable for an NF1-null tumour."}]},{"id":"L2","title":"CDK4/6 inhibition in CDKN2A/B-deleted atypical neurofibromatous neoplasms (ANNUBP) as MPNST interception","mechanism":"Biallelic CDKN2A/CDKN2B inactivation is now the codified molecular definition of ANNUBP on the plexiform-neurofibroma-to-MPNST trajectory (PMID:39500722); loss of the INK4 brake makes CDK4/6-cyclin D-RB the druggable effector node downstream of tumour-suppressor loss, unlike NF1 itself.","approach":"Abemaciclib in NF1 ANNUBP (NCT04750928) with a prespecified CDKN2A/B-status-stratified response analysis, now feasible because consensus-mandated molecular profiling of worrisome noncutaneous lesions supplies the biomarker; track the proposed 'ANNUBP with in-situ transformation' reclassification of low-grade MPNST for eligibility drift; preclinical abemaciclib + MEKi in atypical-neurofibroma models. Resistance: RB1 loss, CCNE1/CDK2, CDK6 upregulation. Window set by proliferating marrow and gut epithelium (neutropenia, diarrhoea).","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"NCT","id":"NCT04750928","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"39500722","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":122,"lastVisit":2,"lastNote":"New independent consensus/WHO-aligned evidence this visit converts the stratification biomarker from aspirational to routine pathology; second evidence-bearing visit, two verified citations.","history":[{"visit":2,"cycle":200,"status":"STRENGTHENED","note":"New independent consensus/WHO-aligned evidence this visit converts the stratification biomarker from aspirational to routine pathology; second evidence-bearing visit, two verified citations."},{"visit":1,"cycle":122,"status":"NEW","note":"New this visit; trial-anchored only, mechanism tagged [KNOWN]. Attractive because it targets the pre-malignant window rather than established MPNST."}]},{"id":"L3","title":"MEK inhibition as the NF1 therapeutic backbone: pain/function endpoints and combination scaffold","mechanism":"Neurofibromin GAP loss leaves RAS-GTP loaded and RAF-MEK-ERK hyperactive in Schwann-cell-lineage tumours; MEK1/2 inhibition shrinks plexiform neurofibromas and reduces pain intensity (-1.65; 95% CI -2.20 to -1.10, I2 71.4%, 7 trials/342 patients). FFPE spatial transcriptomics now resolves niche-level differentiation states and immune/perineurial compartments in PNSTs, giving a route to define the on-treatment and post-progression state.","approach":"Treat MEKi as comparator/backbone; apply FFPE spatial transcriptomics (PMID:39847441) to archival pre- and post-selumetinib specimens from NCT02407405, NCT04590235, NCT05309668, NCT06175637 and NCT04166409 to identify the residual/progressing niche and nominate partners (FAK, CDK4/6, SHP2/SOS1). Open-label pain reporting and I2=71.4% limit the effect-size estimate.","level":"LEAD","confidence":0.7,"citations":[{"kind":"PMID","id":"42176397","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04166409","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT02407405","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05309668","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"39847441","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":122,"lastVisit":2,"lastNote":"No new efficacy data; strengthened only methodologically — an FFPE-compatible spatial assay makes the post-MEKi resistance question answerable from archival tissue. Not promoted since nothing new corroborates the pain/combination hypothesis itself.","history":[{"visit":2,"cycle":200,"status":"STRENGTHENED","note":"No new efficacy data; strengthened only methodologically — an FFPE-compatible spatial assay makes the post-MEKi resistance question answerable from archival tissue. Not promoted since nothing new corroborates the pain/combination hypothesis itself."},{"visit":1,"cycle":122,"status":"NEW","note":"New lead entry consolidating an established standard of care [KNOWN]; the meta-analysis is the first pooled patient-reported pain estimate, and the trial set shows franchise expansion into glioma and infants."}]},{"id":"L4","title":"RAS/MAPK-PI3K targeting for NF1 skeletal disease (pseudarthrosis, low BMD)","mechanism":"Neurofibromin loss in osteoblast/osteoclast lineages dysregulates RAS/MAPK and PI3K/AKT, producing disordered remodelling, low bone mineral density, scoliosis and congenital pseudarthrosis of the tibia","approach":"Explore whether MEK inhibitor exposure (already given for PN) modifies bone-remodelling markers and pseudarthrosis healing, versus bone-directed agents; requires primary-data trials, none identified in this pack","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42464674","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":122,"lastVisit":1,"lastNote":"Held at low confidence: review-level only, no agent, no clinical data. Included because skeletal morbidity is a large unmet need and MEKi bone effects in growing children are an unresolved safety/efficacy question.","history":[{"visit":1,"cycle":122,"status":"NEW","note":"Held at low confidence: review-level only, no agent, no clinical data. Included because skeletal morbidity is a large unmet need and MEKi bone effects in growing children are an unresolved safety/efficacy question."}]},{"id":"L5","title":"PRC2-loss (SUZ12/EED, H3K27me3-negative) MPNST as a BET-dependent stratum","mechanism":"SUZ12 or EED inactivation is now a formal MPNST-defining molecular event (PMID:39500722); [KNOWN] loss of PRC2 core ablates H3K27me3, and [KNOWN] the resulting enhancer reprogramming amplifies RAS/MAPK transcriptional output with acquired BRD4 dependency. [INFERRED] this predicts that H3K27me3-negative MPNST is preferentially sensitive to BET bromodomain inhibition, and [SPECULATIVE] that BETi blunts the transcriptional rebound limiting MEKi durability.","approach":"Stratify MPNST models and archival cohorts by H3K27me3 IHC (already a routine surrogate, zero added assay cost); test a BET inhibitor alone and with selumetinib in PRC2-null versus PRC2-intact NF1 MPNST PDX; read out MYC, RTK and RAS-target transcriptional output. Expected resistance: SPOP/BRD4 stabilisation, kinome bypass. Normal-tissue window is the concern — BETi causes thrombocytopenia and GI toxicity [KNOWN], so intermittent dosing and a MEKi dose-sparing schedule must be modelled before any paediatric consideration.","level":"LEAD","confidence":0.32,"citations":[{"kind":"PMID","id":"39500722","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":200,"lastVisit":2,"lastNote":"Created because the consensus surfaced a defined molecular stratum the desk had ignored, with a free IHC selector; therapeutic arm is inference/speculation from one citation, hence low confidence.","history":[{"visit":2,"cycle":200,"status":"NEW","note":"Created because the consensus surfaced a defined molecular stratum the desk had ignored, with a free IHC selector; therapeutic arm is inference/speculation from one citation, hence low confidence."}]}],"retired":[],"nextQueries":["(\"malignant peripheral nerve sheath tumor\" OR MPNST) AND (SUZ12 OR EED OR PRC2 OR H3K27me3 OR BRD4 OR \"bromodomain\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(neurofibromatosis AND (selumetinib OR mirdametinib) AND (resistance OR biopsy OR \"single-cell\" OR relapse OR progression)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(neurofibromatosis type 1 AND (\"bone mineral density\" OR pseudarthrosis OR tibia OR osteoblast) AND (MEK OR selumetinib OR trametinib)) AND SRC:MED"],"updatedAt":"2026-08-20T01:45:20.560Z"},{"key":"neurofibromatosis type 2","name":"neurofibromatosis type 2","mondo":{"id":"MONDO:0007039","name":"NF2-related schwannomatosis"},"genes":[{"label":"NF2","kind":"causal"}],"visits":2,"openQuestions":["Does the NF2-loss/CRIg+ macrophage/retinoic-acid immunosuppressive programme (PMID:42208538) occur in merlin-null schwannoma and meningioma tissue, and is it copy-loss-specific rather than mutation-specific?","Which TEAD palmitoylation inhibitors have been dosed in vivo in NF2-null models, at what exposure, and do published toxicology data show renal tubular injury consistent with the YAP1/TEAD1-SLC7A5 axis (PMID:41833934)?","What are the primary NF2-SWN data behind brigatinib and the brain-penetrant HDAC inhibitor cited in PMID:41898726 — response rates, hearing endpoints, tumour type?","What defines progression on bevacizumab in NF2-SWN mechanistically (angiogenic switch markers, volume vs oedema, WRS trajectory), and can the 6-8 week preoperative washout be shortened given the bleeding data in PMID:40956079?","Has the NF2-mutant arm of NCT02523014 (GSK2256098 FAK, capivasertib, abemaciclib) reported, and is FAK dependency validated in primary merlin-null schwannoma cells?","Do merlin-loss synthetic-lethal screens outside the Hippo axis (CDK4/6, AXL, dual mTORC1/2, SLC7A5/leucine or glutamine metabolism) show NF2-null selectivity in published DepMap-type data?"],"leads":[{"id":"L1","title":"Bevacizumab (anti-VEGF) as the systemic backbone and comparator arm for NF2-SWN vestibular schwannoma","mechanism":"Merlin loss de-represses VEGF/VEGFR-driven angiogenesis and vascular permeability; hearing benefit likely part oedema-mediated [INFERRED]. VEGFR2 blockade in injured peripheral nerve also suppresses neovascularisation, M1 polarisation and fibrotic scar (PMID:41815350), a possible non-cytoreductive contribution in nerve-sheath tumours [SPECULATIVE]. Normal-tissue VEGF role: vascular homeostasis, wound healing, glomerular endothelium — hypertension, proteinuria, impaired healing define the window [KNOWN].","approach":"Randomised hearing-endpoint (word recognition score) designs of bevacizumab +/- second agent; define progression-on-bevacizumab formally (volume vs oedema vs WRS decline). New operational point: after failure, salvage microsurgery is feasible — 21 NF2-SWN patients, mean 33.7 months of bevacizumab at 10.2 mg/kg monthly, drug stopped mean 5.8 months pre-op, bleeding judged notable in a minority (PMID:40956079); use this to interrogate whether the mandated 6-8 week washout can be shortened. Resistance: FGF/PDGF/ANG2 angiogenic switch, pericyte coverage, rebound on withdrawal.","level":"CANDIDATE","confidence":0.78,"citations":[{"kind":"PMID","id":"42453176","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42012512","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42142209","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42143176","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40956079","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41815350","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":123,"lastVisit":2,"lastNote":"Second evidence-bearing visit with new independent multicentre data on the bevacizumab-failure population; the lead's weakest point (what happens after non-response) now has a partial answer. Small n=21, retrospective, no biomarker of resistance reported.","history":[{"visit":2,"cycle":201,"status":"STRENGTHENED","note":"Second evidence-bearing visit with new independent multicentre data on the bevacizumab-failure population; the lead's weakest point (what happens after non-response) now has a partial answer. Small n=21, retrospective, no biomarker of resistance reported."},{"visit":1,"cycle":123,"status":"NEW","note":"New programme. Four independent 2026 sources (systematic review of 426 patients, a dedicated meta-analysis, and two reviews) converge on durable stabilisation, hearing preservation and manageable toxicity; opened as LEAD only because all evidence arrives on this single visit."}]},{"id":"L2","title":"YAP/TAZ-TEAD transcriptional dependency as the most merlin-proximal druggable node in NF2-SWN","mechanism":"Merlin ([GERMLINE] first hit + [SOMATIC] second hit, often LOH/copy loss) fails to activate LATS1/2, whose full catalytic output requires a newly mapped second autophosphorylation site (LATS1 Ser872 / LATS2 Ser835) for YAP phosphorylation (PMID:42167578); unrestrained YAP/TAZ-TEAD drives proliferation and loss of contact inhibition (PMID:42142209, PMID:42143176). New dimension: NF2 loss also reorganises the immune microenvironment — in mesothelioma it recruited CRIg+ immunosuppressive macrophages via tumour chemokines and retinoic acid, causing CAR-T/anti-PD-1 resistance, and TEAD inhibition reversed it (PMID:42208538). Effect was compartment-specific (pleural, not subcutaneous), so niche de","approach":"Test TEAD palmitoylation-pocket inhibitors in merlin-null human schwannoma/meningioma lines and NF2-conditional Schwann-cell/meningothelial models, reading out both proliferation and macrophage composition; stratify by NF2 copy loss vs point mutation (PMID:42208538 associated the macrophage phenotype with copy loss only). Combination logic: TEAD + bevacizumab (CCN/ANG2-dependent angiogenesis) and TEAD + retinoic-acid-axis blockade [SPECULATIVE]. Window/toxicity: beyond intestinal/hepatic regeneration and cardiac stress, YAP1/TEAD1 sustains SLC7A5 transcription in renal tubule and its loss triggers leucine/mTOR collapse and tubular ferroptosis (PMID:41833934) — monitor urinary KIM-1, tubular ","level":"CANDIDATE","confidence":0.6,"citations":[{"kind":"PMID","id":"42142209","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42143176","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42208538","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42167578","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41833934","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":123,"lastVisit":2,"lastNote":"Promoted: first functional (not review-level) TEAD-inhibitor efficacy in an NF2-null tumour context, independent LATS activation mechanism, and a concrete new on-target organ-toxicity prediction. Still no NF2-SWN-specific pharmacology — schwannoma/meningioma models remain the gap.","history":[{"visit":2,"cycle":201,"status":"STRENGTHENED","note":"Promoted: first functional (not review-level) TEAD-inhibitor efficacy in an NF2-null tumour context, independent LATS activation mechanism, and a concrete new on-target organ-toxicity prediction. Still no NF2-SWN-specific pharmacology — schwannoma/meningioma models remain the gap."},{"visit":1,"cycle":123,"status":"NEW","note":"New. Both 2026 mechanistic reviews name Hippo/YAP-TAZ as a core consequence of merlin deficiency, yet the pack's trial audit shows no NF2-SWN TEAD-directed clinical study — largest mechanism/clinic gap in the programme. Confidence limited: no NF2-specific pharmacological data in this pack (abstract-level only)."}]},{"id":"L3","title":"FAK (and AKT/CDK4-6) inhibition against NF2-mutant meningioma via mutation-stratified basket trial","mechanism":"Merlin loss dysregulates adhesion/integrin-FAK signalling and cytoskeletal coupling, creating a proposed FAK dependency in NF2-mutant meningothelial cells (PMID:42143176); AKT and CDK4/6 arms address parallel PI3K and cell-cycle output of merlin loss [INFERRED]. Meningiomatosis, not vestibular schwannoma, drives much NF2-SWN morbidity/mortality (PMID:42338700).","approach":"Track and extend the NF2-mutant arm of NCT02523014 (GSK2256098; comparator arms capivasertib, abemaciclib, vismodegib); prioritise reporting of the NF2-stratified subgroup and consider FAK + TEAD or FAK + bevacizumab combinations. Resistance: PYK2 compensation, YAP-mediated bypass, RTK reactivation. Normal-tissue FAK role: endothelial barrier and wound repair — watch vascular/mucosal toxicity.","level":"LEAD","confidence":0.4,"citations":[{"kind":"NCT","id":"NCT02523014","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42143176","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42338700","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":123,"lastVisit":1,"lastNote":"New. Only genotype-stratified interventional trial in the pack that is mechanistically applicable to NF2 (unlike the NF1/RAS selumetinib-mirdametinib cluster). Needs the actual NF2-arm response data, not yet in hand.","history":[{"visit":1,"cycle":123,"status":"NEW","note":"New. Only genotype-stratified interventional trial in the pack that is mechanistically applicable to NF2 (unlike the NF1/RAS selumetinib-mirdametinib cluster). Needs the actual NF2-arm response data, not yet in hand."}]},{"id":"L4","title":"Wide dural radiotherapy for NF2-SWN meningiomatosis — efficacy signal versus malignant-transformation liability","mechanism":"Field-wide 48 Gy/30 fx dural irradiation aims to sterilise subclinical meningothelial nests in a diffusely predisposed dura, converting serial focal treatments into one prophylactic field (PMID:42338700). Counter-mechanism: NF2-deficient, already DNA-repair-stressed Schwann/meningothelial tissue may be primed for radiation-induced malignant transformation and cochlear/nerve injury (PMID:42142209).","approach":"Do not generalise from n=10; require multicentre registry capture with >=10-year follow-up for MPNST/sarcomatous transformation and audiometric decline, and prospective comparison against surveillance plus salvage radiosurgery. Explicitly stratify by prior radiation and by germline NF2 variant class.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42338700","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42142209","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42546347","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":123,"lastVisit":1,"lastNote":"New, deliberately low confidence: 100% 2-year local control over 91 meningiomas is striking but the cohort is 10 patients with 45.8-month median follow-up, and two pack sources document malignant transformation of nerve-sheath tumours (including one without NF2 or prior radiation), so the key harm endpoint is untested at this follow-up.","history":[{"visit":1,"cycle":123,"status":"NEW","note":"New, deliberately low confidence: 100% 2-year local control over 91 meningiomas is striking but the cohort is 10 patients with 45.8-month median follow-up, and two pack sources document malignant transformation of nerve-sheath tumours (including one without NF2 or prior radiation), so the key harm endpoint is untested at this follow-up."}]},{"id":"L5","title":"Brigatinib as repurposed multi-kinase therapy in NF2-SWN","mechanism":"A 2026 NF2/NF2-SWN perspective names brigatinib among mechanistically driven agents under renewed evaluation in NF2-SWN alongside bevacizumab (PMID:41898726). [KNOWN] brigatinib is an approved ALK/ROS1 inhibitor with broad off-target kinase coverage; the NF2 rationale is polypharmacology against merlin-loss-driven RTK output rather than a single validated target, which is exactly the weakness to test.","approach":"Obtain the actual NF2-SWN brigatinib efficacy data (per-tumour-type response, hearing outcomes, whether benefit tracks any RTK biomarker); in parallel, define which of brigatinib's kinase targets is responsible in merlin-null schwannoma cells by isogenic knockdown/selective-inhibitor deconvolution. Normal-tissue considerations: ALK is largely dispensable in adult tissue, but brigatinib carries pulmonary, hepatic and hypertensive toxicity [KNOWN] — relevant if combined with bevacizumab. Resistance: bypass RTK reactivation, YAP-mediated survival.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"41898726","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":201,"lastVisit":2,"lastNote":"New. Single review-abstract citation only, so deliberately low confidence; opened because it is a clinic-ready repurposing candidate for a disease with no approved systemic therapy and it must be either substantiated or killed with primary data next visit.","history":[{"visit":2,"cycle":201,"status":"NEW","note":"New. Single review-abstract citation only, so deliberately low confidence; opened because it is a clinic-ready repurposing candidate for a disease with no approved systemic therapy and it must be either substantiated or killed with primary data next visit."}]},{"id":"L6","title":"Brain-penetrant HDAC inhibition and the TbetaR1-RKIP axis as non-Hippo mechanisms in NF2-SWN","mechanism":"The same 2026 perspective reports a novel TbetaR1-RKIP pathogenic axis and a brain-penetrant HDAC inhibitor as emerging NF2-SWN directions (PMID:41898726). [INFERRED] RKIP is a Raf/MAPK and NF-kB suppressor, so a TGF-beta-receptor-I-driven loss of RKIP would license MAPK output independently of the Hippo axis; HDAC inhibition would act as a transcriptional-state reset, plausibly including re-expression of merlin-pathway suppressors [SPECULATIVE].","approach":"Retrieve the primary reports behind both claims; test whether RKIP protein is lost in merlin-null schwannoma tissue and whether TbetaR1 inhibition (e.g. galunisertib-class) or HDAC inhibition reduces growth in NF2-null models; check whether HDACi effect is YAP/TEAD-dependent (epistasis with L2). Window: class-wide HDACi haematologic, cardiac (QT) and fatigue toxicity constrains chronic dosing in a benign-tumour, decades-long disease — a genuine obstacle, not a footnote.","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"41898726","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":201,"lastVisit":2,"lastNote":"New and speculative: only a review abstract, no NF2-specific efficacy or dose data seen. Recorded so the desk pursues the primary literature rather than re-deriving the idea.","history":[{"visit":2,"cycle":201,"status":"NEW","note":"New and speculative: only a review abstract, no NF2-specific efficacy or dose data seen. Recorded so the desk pursues the primary literature rather than re-deriving the idea."}]}],"retired":[],"nextQueries":["(\"NF2\" OR merlin) AND (\"TEAD inhibitor\" OR VT3989 OR IK-930 OR \"palmitoylation inhibitor\") AND (schwannoma OR meningioma OR mesothelioma) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"NF2-related schwannomatosis\" OR \"vestibular schwannoma\") AND (brigatinib OR \"HDAC inhibitor\" OR RKIP OR \"TGF-beta receptor\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"NF2\" OR merlin) AND (\"synthetic lethal\" OR CRISPR OR DepMap OR \"dependency screen\") AND (SLC7A5 OR AXL OR CDK4 OR mTOR OR glutamine) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]"],"updatedAt":"2026-08-20T01:48:48.343Z"},{"key":"dicer1 syndrome","name":"DICER1 syndrome","mondo":{"id":"MONDO:0100216","name":"DICER1-related tumor predisposition"},"genes":[{"label":"DICER1","kind":"causal"},{"label":"KEAP1","kind":"correlated"}],"visits":2,"openQuestions":["Do small-RNA-seq data from human hotspot-mutant DICER1 tumours actually show a selective 5p-arm deficit, or is HMGA2 protein overexpression (PMID:42583679) driven by something other than let-7 loss?","Is HMGA2 a maintenance dependency or only an initiation marker — does HMGA2 knockdown/degradation kill hotspot-mutant models but spare DICER1-wildtype ones?","Can enoxacin or any TRBP-directed agent restore 5p cleavage by hotspot-mutant Dicer in a biochemical assay, or is the hotspot allele pharmacologically uncorrectable?","What are the stage III/IV and relapsed outcomes and failure patterns in ASK, PPB type II/III and DICER1 sarcomas — the population any targeted agent would actually address?","Do DICER1 hotspot-mutant PDX, GEMM or organoid models exist, and has any agent been tested in them?","Does germline DICER1 heterozygosity impose a systemic toxicity constraint on global miRNA-biogenesis enhancement or IGF-axis blockade in children?"],"leads":[{"id":"L1","title":"let-7 5p-strand deficit as the actionable consequence of RNase IIIb hotspot hypomorphism: target IGF1R/IGF2BP1 downstream","mechanism":"Germline DICER1 LOF plus somatic RNase IIIb hotspot missense yields hypomorphic Dicer that cleaves 3p but not 5p pre-miRNA arms (PMID:40940982, PMID:39857323) [INFERRED], depleting 5p-derived let-7 and de-repressing its targets. PMID:42583679 now shows nuclear HMGA2 protein in essentially all DICER1-PV lesion types (CNS spindle cell sarcoma, Sertoli-Leydig, PPB, cystic nephroma, ovarian/cervical eRMS; ~50% of thyroid lesions) with normal control tissue uniformly negative — direct human evidence of a tumour-restricted let-7 target output and of the therapeutic window, since DICER1-heterozygous normal tissue remains 5p-competent. HMGA2 positivity in benign lesions indicates an early/initiating","approach":"Small-RNA-seq for 5p:3p arm ratios on the same registry specimens already scored for HMGA2, paired with let-7 target panel (HMGA2, IGF2BP1/3, MYC, IGF2). Functional test: HMGA2 and IGF2BP1 knockdown/degrader in hotspot-mutant vs DICER1-wildtype paediatric sarcoma lines and any PDX, scoring for hotspot-selective killing; IGF1R blockade only where IGF2/IR-A axis is documented. Use HMGA2 IHC as pharmacodynamic readout, not as an efficacy endpoint. Expected resistance: IR-A/IGF2 autocrine loop, PI3K/AKT or MAPK reactivation, HMGA2-independent epigenetic drift. Research use only.","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"PMID","id":"40940982","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"39857323","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42583679","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42113881","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":124,"lastVisit":2,"lastNote":"Promoted on new independent human tissue evidence (PMID:42583679): the let-7 target output predicted last visit is present in 78 DICER1-PV lesions and absent from normal tissue. Still no small-RNA-seq arm-ratio data and no drug-effect data; HMGA2 may be an initiation marker rather than a dependency.","history":[{"visit":2,"cycle":202,"status":"STRENGTHENED","note":"Promoted on new independent human tissue evidence (PMID:42583679): the let-7 target output predicted last visit is present in 78 DICER1-PV lesions and absent from normal tissue. Still no small-RNA-seq arm-ratio data and no drug-effect data; HMGA2 may be an initiation marker rather than a dependency."},{"visit":1,"cycle":124,"status":"NEW","note":"New this visit. Both citations are reviews that state the mechanism is incompletely understood; the 5p/let-7 step is [INFERRED]/[KNOWN], not shown in the pack. Deliberately capped at LEAD with no drug-effect data."}]},{"id":"L3","title":"Registry/natural-history network as the only available tissue and enrolment pipeline for DICER1 target validation","mechanism":"No interventional targeted trial exists for DICER1 syndrome in either pack; the clinical footprint is observational (NCT01247597, NCT03050268, NCT03382158). Two new registry outputs define the bar and the ascertainment problem: PMID:38807260 (10 registry + 37 published anaplastic sarcoma of kidney cases) reports 2-year EFS 81.8% for stage I–II with most patients receiving upfront chemotherapy, so any targeted proposal must be aimed at stage III/IV or relapsed disease, not localized cases; PMID:42107965 shows that of 868 thoracic tumours submitted over 35 years only 79% were confirmed PPB, with RNase IIIb hotspot variants detected in discrepant cases — misclassification against congenital pul","approach":"Correlative biospecimen substudy on the PPB/DICER1 Registry: paired germline/somatic sequencing, small-RNA 5p:3p arm ratios, let-7 target panel including HMGA2 IHC (PMID:42583679), and PDX/organoid derivation prioritized from stage III/IV ASK and PPB type II/III where the outcome gap is real. Reflex DICER1 testing for all cystic lung lesions initially called CPAM, rhabdomyoblastic thoracic sarcomas, and cervical/genitourinary embryonal rhabdomyosarcoma at any age. Research use only.","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"NCT","id":"NCT03382158","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT01247597","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03050268","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41868466","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"38807260","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42107965","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":124,"lastVisit":2,"lastNote":"Strengthened by two new registry papers that supply the chemotherapy outcome benchmark (answering open question 4 for localized ASK) and quantify diagnostic misclassification, justifying reflex molecular testing.","history":[{"visit":2,"cycle":202,"status":"STRENGTHENED","note":"Strengthened by two new registry papers that supply the chemotherapy outcome benchmark (answering open question 4 for localized ASK) and quantify diagnostic misclassification, justifying reflex molecular testing."},{"visit":1,"cycle":124,"status":"NEW","note":"New. Infrastructure lead, not a therapeutic hypothesis; recorded because it is the rate-limiting step for every other lead and because the pack's total absence of interventional trials is itself the finding of this visit."}]},{"id":"L4","title":"Pharmacologic enhancement of miRNA biogenesis (enoxacin) as miRNA-restoration therapy — gated on whether hotspot Dicer is correctable","mechanism":"PMID:41748289 shows conditional Dgcr8 deletion phenocopies endothelial Dicer1 loss, causing spontaneous angiosarcoma with global mature-miRNA loss, and that enoxacin — a repurposed fluoroquinolone acting through TRBP to enhance pre-miRNA processing [KNOWN] — reduces viability, migration and clonogenicity while raising tumour-suppressive miRNAs and downregulating cell-cycle/angiogenesis programmes. This establishes miRNA biogenesis as pharmacologically re-openable in a Dicer-deficient tumour. [SPECULATIVE] extension to DICER1 syndrome: hotspot RNase IIIb missense retains protein but loses 5p catalysis, so TRBP-mediated enhancement may increase substrate loading onto a catalytically dead 5p si","approach":"Direct falsification first: in vitro Dicer cleavage assays with recombinant hotspot (E1705K/D1709N/E1813) Dicer plus TRBP ± enoxacin, reading 5p vs 3p product ratios; then enoxacin in hotspot-mutant vs DICER1-wildtype sarcoma lines with let-7 qPCR and HMGA2 IHC/immunoblot (PMID:42583679) as the pharmacodynamic readout. If 5p output is not restored, retire immediately rather than proceeding to models. Expected resistance/failure modes: hotspot allele uncorrectable, let-7-independent HMGA2 maintenance, off-target global miRNA shifts.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"41748289","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42583679","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":202,"lastVisit":2,"lastNote":"New from PMID:41748289. Evidence is in complete Dicer1/Dgcr8 loss (angiosarcoma), not hotspot missense — the mechanistic gate is stated explicitly so the desk can kill this cheaply.","history":[{"visit":2,"cycle":202,"status":"NEW","note":"New from PMID:41748289. Evidence is in complete Dicer1/Dgcr8 loss (angiosarcoma), not hotspot missense — the mechanistic gate is stated explicitly so the desk can kill this cheaply."}]}],"retired":[{"title":"Somatic KEAP1 loss / NRF2 hyperactivation as a co-driver dependency in DICER1-related tumours","note":"Retired per visit-1 commitment: confirm or kill. Fresh pack contains no KEAP1/NRF2 data in DICER1 tumours. Recorded as a dead branch.","cycle":202,"ts":"2026-08-20T01:52:12.020Z"}],"nextQueries":["(\"DICER1\" AND (\"small RNA sequencing\" OR \"miRNA profiling\" OR \"5p arm\" OR \"arm switching\")) AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(\"HMGA2\" AND (\"knockdown\" OR \"dependency\" OR \"degrader\" OR \"synthetic lethal\") AND (sarcoma OR rhabdomyosarcoma OR blastoma)) AND SRC:MED","(\"DICER1\" AND (\"patient-derived xenograft\" OR organoid OR \"mouse model\" OR \"cell line\" OR \"hotspot\" AND \"E1705\" OR \"D1709\")) AND SRC:MED"],"updatedAt":"2026-08-20T01:52:12.020Z"},{"key":"rhabdoid tumor predisposition syndrome","name":"rhabdoid tumor predisposition syndrome","mondo":{"id":"MONDO:0016473","name":"familial rhabdoid tumor"},"genes":[{"label":"SMARCB1","kind":"causal"},{"label":"SMARCA4","kind":"correlated"}],"visits":2,"openQuestions":["Is there any published RT-specific preclinical comparison of EZH2 degraders vs catalytic inhibitors (H3K27me3 kinetics, non-catalytic PRC2 loss, CNS exposure), and does the degrader advantage in PMID:41680284 rest on data or expert opinion?","What is the RT-relevant DCAF5 evidence base — are there published DCAF5 binders/degraders, structural data, and dependency-map evidence on DCAF5 essentiality in normal neural and haematopoietic tissue?","What fraction of germline SMARCA4 (RTPS2) tumours retain SMARCA2 protein, given the co-loss reported in SMARCA4-deficient carcinomas (PMID:41744871) — does this leave a real eligible population?","Is TP53 genuinely wild-type across ATRT/MRT subgroups (SHH/TYR/MYC), and does MDM2 amplification or p53-pathway dosage vary by subgroup?","Does the porcine RTPS-1 line (PMID:42352415) develop ATRT/MRT, at what penetrance and latency, and can it support years-long chronic dosing with neurodevelopmental endpoints?","Any human experience — case series or registry — of EZH2-directed therapy or metronomic maintenance in RTPS carriers in remission, with second-tumour rates and infant toxicity?"],"leads":[{"id":"L1","title":"Epigenetic maintenance/secondary prevention in RTPS carriers after first remission","mechanism":"Germline SMARCB1/SMARCA4 loss-of-function [GERMLINE] leaves a PRC2/EZH2-dominant enhancer-silencing state in predisposed tissue, so second-primary and residual rhabdoid tumours arise from persistent polycomb-mediated repression rather than accumulating mutation; suppressing or degrading EZH2 targets the initiation window. Catalytic inhibition is escapable via EZH1 compensation and leaves non-catalytic PRC2 scaffolding intact, which is why the workshop rates EZH2 degraders above inhibitors (PMID:41680284) and why dual EZH1/2 agents are advancing in another PRC2-dependent context (PMID:42257802) [INFERRED].","approach":"Carrier maintenance trial after curative-intent therapy, site-agnostic (intracranial and extracranial RT treated as one biology per PMID:41680284): arm 1 metronomic low-dose chemotherapy, arm 2 selective EZH2 inhibitor, arm 3 dual EZH1/2 inhibitor, arm 4 (preclinical first) EZH2 degrader; primary endpoint metachronous rhabdoid tumour-free survival, enriched by SEER age/size/site/stage strata (PMID:42347697), carriers ascertained through NCT03050268. Window argument: EZH2 and BAF are required for cortical neurogenesis and germinal-centre B-cell biology, so a degrader that removes non-catalytic EZH2 has a narrower infant window than a reversible inhibitor — neurodevelopmental and B-cell readou","level":"CANDIDATE","confidence":0.55,"citations":[{"kind":"PMID","id":"39434925","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40143702","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42213312","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42347697","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03050268","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41680284","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42257802","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":125,"lastVisit":2,"lastNote":"Second evidence-bearing visit: PMID:41680284 [NEW] is an independent expert-consensus endorsement of EZH2 as a priority RT target and of site-agnostic strategy, but it contradicts my visit-1 assumption that tazemetostat-class inhibition is the right modality; arm structure expanded to test degrader vs dual EZH1/2 vs selective inhibitor. PMID:42257802 [NEW] supplies clinical-stage dual EZH1/2 agent","history":[{"visit":2,"cycle":203,"status":"STRENGTHENED","note":"Second evidence-bearing visit: PMID:41680284 [NEW] is an independent expert-consensus endorsement of EZH2 as a priority RT target and of site-agnostic strategy, but it contradicts my visit-1 assumption that tazemetostat-class inhibition is the right modality; arm structure expanded to test degrader vs dual EZH1/2 vs selective inhibitor. PMID:42257802 [NEW] supplies clinical-stage dual EZH1/2 agent"},{"visit":1,"cycle":125,"status":"NEW","note":"New lead, opened this visit. Anchored on PMID:39434925 explicitly proposing maintenance/epigenetic secondary prevention for RTPS; SMARCB1-null epithelioid sarcoma (PMID:42213312) supplies the adjacent SMARCB1-loss histology where EZH2 blockade is clinically established [KNOWN]. Not yet a candidate: no RTPS-specific interventional data in the pack."}]},{"id":"L2","title":"Residual SWI/SNF ATPase paralog dependency: SMARCA4 degradation in SMARCB1-null, SMARCA2 in SMARCA4-deficient rhabdoid tumours","mechanism":"SMARCB1-null BAF remains assembled around residual SMARCA4/BRG1 and depends on it for oncogenic enhancer maintenance [KNOWN]; SMARCA4-deficient tumours can upregulate SMARCA2 as a druggable paralog dependency (PMID:42293462). The symmetry assumption now has a documented exception: SMARCA4-deficient carcinomas frequently co-lose SMARCA2 protein (PMID:41744871), and such dual-ATPase-null tumours cannot be paralog-dependent [INFERRED].","approach":"Eligibility must be double-gated: germline/somatic SMARCA4 inactivation PLUS demonstrated SMARCA2 retention (IHC + sequencing) before SMARCA2 inhibitor/degrader/MabPair exposure; SMARCA4-selective degraders for SMARCB1-null ATRT/MRT remain contingent on infant CNS and haematopoietic toxicology since SMARCA4 is essential in neural and haematopoietic progenitors [KNOWN]. Do not import the immune-checkpoint rationale for adult SMARCA4-deficient tumours (PMID:41367953) into RT, which is TMB-low and immunologically cold [KNOWN]. Resistance: reciprocal paralog upregulation, ARID1A/ARID1B rewiring, non-catalytic BAF scaffolding.","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"42293462","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40036664","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40143702","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41744871","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41367953","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":125,"lastVisit":2,"lastNote":"Weakened: PMID:41744871 [NEW] documents concurrent SMARCA2 loss in SMARCA4-deficient carcinomas, so paralog dependency cannot be assumed from SMARCA4 loss alone; PMID:41367953 [NEW] shifts the SMARCA4-deficient field toward ICI/epigenetic rather than paralog synthetic lethality, and the workshop consensus (PMID:41680284) does not list SMARCA2 among RT priority targets — a notable omission for a le","history":[{"visit":2,"cycle":203,"status":"WEAKENED","note":"Weakened: PMID:41744871 [NEW] documents concurrent SMARCA2 loss in SMARCA4-deficient carcinomas, so paralog dependency cannot be assumed from SMARCA4 loss alone; PMID:41367953 [NEW] shifts the SMARCA4-deficient field toward ICI/epigenetic rather than paralog synthetic lethality, and the workshop consensus (PMID:41680284) does not list SMARCA2 among RT priority targets — a notable omission for a le"},{"visit":1,"cycle":125,"status":"NEW","note":"New lead. PMID:42293462 is the first pack evidence that SMARCA2-directed small molecules, mAbs and a bifunctional MabPair are actually in clinical trials; the SMARCB1-null mirror argument is [INFERRED]/[KNOWN], not yet cited. PMID:40036664 (SMARCA4 missense ATRT with retained INI1/BRG1 by IHC) is a live caveat: protein-retaining variants may lack paralog dependency, so IHC-based eligibility would "}]},{"id":"L3","title":"Porcine RTPS-1 (SMARCB1 exon 4-5 deletion) as the preclinical testbed for chronic prevention dosing","mechanism":"Germline deletion of SMARCB1 exons 4-5 is the most penetrant human predisposing allele and porcine SMARCB1 protein is identical to human at every residue across isoforms, so a CRISPR heterozygous pig models tumour initiation, CNS pharmacology and infant-equivalent chronic toxicity better than existing murine models (PMID:42352415).","approach":"Use the porcine RTPS-1 heterozygotes as the efficacy/toxicity platform for Lead A: measure tumour-free survival under chronic EZH2 inhibition vs metronomic chemotherapy vs observation, with CSF/brain drug exposure and neurodevelopmental and haematologic readouts; secondarily test whether tumours arising in carriers segregate into the ATRT-SHH/TYR/MYC groups seen in humans (PMID:41976393) to validate subgroup-directed dosing.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42352415","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"39434925","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41976393","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":125,"lastVisit":1,"lastNote":"New enabling lead created because the maintenance hypothesis (Lead A) is untestable in humans without a model that supports years-long dosing in a developing brain. Penetrance and tumour spectrum of the pig line are not yet reported in the abstract — this is the first thing to verify next visit.","history":[{"visit":1,"cycle":125,"status":"NEW","note":"New enabling lead created because the maintenance hypothesis (Lead A) is untestable in humans without a model that supports years-long dosing in a developing brain. Penetrance and tumour spectrum of the pig line are not yet reported in the abstract — this is the first thing to verify next visit."}]},{"id":"L4","title":"DCAF5 degradation-dependency: restoring residual SWI/SNF function in SMARCB1-null rhabdoid tumours","mechanism":"In SMARCB1-deficient cells the DDB1-CUL4-DCAF5 E3 ligase recognises and clears the misassembled, SMARCB1-less BAF complex; removing DCAF5 stabilises residual BAF and restores enhancer-directed SWI/SNF activity, collapsing the rhabdoid state [KNOWN]. The workshop names DCAF5 a promising target and prioritises small-molecule binders/degraders (PMID:41680284). Unlike EZH2 blockade this is restorative rather than suppressive, and is genotype-matched to RTPS-1 germline SMARCB1 loss [GERMLINE].","approach":"Chemical-biology first: DCAF5 binder/degrader campaign, then genotype-defined efficacy testing in SMARCB1-null ATRT/MRT models and in RTPS-1 heterozygous tissue (L3 porcine platform) for prevention dosing. Normal-tissue window: DCAF5 has no established essential function in adult haematopoiesis or neurodevelopment [SPECULATIVE — needs a dependency-map check]; degradation-restoration should spare SMARCB1-wild-type cells, which is the therapeutic-window argument. Resistance: acquired loss of the remaining BAF subunits (ARID1A/ARID1B, SMARCA4), MYC-driven state independence, alternative CUL4 substrate receptors clearing residual BAF.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"41680284","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"39434925","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":203,"lastVisit":2,"lastNote":"New lead created directly from the workshop consensus (PMID:41680284) [NEW]; it is the only proposal in the pack that restores rather than suppresses chromatin function, and therefore has the most plausible infant therapeutic window for chronic prevention dosing. No RT-specific in vivo DCAF5 pharmacology in the pack.","history":[{"visit":2,"cycle":203,"status":"NEW","note":"New lead created directly from the workshop consensus (PMID:41680284) [NEW]; it is the only proposal in the pack that restores rather than suppresses chromatin function, and therefore has the most plausible infant therapeutic window for chronic prevention dosing. No RT-specific in vivo DCAF5 pharmacology in the pack."}]},{"id":"L5","title":"MDM2 inhibition in TP53-wild-type rhabdoid tumours, combined with EZH2 blockade and nuclear-export inhibition","mechanism":"Rhabdoid tumours carry near-diploid, mutation-poor genomes in which TP53 is usually wild-type [KNOWN], so p53 is functionally restrained rather than deleted; MDM2 antagonism should reactivate it. The workshop lists MDM2 as a priority novel target and specifically calls for robust preclinical evaluation of EZH2 + MDM2 + selective inhibitor of nuclear export (SINE) combinations (PMID:41680284); mechanistic rationale is convergent, since PRC2-mediated silencing of CDKN2A/p53 effectors and XPO1-dependent nuclear export of p53 both blunt the same axis [INFERRED].","approach":"Preclinical triplet matrix (EZH2 inhibitor or degrader x MDM2 inhibitor x selinexor-class SINE) in SMARCB1-null ATRT/MRT models stratified by TP53 sequencing; only TP53-wild-type models eligible. Window: MDM2 inhibitors are dose-limited by thrombocytopenia and neutropenia and SINE agents by anorexia/hyponatraemia [KNOWN], so this triplet is a relapse/high-risk-disease hypothesis, not a maintenance/prevention one — it must be kept architecturally separate from L1. Resistance: TP53 mutation under selection pressure, MDM4 amplification, p21-mediated cytostasis without apoptosis.","level":"LEAD","confidence":0.38,"citations":[{"kind":"PMID","id":"41680284","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41367953","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":203,"lastVisit":2,"lastNote":"New lead from PMID:41680284 [NEW]. Deliberately positioned as therapy for established/high-risk RT rather than carrier prevention, because the haematologic toxicity of MDM2+SINE is incompatible with years-long dosing in infants.","history":[{"visit":2,"cycle":203,"status":"NEW","note":"New lead from PMID:41680284 [NEW]. Deliberately positioned as therapy for established/high-risk RT rather than carrier prevention, because the haematologic toxicity of MDM2+SINE is incompatible with years-long dosing in infants."}]}],"retired":[],"nextQueries":["(\"DCAF5\" OR \"DDB1-CUL4\") AND (SMARCB1 OR rhabdoid OR \"SWI/SNF\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"EZH2 degrader\" OR \"PRC2 degrader\" OR valemetostat OR tulmimetostat) AND (rhabdoid OR \"atypical teratoid\" OR SMARCB1) AND SRC:MED","(\"rhabdoid tumor predisposition\" OR \"germline SMARCB1\" OR \"germline SMARCA4\") AND (surveillance OR penetrance OR \"second primary\" OR metachronous) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-20T01:55:39.595Z"},{"key":"xeroderma pigmentosum","name":"xeroderma pigmentosum","mondo":{"id":"MONDO:0019600","name":"xeroderma pigmentosum"},"genes":[{"label":"ERCC5","kind":"causal"},{"label":"POLH","kind":"causal"},{"label":"GTF2H4","kind":"causal"},{"label":"ERCC2","kind":"causal"},{"label":"ERCC4","kind":"causal"},{"label":"XPA","kind":"causal"},{"label":"ERCC3","kind":"causal"},{"label":"XPC","kind":"causal"},{"label":"DDB2","kind":"causal"}],"visits":2,"openQuestions":["Is there ANY published XP-specific checkpoint-inhibitor outcome beyond single cases (response rate, new-primary rate, irAE profile), and does XP-SCC TMB/UV-signature load exceed sporadic cutaneous SCC?","Do XP tumours show baseline cGAS-STING activation or, conversely, STING/IFN silencing - i.e. is innate-sensing amplification a real opportunity or already saturated?","Can XPB/TFIIH-directed agents be dosed to degrade RPB1 without inhibiting residual TC-NER in XP-patient fibroblasts, and at what fold separation?","Which epidermal compartment (interfollicular basal versus follicular bulge) must be corrected for durable XP chemoprevention, and does any unpublished/preprint XPC or XPA keratinocyte-graft or base-editing dataset exist?","Is there genotype-stratified evidence on radiotherapy tolerance by complementation group (XP-A/C/D vs XP-B/TTD) beyond single-case anecdote, and can NCT05484570's cohort supply second-tumour-in-field denominators?","What is the somatic driver landscape of XPC-null internal sarcomas (beta-catenin/CTNNB1, SWI/SNF, TP53), given that NER-low carcinogen-driven tumours can be beta-catenin dependent?"],"leads":[{"id":"L1","title":"PD-1/PD-L1 blockade for XP-associated cutaneous SCC (repair-deficiency-driven adaptive immune resistance)","mechanism":"Biallelic germline XPA/XPC loss [GERMLINE] leaves UV photoproducts unrepaired; persistent damage plus UV drives STAT1/interferon signalling and synergistic CD274 (PD-L1) induction in keratinocytes, giving PD-L1-dependent T-cell inhibition on a very high UV-signature mutational background [KNOWN]; PD-L1 neutralisation restores T-cell engagement in vitro.","approach":"Anti-PD-1 (cemiplimab/pembrolizumab) in unresectable/multifocal XP-SCC, ideally neoadjuvant; correlatives = PD-L1/STAT1 IHC, TMB/UV signature, B2M and JAK1/2 status. Predicted resistance: B2M/JAK-STAT/IFNGR loss, PD-L1-independent new primaries from untreated field. Nest in a DNA-repair-disorder natural history cohort (NCT05484570) to capture new-primary rate and irAE signal.","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"42173765","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41908666","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42445768","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05484570","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":1,"createdCycle":126,"lastVisit":2,"lastNote":"Dedicated 2020-2026 Europe PMC query for XP + PD-1/PD-L1 returned zero new XP-specific clinical or preclinical evidence this visit; the lead is unfalsified but stagnant, so confidence trimmed from 0.6. Still rests on one patient plus one keratinocyte line.","history":[{"visit":2,"cycle":205,"status":"WEAKENED","note":"Dedicated 2020-2026 Europe PMC query for XP + PD-1/PD-L1 returned zero new XP-specific clinical or preclinical evidence this visit; the lead is unfalsified but stagnant, so confidence trimmed from 0.6. Still rests on one patient plus one keratinocyte line."},{"visit":1,"cycle":126,"status":"NEW","note":"New lead from P4: XPA-knockdown + UV synergistically induces PD-L1; PD-L1 blockade abolishes enhanced Jurkat-keratinocyte attachment; XP-SCC upregulates CD274/PDCD1/STAT1. Evidence is one patient plus one keratinocyte line - no in vivo or clinical response data yet."}]},{"id":"L2","title":"Ex vivo lentiviral correction of epidermal stem cells for XPC/XPA chemoprevention (not AAV dermal delivery)","mechanism":"XP skin carcinogenesis originates in interfollicular basal keratinocytes and follicular stem cells; durable XPC/XPA cDNA restoration in holoclone-forming epidermal stem cells should restore global genome NER and blunt UV mutation accrual [INFERRED]. AAVrh32.33 dermal/bulge tropism is a compartment mismatch for keratinocyte-derived SCC.","approach":"Autologous LV- or base-edited keratinocyte sheet grafts to high-risk facial fields, benchmarked on the ARTEGENE ex vivo CD34+ platform in another DNA-repair disorder (DCLRE1C). Risks: insertional mutagenesis in an already hypermutable genome, mosaic field escape, clonal exhaustion.","level":"LEAD","confidence":0.26,"citations":[{"kind":"PMID","id":"42070083","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05071222","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":126,"lastVisit":2,"lastNote":"Targeted query (XPC/XPA/ERCC2/ERCC3 AND gene therapy OR base editing OR keratinocyte stem cell OR epidermal graft OR lentiviral, 2020-2026) returned no XP-specific data. Weakened on documented absence of enabling preclinical work; the analogy to DCLRE1C is now the only support.","history":[{"visit":2,"cycle":205,"status":"WEAKENED","note":"Targeted query (XPC/XPA/ERCC2/ERCC3 AND gene therapy OR base editing OR keratinocyte stem cell OR epidermal graft OR lentiviral, 2020-2026) returned no XP-specific data. Weakened on documented absence of enabling preclinical work; the analogy to DCLRE1C is now the only support."},{"visit":1,"cycle":126,"status":"NEW","note":"New lead assembled from P5 + T2. P5 is the enabling delivery paper but argues against systemic AAV for keratinocyte-derived XP cancer; T2 shows regulatory/technical feasibility of ex vivo gene therapy in a DNA-repair disorder."}]},{"id":"L3","title":"XPB(ERCC3)-directed transcription inhibition (Minnelide) for chemo-refractory XP-associated internal sarcomas","mechanism":"Triptolide engages XPB, the TFIIH ATPase, altering RPB1 phosphorylation and driving RPB1 degradation and apoptosis in transcription-addicted sarcoma. P4 now shows TFIIH's p62-PH and XPD interfaces are required to assemble a catalytically competent NER complex and to license ERCC1-XPF 5' incision, so drugging TFIIH also threatens the residual repair capacity XP patients depend on (TC-NER in XP-C, GG-NER in XP-E) [INFERRED].","approach":"Before any PDX work, establish dose separation between XPB/RPB1-degradation activity and NER inhibition in XP-patient primary fibroblasts (UDS, unhooking/incision assays) across complementation groups; only then test XPC-null sarcoma models, strictly ERCC3-wild-type genotypes.","level":"LEAD","confidence":0.14,"citations":[{"kind":"PMID","id":"42302177","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41908666","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41641700","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":126,"lastVisit":2,"lastNote":"PMID:41641700 [NEW] converts the therapeutic-window unknown into a concrete liability: TFIIH interface integrity is load-bearing for the residual NER of XP patients, so on-target normal-tissue toxicity is expected, not speculative. Confidence 0.20 -> 0.14; gated behind a fibroblast NER-sparing assay.","history":[{"visit":2,"cycle":205,"status":"WEAKENED","note":"PMID:41641700 [NEW] converts the therapeutic-window unknown into a concrete liability: TFIIH interface integrity is load-bearing for the residual NER of XP patients, so on-target normal-tissue toxicity is expected, not speculative. Confidence 0.20 -> 0.14; gated behind a fibroblast NER-sparing assay."},{"visit":1,"cycle":126,"status":"NEW","note":"New, frankly speculative cross-over lead: P7 supplies the XPB-dependent mechanism and clinical de-risking of Minnelide; P8 supplies the unmet need (both XPC-null internal sarcomas failed or relapsed after chemotherapy)."}]},{"id":"L4","title":"Radiotherapy is not categorically contraindicated in XP: HDR interstitial brachytherapy for unresectable facial SCC","mechanism":"XP defects lie in nucleotide excision repair, not double-strand-break repair, so intrinsic clinical radiosensitivity should not mirror ataxia-telangiectasia [KNOWN]; conformal brachytherapy further limits dose to surrounding field-cancerised skin.","approach":"Prospective genotype-stratified dose-escalation/observational cohort of HDR interstitial brachytherapy for unresectable or cosmetically prohibitive head/neck XP-SCC, with acute/late skin toxicity and second-tumour-in-field endpoints; potential rationale for RT + anti-PD-1 sequencing.","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"41958690","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42445768","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":126,"lastVisit":1,"lastNote":"New lead from P9, a single eight-year durable local control case that explicitly challenges the absolute RT contraindication; weight is low (n=1, no complementation group stated), and surgery with grafting remains the documented mainstay (P6).","history":[{"visit":1,"cycle":126,"status":"NEW","note":"New lead from P9, a single eight-year durable local control case that explicitly challenges the absolute RT contraindication; weight is low (n=1, no complementation group stated), and surgery with grafting remains the documented mainstay (P6)."}]},{"id":"L5","title":"STING-pathway amplification (Mn2+-potentiated cGAS-STING) without ATM inhibition, as immunotherapy sensitiser in XP-associated sarcoma and SCC","mechanism":"Bone-targeted GSH-responsive nanoparticles delivering Mn2+ with ATM and PRMT5 inhibitors amplify DNA damage, drive cytosolic DNA sensing via cGAS-STING and remodel an immunosuppressive osteosarcoma microenvironment (PMID:42006004). XP tumours already accumulate unrepaired UV/adduct lesions and cytosolic DNA constitutively, so the innate-sensing arm may be exploitable without adding genotoxic load; the ATM-inhibitor component is contraindicated in a globally repair-deficient host and must be dropped [SPECULATIVE].","approach":"Test Mn2+ or a free STING agonist alone versus agonist + anti-PD-1 in XPC-null / XPA-null murine UV-SCC and XP sarcoma models; readouts = IFN-beta/CXCL10 induction, CD8 infiltration, and critically normal-skin/haematologic tolerance. Predicted failure modes: STING silencing in tumour, IFN-driven PD-L1 escape (links to L1), systemic cytokine toxicity.","level":"LEAD","confidence":0.15,"citations":[{"kind":"PMID","id":"42006004","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42173765","verified":true,"isNew":false,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":205,"lastVisit":2,"lastNote":"New low-weight lead built from the only mechanistically transferable item in this pack; explicitly strips the ATM-inhibition arm because germline NER deficiency plus DSB-repair inhibition is a predictable toxicity trap.","history":[{"visit":2,"cycle":205,"status":"NEW","note":"New low-weight lead built from the only mechanistically transferable item in this pack; explicitly strips the ATM-inhibition arm because germline NER deficiency plus DSB-repair inhibition is a predictable toxicity trap."}]}],"retired":[],"nextQueries":["(\"xeroderma pigmentosum\") AND (cemiplimab OR pembrolizumab OR nivolumab OR \"checkpoint\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]","(XPC OR XPA OR \"nucleotide excision repair\") AND (STING OR cGAS OR \"type I interferon\" OR \"innate immune\") AND SRC:MED AND PUB_YEAR:[2019 TO 2026]","(\"xeroderma pigmentosum\") AND (sarcoma OR \"internal malignancy\" OR \"exome\" OR \"mutational signature\") AND SRC:MED AND PUB_YEAR:[2015 TO 2026]"],"updatedAt":"2026-08-20T02:02:58.925Z"},{"key":"bloom syndrome","name":"Bloom syndrome","mondo":{"id":"MONDO:0008876","name":"Bloom syndrome"},"genes":[{"label":"BLM","kind":"causal"}],"visits":2,"openQuestions":["What are the per-agent dose reductions, conditioning regimens and grade 3-5 toxicities in the nine-patient BS cohort (full text of PMID:40641635), and do the four relapses cluster with dose de-escalation rather than with tumour biology?","Is there any BS-specific evidence on PARP inhibitor exposure, given that BLM suppression synergises with olaparib and BS normal tissue is constitutively BLM-null?","Do BS-derived tumour lines show a dependency (G4 resolvase, ATR/CHK1, WEE1) absent from BS non-malignant BLM-null cells — i.e. does any therapeutic window exist in this syndrome?","What is the measured immune phenotype of BS patients with malignancy (immunoglobulins, memory B cells, TCR diversity) and the TMB/neoantigen load of BS tumours, before checkpoint blockade is proposed?","Which somatic co-lesions recur in BS tumours (ARID1A, TP53, MSI, ALT), and do the characteristic BS structural-variant signatures identify a rerouted checkpoint dependency?","Are WRN, RECQL4, RECQL5, DHX36 or PIF1 upregulated or functionally compensating in BLM-null human cells, making paralogue inhibition prohibitively toxic in BS?"],"leads":[{"id":"L1","title":"Genotoxin-sparing treatment architecture for BS-associated malignancy (osteosarcoma, MDS/AML)","mechanism":"Biallelic germline BLM loss [GERMLINE] impairs fork restart and HR resolution in every proliferating tissue, so alkylators, topoisomerase poisons and radiation produce disproportionate host toxicity while tumours remain BLM-null; new clinical series confirms dose reductions, prolonged aplasia, sepsis, early discontinuation and a toxic death, yet also curative remissions (PMID:40641635). New in vitro data that BLM suppression synergises with olaparib (PMID:42087785) predicts, by symmetry, that BLM-null normal tissue in BS is PARPi-hypersensitive [INFERRED] — PARPi is therefore a caution, not a sparing option.","approach":"Extract per-agent dose intensity, conditioning regimen and toxicity grade from the multicentre cohort (full text) and extend by registry assembly; test whether reduced-intensity conditioning HSCT and non-genotoxic targeted agents preserve remission rates; prospectively exclude PARPi and full-dose alkylator/radiation exposure; benchmark BS osteosarcoma outcomes on reduced methotrexate/doxorubicin/cisplatin against sarcoma standards.","level":"CANDIDATE","confidence":0.62,"citations":[{"kind":"PMID","id":"41652616","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41595160","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41064806","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40641635","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42087785","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":127,"lastVisit":2,"lastNote":"First BS-specific clinical toxicity/outcome data (9 patients, dose reductions, 1 toxic death, 5 remissions) replaces expert opinion; promoted to CANDIDATE. PARPi added to the avoid-list by inference from new BLM-suppression/olaparib synergy. Abstract lacks per-agent doses and conditioning detail.","history":[{"visit":2,"cycle":206,"status":"STRENGTHENED","note":"First BS-specific clinical toxicity/outcome data (9 patients, dose reductions, 1 toxic death, 5 remissions) replaces expert opinion; promoted to CANDIDATE. PARPi added to the avoid-list by inference from new BLM-suppression/olaparib synergy. Abstract lacks per-agent doses and conditioning detail."},{"visit":1,"cycle":127,"status":"NEW","note":"New lead. P2 and P3 supply the two clinical settings (syndrome-driven osteosarcoma; germline-predisposed MDS/AML where germline status changes HSCT strategy); P1 supplies the helicase-deficiency mechanism. No BS-specific dosing data in the pack — abstracts only, hypothesis-generating."}]},{"id":"L2","title":"Checkpoint rerouting (Chk1-to-Chk2, p21, ATR) as the tumour-selective axis on a BLM-null background","mechanism":"Helicase inhibition rewires damage-checkpoint choice rather than simply adding damage: WRN loss in ARID1A-mutant cells disables Chk1 signalling, forces compensatory Chk2 activation and G1 arrest, and p21 co-inhibition converts arrest into mitotic catastrophe (P8); dysregulated BLM activity in the opposite direction drives ATR-dependent fork/telomere stress (P10). In BS tumours the selective agent must exploit a somatic lesion (e.g. ARID1A, MSI, ALT, oncogene-driven replication stress) superimposed on constitutive BLM loss, since BLM loss itself is not tumour-restricted.","approach":"Isogenic BLM-null vs BLM-restored BS fibroblast/lymphoblast and BS-tumour-derived lines; screen ATR (ceralasertib-class), CHK1, WEE1 and p21-pathway inhibitors with and without a somatic ARID1A or ALT lesion; read out Chk1/Chk2 phosphorylation, G1 vs G2-M arrest, SCE burden. Explicit falsification test: measure normal-tissue window in BLM-null non-malignant cells before nominating any agent. Predicted resistance: ATR-inhibitor escape via CHK1 amplification, POLQ/RAD52-dependent break tolerance.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42247504","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42098304","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41064806","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":127,"lastVisit":1,"lastNote":"New lead built by analogy from WRN/ARID1A (P8), not by direct BS evidence. P10 delivers a hard negative that shapes it: SLX4IP/FANCM co-depletion lethality in ALT-positive cells is fully rescued by BLM loss, so ALT-directed FANCM strategies are predicted inert in BLM-null tumours — do not re-propose.","history":[{"visit":1,"cycle":127,"status":"NEW","note":"New lead built by analogy from WRN/ARID1A (P8), not by direct BS evidence. P10 delivers a hard negative that shapes it: SLX4IP/FANCM co-depletion lethality in ALT-positive cells is fully rescued by BLM loss, so ALT-directed FANCM strategies are predicted inert in BLM-null tumours — do not re-propose."}]},{"id":"L3","title":"Mirror programme: pharmacological BLM suppression in BLM-overexpressing sporadic tumours, and BLM lactylation as the switch","mechanism":"BLM is overexpressed across malignancies and acts as a G4 unwindase at oncogene promoters: pSTAT1 recruitment to a parallel BLM-promoter G4 drives BLM transcription, and berberine/coptisine competitively displace STAT1 to suppress BLM in colon cancer, synergising with olaparib (PMID:42087785); the fangchinoline derivative LYY-34 blocks BLM-mediated unfolding of the c-MYC promoter G4, lowering MYC and suppressing TNBC (PMID:41941995). FMD-108 and BLM lactylation remain earlier, single-group leads.","approach":"Use LYY-34 (enzyme/3'-overhang-directed, not a G4 stabiliser) rather than coptisine as the phenocopy probe in isogenic BLM-null vs BLM-restored BS lines; verify on-target engagement (BLM knockdown epistasis, MYC readout) before any screening use. Separately test BLM inhibitor + platinum and BLM inhibitor + olaparib in BLM-high colon/TNBC/melanoma models. Normal tissue: BLM is required for fork protection and SCE suppression in haematopoietic and epithelial compartments — predicted myelosuppression; explicitly NOT applicable to BS patients.","level":"CANDIDATE","confidence":0.45,"citations":[{"kind":"PMID","id":"42323025","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42346100","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41064806","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42087785","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41941995","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":2,"createdVisit":1,"createdCycle":127,"lastVisit":2,"lastNote":"Two independent 2026 reports with orthogonal chemistry and defined mechanism (promoter-G4/STAT1 transcriptional suppression; c-MYC G4 unwinding inhibition) corroborate the mirror programme; promoted to CANDIDATE. Coptisine's pan-genomic G4 stabilisation disqualifies it as a selective probe.","history":[{"visit":2,"cycle":206,"status":"STRENGTHENED","note":"Two independent 2026 reports with orthogonal chemistry and defined mechanism (promoter-G4/STAT1 transcriptional suppression; c-MYC G4 unwinding inhibition) corroborate the mirror programme; promoted to CANDIDATE. Coptisine's pan-genomic G4 stabilisation disqualifies it as a selective probe."},{"visit":1,"cycle":127,"status":"NEW","note":"New lead. P4 is a single-group first-in-class report (target engagement/selectivity not verifiable from abstract); P6 is a review describing BLM lactylation in bladder models, mechanistically inferred rather than proven. Value to this programme is primarily as a probe supply and a window-argument counterexample."}]},{"id":"L4","title":"BS as an inborn error of immunity: immune competence gates checkpoint blockade as the genotoxin-sparing modality","mechanism":"DNA-repair disorders are formally inborn errors of immunity, spanning hypogammaglobulinaemia to combined immunodeficiency with immune dysregulation and elevated malignancy risk (PMID:42131344); germline predisposition to paediatric lymphoid malignancy converges on defects in DNA recombination/damage recognition and lymphocyte development (PMID:40925926), and IEI is frequently unmasked only at haematological cancer diagnosis (PMID:42104472). If BS patients have impaired B-cell and restricted T-cell repertoires [KNOWN for BS hypogammaglobulinaemia], PD-1/CTLA-4 blockade may lack the effector substrate that the high-SCE/high-instability rationale assumes, and carries added autoimmune risk on a ","approach":"Before nominating checkpoint blockade in BS, profile immunoglobulin levels, class-switched memory B cells, TCR repertoire diversity and T-cell proliferative response in BS patients and BS tumours; measure tumour mutational burden/neoantigen load and MHC-I expression in BS-derived tumours to test whether the instability phenotype actually generates immunogenic burden; pair any immunotherapy proposal with immunoglobulin replacement and infection-risk mitigation.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42131344","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40925926","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42104472","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"40641635","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":206,"lastVisit":2,"lastNote":"New lead splitting the immunotherapy limb out of L1 and weakening its default optimism: three reviews establish DNA-repair syndromes as immunodeficiency states, so checkpoint blockade cannot be assumed effective or safe here. No BS-specific TMB or immunotherapy data in the pack.","history":[{"visit":2,"cycle":206,"status":"NEW","note":"New lead splitting the immunotherapy limb out of L1 and weakening its default optimism: three reviews establish DNA-repair syndromes as immunodeficiency states, so checkpoint blockade cannot be assumed effective or safe here. No BS-specific TMB or immunotherapy data in the pack."}]},{"id":"L5","title":"Unresolved G-quadruplex burden and backup G4 resolvases as a candidate axis in BLM-null cells","mechanism":"BLM unwinds promoter and telomeric G4s; loss should leave persistent G4 structures, altered oncogene output (c-MYC is BLM-dependent in TNBC, PMID:41941995) and dependence on backup resolvases (WRN, DHX36, PIF1, RECQL5) and on structure-forming-region tolerance pathways — consistent with the characteristic structural-variant signatures ascribed to Bloom syndrome from fork stalling/template switching and break-induced replication (PMID:42389213). Because BLM is absent in all BS tissues, any paralogue-directed strategy has an a priori window problem [INFERRED].","approach":"In isogenic BLM-null vs BLM-restored BS fibroblasts/lymphoblasts and BS tumour-derived lines, map G4 landscape (G4-CUT&Tag) and MYC dependency; CRISPR-score WRN, DHX36, PIF1, RECQL5, POLQ and RAD52; test G4 stabilisers (pyridostatin class) for differential lethality. Mandatory falsification step: any hit must show a >5-fold window in BLM-null non-malignant cells before nomination. Predicted resistance: POLQ/RAD52 break tolerance, MYC-independent proliferative rewiring.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"41941995","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42087785","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42389213","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"42599232","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":206,"lastVisit":2,"lastNote":"New lead generated by the G4 mechanism reported this visit; addresses open question 4 (paralogue compensation) with an explicit toxicity-window falsification test rather than assuming a window exists.","history":[{"visit":2,"cycle":206,"status":"NEW","note":"New lead generated by the G4 mechanism reported this visit; addresses open question 4 (paralogue compensation) with an explicit toxicity-window falsification test rather than assuming a window exists."}]}],"retired":[],"nextQueries":["(\"Bloom syndrome\" OR BLM) AND (\"PARP inhibitor\" OR olaparib OR talazoparib) AND (sensitivity OR \"synthetic lethal\" OR toxicity) AND SRC:MED","\"Bloom syndrome\" AND (immunodeficiency OR hypogammaglobulinemia OR \"T cell repertoire\" OR \"tumor mutational burden\" OR immunotherapy) AND SRC:MED","(BLM OR \"Bloom syndrome\") AND (\"G-quadruplex\" OR DHX36 OR PIF1 OR RECQL5 OR WRN) AND (CRISPR OR \"dependency\" OR \"synthetic lethal\") AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-20T02:06:26.104Z"},{"key":"werner syndrome","name":"Werner syndrome","mondo":{"id":"MONDO:0010196","name":"Werner syndrome"},"genes":[{"label":"WRN","kind":"causal"}],"visits":1,"openQuestions":["Are there WRN-null patient-derived tumour models (WS osteosarcoma, sarcoma, thyroid) with published drug-sensitivity or CRISPR-dependency data, and do any co-dependencies survive a normal-WS-fibroblast toxicity control?","Is SMARCAL1 pharmacologically tractable, and would SMARCAL1 stabilisation/activation rather than inhibition sensitise MSI-H tumours to WRN inhibitors?","Do the PD-1 combination arms (NCT07262619, NCT06710847) rest on a stated cGAS-STING/DSB-neoantigen rationale, and is there preclinical evidence that WRN inhibition raises immunogenicity in MSI-H beyond baseline checkpoint sensitivity?","Do WRN helicase-domain resistance mutations retain enough catalytic and MSI-buffering function to be trackable in ctDNA, and does any trial protocol prespecify such monitoring?","Does WRN loss in the germline WS context alter telomere-maintenance dependence (ALT vs telomerase) in the resulting sarcomas, offering an orthogonal target?","Which repair pathway substitutes for WRN in long-lived WRN-null normal tissue, since that pathway defines the toxicity ceiling for any WS-directed agent?"],"leads":[{"id":"L1","title":"Chemotype rotation / next-generation covalent inhibitors against on-target WRN helicase-domain resistance","mechanism":"MSI-H cells under HRO761 or related inhibitors rapidly acquire clustered missense mutations in the WRN helicase domain that either block inhibitor binding or lock a non-engageable conformation; dMMR hypermutation accelerates emergence. L528S, C727R and F730L are chemotype-selective, implying non-overlapping escape landscapes between covalent and non-covalent scaffolds.","approach":"Cross-profile HRO761, the covalent WC-2 series and the four clinical agents (MOMA-341, NDI-219216, EIK1005, GSK4418959) against an isogenic panel of L528S/C727R/F730L knock-ins; design next-gen covalent binders retaining activity on mutants; prospective ctDNA WRN-domain sequencing at progression to drive sequential rather than escalating dosing. Expected resistance routes beyond this: loss of SMARCAL1/MRN, MMR restoration, TA-repeat contraction.","level":"LEAD","confidence":0.7,"citations":[{"kind":"PMID","id":"41656870","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42593940","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41962327","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06974110","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06898450","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07262619","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06710847","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":128,"lastVisit":1,"lastNote":"New this visit: first systematic map of on-target WRN resistance mutations with scaffold selectivity (PMID:41656870), plus an orally bioavailable low-reactivity covalent candidate (PMID:42593940) that makes rotation practical.","history":[{"visit":1,"cycle":128,"status":"NEW","note":"New this visit: first systematic map of on-target WRN resistance mutations with scaffold selectivity (PMID:41656870), plus an orally bioavailable low-reactivity covalent candidate (PMID:42593940) that makes rotation practical."}]},{"id":"L2","title":"SMARCAL1/MRN axis as response biomarker and as a combination anti-pattern for WRN inhibitors","mechanism":"Genome-wide CRISPR screens in CRC show SMARCAL1 ATPase/translocase activity antagonises WRN and sustains the cruciform TA-repeat substrate, so SMARCAL1 loss confers resistance; MRE11-RAD50-NBS1 (not MUS81 or ERCC1/XPF) executes the DSB-generating step, acting through both ATM signalling and MRE11 nuclease, with acute MRN disruption giving profound resistance and ATM loss a milder effect. [SOMATIC]","approach":"Add SMARCAL1, MRE11/RAD50/NBS1 and ATM status (plus TA-dinucleotide repeat burden) to pre-treatment and progression biopsies in the running phase I WRN trials; assay these as intrinsic-resistance predictors. Negative corollary to record: combining WRN inhibitors with ATM or MRE11 nuclease inhibitors is predicted antagonistic [INFERRED] and should not be proposed.","level":"LEAD","confidence":0.65,"citations":[{"kind":"PMID","id":"42484294","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41962327","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":128,"lastVisit":1,"lastNote":"New mechanistic epistasis defining who responds and which combinations are self-defeating; converts a plausible ATM/MRN combination idea into a documented dead end before it costs a trial arm.","history":[{"visit":1,"cycle":128,"status":"NEW","note":"New mechanistic epistasis defining who responds and which combinations are self-defeating; converts a plausible ATM/MRN combination idea into a documented dead end before it costs a trial arm."}]},{"id":"L3","title":"WRN inhibition to resensitise MSS tumours to DNA-damaging chemotherapy in the eIF4E2-low/WRN-high state","mechanism":"eIF4E2 recruits miRISC/CCR4-NOT via hsa-miR-130b-3p/301b-3p to the WRN 3'UTR, repressing WRN translation. eIF4E2 loss de-represses WRN protein, boosting repair of platinum-induced lesions and driving resistance to diverse DNA-damaging agents in NSCLC; HRO761 plus cisplatin restores cytotoxicity in resistant cells. [SOMATIC]","approach":"Test eIF4E2-low / WRN-protein-high as a companion biomarker in an MSS expansion cohort of a WRN inhibitor plus platinum or irinotecan (NCT06974110 already pairs its agent with irinotecan); confirm WRN protein, not mRNA, as the operative readout. Anticipated resistance: WRN helicase-domain mutation (see lead 1), NER/HR rewiring, ABC-transporter-mediated platinum efflux.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42441405","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06974110","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":128,"lastVisit":1,"lastNote":"First credible non-MSI indication for this drug class in the pack; based on abstract-level data only, no in vivo combination durability reported.","history":[{"visit":1,"cycle":128,"status":"NEW","note":"First credible non-MSI indication for this drug class in the pack; based on abstract-level data only, no in vivo combination durability reported."}]},{"id":"L4","title":"Germline WRN-null tumours require second-hit synthetic lethality, not fork-stress agents","mechanism":"In Werner syndrome the tumour and every normal tissue share biallelic germline WRN loss [GERMLINE], so agents that exploit WRN deficiency or general replication-fork stress have no therapeutic window; impaired wound healing and premature arteriosclerosis further narrow tolerance of cytotoxic and surgical management. WRN inhibitors are mechanistically inapplicable here [INFERRED]. The remaining tractable route is a somatic co-dependency of the WS tumour genotype itself, e.g. residual reliance on SMARCAL1-generated substrates or MRN-mediated fork processing.","approach":"Assemble WS patient-derived osteosarcoma/sarcoma and thyroid models; run isogenic WRN-null vs WRN-restored dependency screens to find WRN-loss-specific co-dependencies distinct from the MSI cruciform axis; explicitly benchmark normal WS fibroblast toxicity for every hit as the window test. Reconstructive/supportive management of WS ulceration is documented but is not an oncology lead.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"41652616","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42254035","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42484294","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":128,"lastVisit":1,"lastNote":"Programme-defining framing for the actual MONDO target; deliberately low confidence because the pack contains no WS-tumour pharmacology, and it records the closed door (no WRN inhibitors in WRN-null disease) so the desk cannot re-propose it.","history":[{"visit":1,"cycle":128,"status":"NEW","note":"Programme-defining framing for the actual MONDO target; deliberately low confidence because the pack contains no WS-tumour pharmacology, and it records the closed door (no WRN inhibitors in WRN-null disease) so the desk cannot re-propose it."}]}],"retired":[],"nextQueries":["(\"Werner syndrome\" OR WRN) AND (\"patient-derived\" OR xenograft OR fibroblast) AND (\"drug sensitivity\" OR \"CRISPR screen\" OR dependency) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(WRN OR \"WRN inhibitor\" OR HRO761) AND (\"STING\" OR immunogenic OR \"PD-1\" OR neoantigen) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(SMARCAL1 OR \"MRE11\" OR \"replication fork remodel\") AND (WRN OR \"microsatellite instability\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T21:31:40.953Z"},{"key":"rothmund-thomson syndrome","name":"Rothmund-Thomson syndrome","mondo":{"id":"MONDO:0010002","name":"Rothmund-Thomson syndrome"},"genes":[{"label":"ANAPC1","kind":"causal"},{"label":"CRIPT","kind":"causal"},{"label":"RECQL4","kind":"causal"},{"label":"DNA2","kind":"causal"}],"visits":1,"openQuestions":["Do human RTS-2 RECQL4 truncation products bear functional C-degrons (KLHDC2/3, FEM1 family), or are they eliminated by NMD before protein-level degradation becomes relevant?","Does the helicase-less N-terminal 480-aa RECQL4 fragment also support non-replicative functions (mitochondrial DNA maintenance, telomere and G4 metabolism), or only bulk replication?","Is there any tumour-restricted replication-stress dependence in RTS osteosarcoma (second hits, MYC/CDK4 amplification) that would open a therapeutic window absent in RECQL4-mutant normal tissue?","What are the mechanisms and cancer risks of the non-RECQL4 anchors — ANAPC1 (APC/C), CRIPT, DNA2 [GERMLINE] — and do they converge on replication stress or on distinct pathways?","Which G4-resolving helicase (WRN, BLM, FANCJ, DHX36, PIF1) is the strongest synthetic-lethal partner of RECQL4 loss in an isogenic setting?","What is the documented chemotherapy/radiotherapy toxicity profile of RTS patients treated for osteosarcoma, by genotype?"],"leads":[{"id":"L1","title":"C-degron/CRL2 blockade to raise steady-state levels of truncated RECQL4 in RTS-2","mechanism":"RECQL4 [GERMLINE, biallelic in RTS-2] supports DNA replication through an N-terminal ~480-aa scaffold that does not require ATP-dependent helicase activity; in mice a KLHDC3-recognised C-degron destroys this fragment, and KLHDC3 loss restores proliferation and replication. Most human RTS-2 alleles are truncating [KNOWN], generating novel C-termini plausibly read by C-degron E3s (KLHDC2/3, FEM1A-C) [INFERRED], so pharmacological CRL2 substrate-receptor blockade could push residual protein above the low functional threshold.","approach":"Express patient truncation panel with native C-termini; measure half-life +/- KLHDC2/KLHDC3/CUL2 knockout and +/- NEDD8-pathway inhibition (pevonedistat as tool only [SPECULATIVE, non-selective]); global degron proteomics to assign each allele to an E3; readouts = fork progression (DNA combing), 53BP1/RPA foci, colony formation in patient fibroblasts/LCLs. Resistance/failure routes: alleles degraded by NMD rather than C-degron; fragment non-functional for non-replication roles; CRL2 substrate stabilisation causes broad proteotoxicity.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"41807760","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40728512","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":129,"lastVisit":1,"lastNote":"New from P8. Explicitly scoped: the murine neo-degron is Cre-derived and the authors state it does not apply to human mutations, so the human C-degron premise is INFERRED and is the first thing to test or kill.","history":[{"visit":1,"cycle":129,"status":"NEW","note":"New from P8. Explicitly scoped: the murine neo-degron is Cre-derived and the authors state it does not apply to human mutations, so the human C-degron premise is INFERRED and is the first thing to test or kill."}]},{"id":"L2","title":"Minimal mini-RECQL4 (N-terminal 480 aa) transgene for the hematopoietic compartment, delivered without genotoxic conditioning","mechanism":"If the helicase-less N-terminal fragment suffices for replication and viability, the therapeutic cargo shrinks from ~1208 aa to ~480 aa, easing AAV/lentiviral packaging [INFERRED]. RECQL4-deficient T-cell/SCID phenotype is intrinsic to hematopoietic cells and was corrected by unmanipulated marrow infusion with no conditioning, defining both a target compartment and a route that avoids the alkylator/irradiation intolerance imposed by the DNA-repair defect.","approach":"Compare full-length vs mini-RECQL4 lentiviral constructs in RECQL4-mutant CD34+ cells and Recql4-mutant mice for engraftment, thymopoiesis, replication-stress markers and clonality; benchmark against unconditioned allogeneic infusion. Normal-tissue argument: RECQL4 is ubiquitously required for replication, so partial restoration in a proliferating compartment is the point, not overexpression. Risks: fragment fails to support non-replicative RECQL4 functions (mitochondrial, telomeric) [KNOWN, unresolved]; insertional genotoxicity in a genome-instability background; unconditioned engraftment may be too low outside SCID niches.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"41807760","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41798738","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":129,"lastVisit":1,"lastNote":"New; created by joining P8's minimal-cargo finding to P5's demonstration that the immune defect is hematopoietic-intrinsic and correctable without conditioning.","history":[{"visit":1,"cycle":129,"status":"NEW","note":"New; created by joining P8's minimal-cargo finding to P5's demonstration that the immune defect is hematopoietic-intrinsic and correctable without conditioning."}]},{"id":"L3","title":"G4/replication-stress synthetic lethality in RECQL4-deficient osteosarcoma — window-limited","mechanism":"RECQL4 loss impairs G4 unwinding and fork restart, predicting dependence on residual G4-metabolising helicases (WRN, BLM, FANCJ/BRIP1, DHX36, PIF1) and on ATR-mediated checkpoint tolerance [INFERRED from P1, P2]. RTS osteosarcoma is the dominant malignancy [PMID:41652616].","approach":"Isogenic RECQL4-null vs WT osteosarcoma lines: CRISPR dependency screen focused on G4 helicases; dose-response to ATR inhibitors (ceralasertib, elimusertib), G4 stabilisers (pyridostatin, CX-5461), PARP; require a selectivity index against patient-derived non-malignant RECQL4-mutant fibroblasts before any translational claim. Named resistance routes: ATR-inhibitor escape via CDC25A/WEE1 rewiring, POLQ/TMEJ upregulation, loss of SLFN11.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"41975004","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40728512","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41652616","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41379383","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":129,"lastVisit":1,"lastNote":"New. Deliberately entered with the window caveat foregrounded: in RTS-2 the germline defect is shared by normal tissue, and documented radiosensitivity (P5) plus chemo intolerance [KNOWN] make on-target normal-tissue toxicity the likely killer of this lead.","history":[{"visit":1,"cycle":129,"status":"NEW","note":"New. Deliberately entered with the window caveat foregrounded: in RTS-2 the germline defect is shared by normal tissue, and documented radiosensitivity (P5) plus chemo intolerance [KNOWN] make on-target normal-tissue toxicity the likely killer of this lead."}]},{"id":"L4","title":"Radiation- and alkylator-sparing treatment architecture for RTS malignancy and immunodeficiency","mechanism":"DNA-repair deficiency makes conditioning and radiotherapy disproportionately toxic; unmanipulated marrow infusion without conditioning was sufficient to rescue RECQL4-/- SCID, showing that in some compartments the genotoxic step can be omitted entirely.","approach":"Systematic genotype-stratified toxicity capture through predisposition cohorts (NCT03050268) to define which RTS genotypes tolerate anthracycline/platinum osteosarcoma backbones; prospective registry of reduced-/no-conditioning HSCT outcomes; prioritise non-genotoxic modalities (antibody-drug conjugates, immunotherapy) for RTS osteosarcoma. Not medical advice; a research-design and evidence-gathering hypothesis for expert review.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"41798738","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41652616","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03050268","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":129,"lastVisit":1,"lastNote":"New. Records the negative/constraint knowledge from P5 so the desk never proposes radiation- or alkylator-intensive regimens for RTS without explicit justification.","history":[{"visit":1,"cycle":129,"status":"NEW","note":"New. Records the negative/constraint knowledge from P5 so the desk never proposes radiation- or alkylator-intensive regimens for RTS without explicit justification."}]}],"retired":[],"nextQueries":["(\"RECQL4\" OR \"RTS\") AND (\"synthetic lethal\" OR \"CRISPR screen\" OR \"dependency\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"C-degron\" OR \"KLHDC2\" OR \"KLHDC3\" OR \"CRL2\") AND (truncating OR \"nonsense\" OR \"frameshift\") AND (stabilization OR degradation) AND SRC:MED","(\"ANAPC1\" OR \"CRIPT\" OR \"DNA2\") AND (\"Rothmund-Thomson\" OR poikiloderma OR \"cancer predisposition\") AND SRC:MED"],"updatedAt":"2026-08-19T21:35:07.389Z"},{"key":"nijmegen breakage syndrome","name":"Nijmegen breakage syndrome","mondo":{"id":"MONDO:0009623","name":"Nijmegen breakage syndrome"},"genes":[{"label":"NBN","kind":"causal"}],"visits":1,"openQuestions":["Do NBS-associated lymphomas/solid tumours carry a somatic second hit at NBN (LOH or loss of the residual hypomorphic allele), which is the only condition under which HR-directed synthetic lethality (PARP/ATR/POLQ) has a therapeutic window?","What are the long-term post-HSCT second-malignancy and neurologic outcomes in NBS, given that transplant does not correct the germline NBN defect outside the haematopoietic compartment?","How does low-dose treosulfan+PTCy (NCT06198842) compare with fludarabine/melphalan or FA-adapted regimens in NBS for engraftment, VOD, GvHD and immune reconstitution?","Is residual p70-NBS1/MRN assembly R2TP/HSP90-dependent, and are NBN-hypomorph cells hypersensitive to HSP90 or RUVBL1/2 inhibitors?","Do reported NBS1/RAD51/XLF lactylation events modulate residual MRN function, making LDHA or glycolytic inhibition a modifier of chemosensitivity in NBN-hypomorph tumours?","Is there any registry signal linking rhGH/IGF-1 axis exposure to malignancy incidence in NBS or RAD50-deficient patients?"],"leads":[{"id":"L1","title":"Reduced-toxicity, radiation-sparing conditioning for allogeneic HSCT in NBS (low-dose treosulfan + PTCy)","mechanism":"Hypomorphic germline NBN [GERMLINE] cripples MRN-dependent DSB sensing/repair, conferring cellular hypersensitivity to ionising radiation and radiomimetic/alkylating conditioning [KNOWN]; substituting treosulfan at reduced dose with PTCy for GvHD control is intended to achieve engraftment and immune reconstitution below the DSB-toxicity threshold of NBN-deficient normal tissue.","approach":"Track NCT06198842 (phase 2, treosulfan + PTCy) for engraftment, VOD/mucositis/hepatic toxicity, T/B reconstitution; benchmark against fludarabine-based FA-adapted regimens reported in the A-T/FA/NBS literature; mandate long-term second-malignancy surveillance since HSCT does not correct extrahaematopoietic NBN deficiency [INFERRED].","level":"LEAD","confidence":0.6,"citations":[{"kind":"NCT","id":"NCT06198842","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42244353","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":130,"lastVisit":1,"lastNote":"Opened this visit. NCT06198842 is the only NBS-specific interventional item in the pack; PMID:42244353 [NEW] independently endorses radiation-sparing, fludarabine-based conditioning in MRN/ATM-family disorders and documents VOD/GvHD/hepatic failure after myeloablation, supporting the dose-de-escalation rationale. Abstract-level only: no NBS outcome numbers available.","history":[{"visit":1,"cycle":130,"status":"NEW","note":"Opened this visit. NCT06198842 is the only NBS-specific interventional item in the pack; PMID:42244353 [NEW] independently endorses radiation-sparing, fludarabine-based conditioning in MRN/ATM-family disorders and documents VOD/GvHD/hepatic failure after myeloablation, supporting the dose-de-escalation rationale. Abstract-level only: no NBS outcome numbers available."}]},{"id":"L2","title":"R2TP/HSP90 chaperone dependency of residual NBS1-p70/MRN assembly — contraindication test and tumour vulnerability","mechanism":"R2TP (RUVBL1-RUVBL2-RPAP3-PIH1D1) with HSP90/HSP70 assembles PIKKs (ATM/ATR/DNA-PK) and the MRE11-RAD50-NBS1 complex; if the truncated p70-NBS1 product of 657del5 requires R2TP/HSP90 for folding into functional MRN [SPECULATIVE], chaperone inhibition would further deplete an already marginal repair reserve in NBS normal tissue, while tumours that have lost the residual allele could be selectively dependent.","approach":"Co-IP/proximity assays for RUVBL1/2-PIH1D1 binding to p70-NBS1 in NBS patient LCLs vs wild-type; dose-response to HSP90 inhibitors and RUVBL1/2 ATPase inhibitors with gamma-H2AX/comet readouts; if hypersensitivity confirmed, flag HSP90-inhibitor trials as an exclusion for NBN-hypomorph carriers.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42248294","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":130,"lastVisit":1,"lastNote":"New mechanistic thread from PMID:42248294 [NEW], which places MRN among R2TP client complexes. Purely a preclinical pharmacology hypothesis; no NBS data exist, so framed first as a safety/contraindication experiment rather than a therapy.","history":[{"visit":1,"cycle":130,"status":"NEW","note":"New mechanistic thread from PMID:42248294 [NEW], which places MRN among R2TP client complexes. Purely a preclinical pharmacology hypothesis; no NBS data exist, so framed first as a safety/contraindication experiment rather than a therapy."}]},{"id":"L3","title":"c-MYC/NBS1 axis collapse plus replication-stress chemotherapy in MYC-driven NBS-associated lymphoma","mechanism":"c-MYC transcriptionally sustains NBS1 and broader DDR capacity; alloimperatorin lowers c-MYC and NBS1 and synergises with gemcitabine to produce sustained unrepaired DSBs in solid tumour models. NBS malignancies are predominantly MYC-translocated B-NHL/DLBCL [KNOWN], so MYC-driven NBS1 output may be the residual repair capacity that permits tumour survival despite the germline hypomorph [INFERRED].","approach":"Test MYC/NBS1-axis suppression (alloimperatorin, or BET/MYC-directed agents) with gemcitabine or other replication-stress agents in NBN-hypomorph lymphoma lines and isogenic 657del5 models; quantify the differential against NBN-hypomorph non-malignant LCLs to define whether any window exists at all.","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"42567300","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42059277","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":130,"lastVisit":1,"lastNote":"Opened from PMID:42567300 [NEW] (mechanism validated only in pancreatic/other solid lines, not NBS) plus PMID:42059277 [NEW] for c-MYC as a DDR/resistance node. Flagged window-limited: normal tissue in NBS is itself NBN-deficient, so this is not transferable without demonstrating a somatic second hit.","history":[{"visit":1,"cycle":130,"status":"NEW","note":"Opened from PMID:42567300 [NEW] (mechanism validated only in pancreatic/other solid lines, not NBS) plus PMID:42059277 [NEW] for c-MYC as a DDR/resistance node. Flagged window-limited: normal tissue in NBS is itself NBN-deficient, so this is not transferable without demonstrating a somatic second hit."}]},{"id":"L4","title":"Growth-hormone/IGF-1 axis exposure as a modifiable risk hazard in MRN-deficiency syndromes (safety lead)","mechanism":"NBS and NBS-like RAD50 disease present as syndromic microcephalic short stature, inviting empiric rhGH before genetic diagnosis; GH/IGF-1 signalling is mitogenic and replication-stress-promoting, a plausible accelerant of transformation on a chromosomal-instability background [SPECULATIVE].","approach":"Retrospective registry query: rhGH exposure duration versus lymphoid/solid malignancy incidence in NBS and RAD50-deficient cohorts; require MRN-panel genetics before rhGH in microcephalic short stature. Not a treatment proposal.","level":"LEAD","confidence":0.18,"citations":[{"kind":"PMID","id":"41798197","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":130,"lastVisit":1,"lastNote":"Triggered by PMID:41798197 [NEW], a single NBS-like RAD50 case given ~5.75 years of unplanned rhGH before diagnosis. n=1, no oncologic outcome reported in the abstract; recorded so the desk treats GH exposure as a covariate rather than a therapy.","history":[{"visit":1,"cycle":130,"status":"NEW","note":"Triggered by PMID:41798197 [NEW], a single NBS-like RAD50 case given ~5.75 years of unplanned rhGH before diagnosis. n=1, no oncologic outcome reported in the abstract; recorded so the desk treats GH exposure as a covariate rather than a therapy."}]}],"retired":[],"nextQueries":["(\"Nijmegen breakage syndrome\" OR \"NBN\" OR \"NBS1\") AND (transplantation OR conditioning OR treosulfan OR fludarabine) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"NBN\" OR \"NBS1\") AND (lymphoma OR \"loss of heterozygosity\" OR \"somatic\" OR \"PARP inhibitor\" OR \"ATR inhibitor\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"MRE11-RAD50-NBS1\" OR MRN) AND (RUVBL1 OR RUVBL2 OR R2TP OR HSP90) AND SRC:MED"],"updatedAt":"2026-08-19T21:38:34.720Z"},{"key":"dyskeratosis congenita","name":"dyskeratosis congenita","mondo":{"id":"MONDO:0015780","name":"dyskeratosis congenita"},"genes":[{"label":"NOP10","kind":"causal"},{"label":"ACD","kind":"causal"},{"label":"DKC1","kind":"causal"},{"label":"TERC","kind":"causal"},{"label":"RTEL1","kind":"causal"},{"label":"TERT","kind":"causal"},{"label":"TINF2","kind":"causal"},{"label":"WRAP53","kind":"causal"},{"label":"DCLRE1B","kind":"causal"},{"label":"TYMS","kind":"causal"},{"label":"NHP2","kind":"causal"},{"label":"PARN","kind":"correlated"}],"visits":1,"openQuestions":["Is there any direct evidence that PAPD5/TENT4B inhibition raises TERC and elongates telomeres in DKC1-, PARN- or TERC-mutant human HSPCs, and what is the hepatic/erythroid toxicity of dihydroquinolizinone PAPD5/7 inhibitors?","What is the permissive dyskerin expression window in pTERC-DKC1-corrected HSPCs (vector copy number vs telomere and rRNA correction), and does correction persist through serial in vivo proliferative stress?","Does deoxycytidine/deoxythymidine supplementation act telomerase-dependently, and are there interim telomere-length or hematologic readouts from NCT06817590?","Which interventions, if any, address TBD pulmonary fibrosis/chILD rather than marrow failure — is there evidence for antifibrotics (nintedanib/pirfenidone) or lung-directed telomerase restoration in TBD-specific cohorts?","How should somatic clonal evolution (NPM1, and reported somatic TERT-promoter/POT1 rescue events) be monitored or exploited after any restorative therapy in this cancer-predisposition background?","Does the quercetin phase 1 (NCT07628972) declare a senescence-biomarker mechanism, and is senolysis safe in a hypocellular TBD marrow?"],"leads":[{"id":"L1","title":"PAPD5/TENT4B inhibition to restore TERC steady-state levels in PARN- and DKC1-mutant TBD","mechanism":"PARN trims oligo(A) tails from TERC precursors; loss of PARN (or dyskerin-dependent H/ACA protection) leaves TERC hyperadenylated and exosome-degraded, collapsing telomerase RNP assembly [KNOWN]. PMID:42337823 consolidates PARN/telomerase as coupled tail modifiers and links p53 signalling to both telomere attrition and negative regulation of PARN activity; PMID:40234053 shows TERC availability is limiting for holoenzyme assembly. Blocking the opposing poly(A) polymerase PAPD5/TENT4B should raise functional TERC without introducing exogenous TERT [INFERRED].","approach":"Repurpose dihydroquinolizinone PAPD5/7 inhibitors (HBV antiviral chemotypes) [KNOWN] in patient-derived PARN-, DKC1-, TERC-mutant iPSC/HSPC lines from the cord-blood editing platform of PMID:42564579; endpoints = TERC 3'-end sequencing, telomerase activity, telomere restriction fragment length, CFU output under serial replating stress. Normal-tissue window: PAPD5/7 maintains mRNA stability broadly and TENT4 loss is tolerated in adult tissue [SPECULATIVE] — must profile hepatocyte and erythroid toxicity. Resistance/failure routes: exosome-independent TERC loss in structurally destabilising TERC alleles; DKC1 mutants where the defect is dyskerin catalytic pseudouridylation rather than TERC abu","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42337823","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"40234053","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42564579","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":131,"lastVisit":1,"lastNote":"Opened this visit on the strength of the PARN/telomerase tail-modifier review; the druggable node is inferred, not demonstrated in DC cells in this pack.","history":[{"visit":1,"cycle":131,"status":"NEW","note":"Opened this visit on the strength of the PARN/telomerase tail-modifier review; the druggable node is inferred, not demonstrated in DC cells in this pack."}]},{"id":"L2","title":"Dosage-calibrated DKC1 gene therapy for X-linked DC HSPCs using TERC-promoter-driven dyskerin","mechanism":"Dyskerin is a dosage-sensitive multifunctional protein (H/ACA RNP core: TERC stabilisation plus rRNA pseudouridylation) [GERMLINE, X-linked]. In DKC1 frameshift and hypomorphic c.196A>G cord-blood CD34+ models, strong constitutive PGK-driven dyskerin restored only proliferation, whereas expression driven by TERC regulatory sequences additionally corrected telomere maintenance and rRNA maturation, without perturbing healthy HSPCs (PMID:42564579). Physiological/feedback-coupled expression, not maximal expression, is the design requirement.","approach":"Advance pTERC-DKC1 lentivector toward preclinical HSPC autologous gene therapy; benchmark against base/prime editing of the recurrent c.196A>G allele. Required next data: vector copy number vs correction dose-response, in vivo xenograft repopulation with serial stress (per PMID:42497987 5-FU/transplant paradigm), insertional-mutagenesis and clonal-tracking readouts in a cancer-predisposing genome, and whether extrahematopoietic (lung, epithelial) disease is untouched (PMID:42316340).","level":"LEAD","confidence":0.6,"citations":[{"kind":"PMID","id":"42564579","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42497987","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42316340","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":131,"lastVisit":1,"lastNote":"New; strongest translational datum in the pack, with an explicit promoter-strength/stoichiometry mechanism rather than a generic 'add the gene back' claim.","history":[{"visit":1,"cycle":131,"status":"NEW","note":"New; strongest translational datum in the pack, with an explicit promoter-strength/stoichiometry mechanism rather than a generic 'add the gene back' claim."}]},{"id":"L3","title":"Deoxynucleoside (dC/dT) supplementation to relieve dNTP-limited telomere maintenance","mechanism":"Telomere synthesis and replication-fork progression through telomeric repeats are dNTP-supply-dependent; the Monarch anchor set includes TYMS (thymidylate synthase), placing thymidine nucleotide flux inside the disease gene space. Restoring dCTP/dTTP pools may partially rescue telomere elongation and reduce replication stress in telomerase-hypomorphic HSPCs [SPECULATIVE, mechanism not demonstrated in this pack]. PMID:42497987 shows the failure mode is stress-dependent progenitor depletion with focal critically short telomeres — consistent with a replication-stress-sensitive lesion.","approach":"Track NCT06817590 (phase 1, deoxycytidine + deoxythymidine in telomere biology disorders) for telomere-length trajectory, marrow response and toxicity; in parallel, test whether dC/dT rescue is telomerase-dependent by comparing TERT/TERC hypomorphs vs RTEL1 and CTC1 replication-arm mutants in the CD34+ editing system (PMID:42564579). Failure routes: nucleoside catabolism/imbalance-driven mutagenesis, and no benefit in mutants where telomerase catalysis rather than substrate supply is limiting.","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT06817590","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42497987","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42564579","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":131,"lastVisit":1,"lastNote":"New; anchored on an active recruiting phase 1 plus the TYMS gene anchor. Mechanistic rationale explicitly flagged as unproven in the supplied abstracts.","history":[{"visit":1,"cycle":131,"status":"NEW","note":"New; anchored on an active recruiting phase 1 plus the TYMS gene anchor. Mechanistic rationale explicitly flagged as unproven in the supplied abstracts."}]},{"id":"L4","title":"Radiation- and alkylator-free reduced-toxicity conditioning as marrow-only, stress-minimising HSCT for DC","mechanism":"Telomere-limited HSCs have reduced reserve specifically under proliferative and genotoxic stress: Rtel1 M492K 'Telomouse' animals with human-length telomeres are hematologically normal at baseline but lose progenitors after serial 5-FU or transplant, with excess critically short telomeres, gammaH2AX foci and cleaved caspase-3 (PMID:42497987). This supplies a mechanistic rationale for eliminating TBI/alkylators and minimising engraftment-associated proliferative demand in TBD recipients.","approach":"Comparative evaluation of NCT01659606 (alemtuzumab/fludarabine, radiation- and alkylator-free, DC-specific), NCT03579875 (alpha/beta TCD), NCT01962415 (RIC for non-malignant disease), plus graft-composition strategies such as cord-augmented matched-unrelated grafts (PMID:41840938, aplastic anaemia; 100% OS in fully matched URD-cord subset but small n and not DC-specific). Explicit limitation: this lead is marrow-only — TBD-associated childhood ILD was severe in 7/10 registry patients (PMID:42316340), so pulmonary and hepatic endpoints must be pre-specified, and secondary malignancy surveillance is mandatory in a cancer-predisposition syndrome (NCT00027274).","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"42497987","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT01659606","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41840938","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42316340","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT00027274","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":131,"lastVisit":1,"lastNote":"New; the Telomouse stress-dependence result upgrades conditioning intensity from a tolerability variable to a mechanistic one, while the chILD cohort caps the achievable benefit.","history":[{"visit":1,"cycle":131,"status":"NEW","note":"New; the Telomouse stress-dependence result upgrades conditioning intensity from a tolerability variable to a mechanistic one, while the chILD cohort caps the achievable benefit."}]},{"id":"L5","title":"Senotherapeutic quercetin as symptom/attrition modifier in DC/TBD — low prior, mechanism unspecified","mechanism":"Critically short telomeres drive DNA-damage signalling and senescence-associated secretory phenotype in marrow and lung, plausibly amplifying fibrosis and stem-cell attrition [KNOWN]; PMID:42497987 documents gammaH2AX and caspase-3 activation as the proximal stress readout. Quercetin is a flavonoid senolytic component (classically with dasatinib) [KNOWN]; whether it acts on telomere biology at all in TBD is undetermined by anything in this pack.","approach":"Follow NCT07628972 (phase 1, quercetin in DC/TBD) for its declared mechanistic endpoints — senescence markers, inflammatory cytokines, marrow and pulmonary function — before any resource commitment. Pre-register the killing condition: if no senescence-biomarker movement or no organ-function signal, retire. Risk: senolysis in an already hypocellular marrow could deplete rather than rejuvenate the stressed HSC pool [SPECULATIVE].","level":"LEAD","confidence":0.22,"citations":[{"kind":"NCT","id":"NCT07628972","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42497987","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":131,"lastVisit":1,"lastNote":"New but deliberately low-confidence and pre-committed to retirement criteria; logged so the desk tracks the trial rather than re-deriving the idea.","history":[{"visit":1,"cycle":131,"status":"NEW","note":"New but deliberately low-confidence and pre-committed to retirement criteria; logged so the desk tracks the trial rather than re-deriving the idea."}]}],"retired":[],"nextQueries":["(PAPD5 OR TENT4B OR PAPD7 OR \"poly(A) polymerase\") AND (TERC OR telomerase OR \"telomere\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"telomere biology disorder\" OR \"dyskeratosis congenita\" OR \"short telomere syndrome\") AND (\"pulmonary fibrosis\") AND (nintedanib OR pirfenidone OR danazol OR androgen OR treatment) AND SRC:MED AND PUB_YEAR:[2022 TO 2026","(\"dyskeratosis congenita\" OR \"telomere biology disorder\") AND (\"somatic\" AND (\"clonal hematopoiesis\" OR \"TERT promoter\" OR POT1 OR NPM1 OR \"myelodysplastic\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T21:42:12.523Z"},{"key":"breast cancer","name":"breast cancer","mondo":{"id":"MONDO:0007254","name":"breast cancer"},"genes":[{"label":"AKT1","kind":"causal"},{"label":"KRAS","kind":"causal"},{"label":"PIK3CA","kind":"causal"},{"label":"PPM1D","kind":"causal"},{"label":"TP53","kind":"causal"},{"label":"RB1CC1","kind":"causal"},{"label":"SLC67A1","kind":"causal"},{"label":"CDH1","kind":"causal"},{"label":"ESR1","kind":"causal"},{"label":"NQO2","kind":"correlated"},{"label":"BRIP1","kind":"correlated"},{"label":"ATM","kind":"correlated"}],"visits":1,"openQuestions":["Does IRS2 protein/RNA abundance in archival tumour tissue predict progression on alpelisib, inavolisib or capivasertib, and is the rise detectable on-treatment biopsy?","Can IGF1R-selective blockade (sparing INSR) suppress the IRS2 feedback arm without compounding PI3Ki hyperglycaemia, or is tumour-restricted IRS2 degradation the only viable route?","What are the response rates and resistance mechanisms for pan-HER inhibition in HER2-mutant, CDH1-null lobular carcinoma, and does PIK3CA co-mutation abolish benefit?","Is ferroptosis dependency in anthracycline-resistant breast cancer subtype-restricted (mesenchymal/TNBC vs HR+), and does FSP1 status gate it?","What is the current evidence base for HER2-ultralow ADC benefit (T-DXd, NCT05945732) and does membrane HER2 quantity or payload trafficking set the threshold?"],"leads":[{"id":"L1","title":"IRS2 adaptor feedback as the resistance node for PI3Kalpha/AKT inhibition in PIK3CA-mutant breast cancer","mechanism":"PIK3CA-mutant tumours suppress IRS2 mRNA/protein; PI3K-pathway inhibition relieves FOXO1/FOXO3-mediated repression, raising IRS2 and re-coupling receptor input to PI3K. IRS1 is unchanged, indicating adaptor-selective feedback. IRS2 abundance tracks with inhibitor resistance across PIK3CA-mutant lines. [SOMATIC driver context: PIK3CA/AKT1]","approach":"Preclinical: IRS2 knockdown/degrader plus alpelisib, inavolisib or capivasertib in PIK3CA-mutant (H1047R vs E545K) PDX and organoid panels, with FOXO ChIP to confirm the transcriptional arm; test selective IGF1R blockade as the pharmacological surrogate while avoiding INSR to limit hyperglycaemia. Clinical-correlative: retrospective IRS2 IHC/RNA on archival tissue from PI3K/AKT inhibitor-treated cohorts as a resistance biomarker. Expected resistance routes: PTEN loss, mTORC1/S6K reactivation, ERa transcriptional escape, HER2/HER3 bypass. Normal-tissue window: IRS2 is the dominant hepatic and beta-cell insulin adaptor, so systemic IRS2/INSR suppression risks metabolic toxicity on top of drug-","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"42575435","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":133,"lastVisit":1,"lastNote":"New this visit from P10; the only pack item with a mechanistically complete, genotype-selective resistance model that maps onto the PIK3CA/AKT1 anchors.","history":[{"visit":1,"cycle":133,"status":"NEW","note":"New this visit from P10; the only pack item with a mechanistically complete, genotype-selective resistance model that maps onto the PIK3CA/AKT1 anchors."}]},{"id":"L2","title":"HER2 kinase-domain mutations as a direct oncogene target in CDH1-deficient lobular breast cancer","mechanism":"Invasive lobular carcinoma arises on biallelic CDH1 loss [GERMLINE predisposition, somatic second hit] and is enriched for activating HER2 mutations that drive ligand-independent HER dimer signalling; these are direct-inhibition targets rather than tumour-suppressor synthetic-lethal problems.","approach":"Neoadjuvant covalent pan-HER inhibition (neratinib) with endocrine therapy in stage I-III HER2-mutant lobular disease, with paired pre/post biopsies for pathway suppression and emergent bypass; NCT05919108 is the active vehicle. Watch for secondary HER2 mutation, PIK3CA co-mutation, and HER3/NRG1-mediated escape; normal-tissue window is EGFR-driven gut/skin toxicity [KNOWN]","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT05919108","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":133,"lastVisit":1,"lastNote":"New this visit from T3; ties the CDH1 anchor to an actionable somatic oncogene in a histology-defined subset. Trial is recruiting, no efficacy data yet.","history":[{"visit":1,"cycle":133,"status":"NEW","note":"New this visit from T3; ties the CDH1 anchor to an actionable somatic oncogene in a histology-defined subset. Trial is recruiting, no efficacy data yet."}]},{"id":"L3","title":"Ferroptosis sensitisation to reverse anthracycline resistance (PVT1-GSH-GPX4 axis)","mechanism":"lncRNA PVT1 is elevated in doxorubicin-resistant breast cancer plasma and lines; its silencing depletes GSH, raises ROS and lipid peroxidation, and restores doxorubicin sensitivity in vivo, with rescue by ferroptosis inhibitors placing the effect on the GPX4 axis. Independent chemistry converges on the same node by Fe-driven GSH depletion and GPX4 inactivation.","approach":"Test whether anthracycline-resistant PDXs are GPX4/SLC7A11-dependent (erastin/imidazole-ketone-erastin, cyst(e)ine deprivation, or repurposed artesunate) and whether plasma PVT1 prospectively marks that dependency. Deprioritise nanoplatform formulation as a near-term asset. Resistance routes: FSP1/CoQ10 bypass, MUFA/ACSL3 rewiring, NRF2 activation. Window: GPX4 loss is toxic to kidney tubule and T cells [KNOWN], so systemic GPX4 inhibition is a genuine liability","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42524322","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42540475","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":133,"lastVisit":1,"lastNote":"New this visit; two independent pack items converge on GSH/GPX4, but neither is a clinical-grade agent and PVT1 itself is not druggable, hence low confidence.","history":[{"visit":1,"cycle":133,"status":"NEW","note":"New this visit; two independent pack items converge on GSH/GPX4, but neither is a clinical-grade agent and PVT1 itself is not druggable, hence low confidence."}]}],"retired":[],"nextQueries":["(IRS2 OR \"insulin receptor substrate 2\" OR IGF1R) AND (alpelisib OR inavolisib OR capivasertib OR \"PI3K inhibitor\") AND \"breast cancer\" AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"lobular\" AND \"breast cancer\") AND (CDH1 OR \"HER2 mutation\" OR ERBB2) AND (neratinib OR \"pan-HER\" OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"breast cancer\" AND (GPX4 OR SLC7A11 OR FSP1 OR ferroptosis) AND (resistance OR doxorubicin OR anthracycline) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T21:48:54.093Z"},{"key":"ovarian cancer","name":"ovarian cancer","mondo":{"id":"MONDO:0008170","name":"ovarian cancer"},"genes":[{"label":"PIK3CA","kind":"causal"},{"label":"PRKN","kind":"causal"},{"label":"AKT1","kind":"causal"},{"label":"OPCML","kind":"causal"},{"label":"CDH1","kind":"causal"},{"label":"CTNNB1","kind":"causal"},{"label":"ERBB2","kind":"causal"},{"label":"DICER1","kind":"correlated"},{"label":"FOXL2","kind":"correlated"},{"label":"SMARCA4","kind":"correlated"},{"label":"INHBA","kind":"correlated"},{"label":"BMP15","kind":"correlated"}],"visits":1,"openQuestions":["Does NCT04644068 report ovarian-specific efficacy and, critically, lower grade 3/4 anaemia than first-generation PARPi + platinum combinations?","Which non-BRCA HR/DNA-repair genotypes (RAD51C/D, PALB2, BRIP1, CDK12) confer talazoparib or AZD5305 sensitivity, and can [18F]-FTT uptake predict it independently of genotype?","Is there SMARCA4- or ARID1A-stratified ovarian data for tulmimetostat or any dual EZH1/2 inhibitor, and does dual inhibition outperform tazemetostat in SCCOHT models?","Is there any primary (non-review) ovarian evidence that GPX4, SLC7A11 or FDX1/cuproptosis dependency is enriched in platinum-resistant versus naive tumours?","Are clinical-stage KIF18A inhibitors being tested in HGSOC, and does WGD status stratify response in ovarian models?","What is AZD6750 (NCT07115043) mechanistically, and does the rilvegostomig combination carry an ovarian rationale worth a lead?"],"leads":[{"id":"L1","title":"PARP1-selective inhibition (AZD5305) as the combination backbone in HRD/HGSOC","mechanism":"PARP1-selective trapping retains synthetic lethality with HR deficiency while sparing PARP2-dependent haematopoiesis, widening the window for combination with platinum/taxane and TOP1-payload ADCs (T-DXd, Dato-DXd); [18F]-fluorthanatrace PET reports PARP-1 abundance/occupancy as a pharmacodynamic biomarker","approach":"Track NCT04644068 combination cohorts for ovarian-specific response and haematologic AE rates vs historical olaparib+chemo; use NCT04550494 to define non-BRCA DNA-repair variants that confer sensitivity; nest NCT03604315-style [18F]-FTT imaging as pre/post target-engagement readout; model resistance via BRCA reversion, 53BP1/Shieldin loss, ABCB1","level":"LEAD","confidence":0.55,"citations":[{"kind":"NCT","id":"NCT04644068","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04550494","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03604315","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":134,"lastVisit":1,"lastNote":"New programme lead built from three fresh trials in the pack; strongest near-term translational path, all agents already in humans.","history":[{"visit":1,"cycle":134,"status":"NEW","note":"New programme lead built from three fresh trials in the pack; strongest near-term translational path, all agents already in humans."}]},{"id":"L2","title":"Dual EZH1/EZH2 inhibition in SMARCA4-deficient SCCOHT and ARID1A-mutant clear-cell ovarian cancer","mechanism":"SWI/SNF subunit loss [SOMATIC] creates dependence on residual PRC2-mediated repression; dual EZH1/EZH2 blockade should suppress the residual-activity escape route left by EZH2-selective agents [SPECULATIVE]","approach":"Seek SMARCA4/ARID1A-stratified expansion within NCT04104776 (tulmimetostat); preclinically confirm PRC2 dependency in SCCOHT and ARID1A-null clear-cell lines; monitor EZH2 Y111/Y661 gatekeeper mutations and PRC2-independent escape; watch B-cell/HSC toxicity as the window constraint","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT04104776","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":134,"lastVisit":1,"lastNote":"New: links KG anchor SMARCA4 (correlated/somatic) to a live dual EZH1/2 agent; needs ovarian-specific cohort evidence next visit.","history":[{"visit":1,"cycle":134,"status":"NEW","note":"New: links KG anchor SMARCA4 (correlated/somatic) to a live dual EZH1/2 agent; needs ovarian-specific cohort evidence next visit."}]},{"id":"L3","title":"Redox/metal-ion vulnerability of platinum-resistant ovarian cancer (ferroptosis and cuproptosis induction)","mechanism":"Cisplatin resistance is accompanied by elevated GSH/H2S buffering and remodelled mitochondrial Cu/Fe handling; forcing lipid peroxidation (xCT/GPX4 axis) or Cu overload (lipoylated TCA protein aggregation) attacks the resistant state through death routes orthogonal to apoptosis","approach":"Isogenic cisplatin-sensitive/resistant HGSOC panels tested with repurposed agents (sulfasalazine, auranofin, disulfiram-Cu, elesclomol) plus GPX4/FSP1 and SLC7A11 dependency profiling; explicitly assay FSP1-CoQ10 and MUFA/ACSL3 escape; GPX4 essentiality in normal tissue is the principal window risk","level":"LEAD","confidence":0.28,"citations":[{"kind":"PMID","id":"42343901","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42582447","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42275298","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42318797","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":134,"lastVisit":1,"lastNote":"New but deliberately low confidence: pack supplies only review-level ovarian evidence, no primary data and no clinical agent.","history":[{"visit":1,"cycle":134,"status":"NEW","note":"New but deliberately low confidence: pack supplies only review-level ovarian evidence, no primary data and no clinical agent."}]},{"id":"L4","title":"KIF18A inhibition as a CIN/whole-genome-doubling-selective vulnerability in HGSOC","mechanism":"WGD/CIN-high cells require the mitotic kinesin KIF18A for tolerable spindle dynamics; KIF18A loss triggers SAC-dependent mitotic delay and death, sparing near-diploid cells","approach":"Test KIF18A inhibitors in WGD-high, TP53-null HGSOC models and PDXs with CIN/WGD scoring as the selection biomarker; predicted resistance is SAC attenuation (MAD2/BUB1B loss) or ploidy reversion; germ-cell/fertility effects of KIF18A loss are the window question","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42328720","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":134,"lastVisit":1,"lastNote":"New; extrapolated from an osteosarcoma-only paper, so ovarian relevance is INFERRED and must be confirmed by primary HGSOC data before any promotion.","history":[{"visit":1,"cycle":134,"status":"NEW","note":"New; extrapolated from an osteosarcoma-only paper, so ovarian relevance is INFERRED and must be confirmed by primary HGSOC data before any promotion."}]}],"retired":[],"nextQueries":["(\"ovarian\" AND (SMARCA4 OR ARID1A) AND (EZH2 OR PRC2 OR tazemetostat OR tulmimetostat)) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"ovarian\" AND (AZD5305 OR \"PARP1-selective\" OR saruparib OR \"fluorthanatrace\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"ovarian cancer\" AND (\"platinum-resistant\" OR \"cisplatin-resistant\") AND (GPX4 OR SLC7A11 OR FSP1 OR FDX1 OR cuproptosis) AND (xenograft OR PDX OR \"cell line\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T21:52:07.028Z"},{"key":"prostate cancer","name":"prostate cancer","mondo":{"id":"MONDO:0008315","name":"prostate cancer"},"genes":[{"label":"RNASEL","kind":"causal"},{"label":"PTEN","kind":"causal"},{"label":"ZFHX3","kind":"causal"},{"label":"CHEK2","kind":"causal"},{"label":"MAD1L1","kind":"causal"},{"label":"MXI1","kind":"causal"},{"label":"KLF6","kind":"causal"},{"label":"ELAC2","kind":"correlated"},{"label":"EHBP1","kind":"correlated"},{"label":"HOXB13","kind":"correlated"},{"label":"BRCA2","kind":"correlated"},{"label":"BRCA1","kind":"correlated"}],"visits":1,"openQuestions":["Which PTEN-loss assay (IHC vs biallelic genomic loss vs transcriptional signature) actually predicted capivasertib benefit in CAPItello-281, and does benefit extend to mCRPC or PIK3CA/AKT1-mutant PTEN-intact tumours?","Is SLC3A1 upregulation reproducible in independent enzalutamide-resistant models and patient tissue, and does cystine deprivation or GPX4 inhibition resensitise in vivo?","Does AKT inhibition and ferroptosis induction synergise, i.e. is the SLC3A1-AKT link causal or correlative?","What are the reported salivary/renal toxicity and PSMA-loss/neuroendocrine escape rates with 225Ac-J591 and other alpha-emitters, and any signal for radioligand+PARPi combinations?","Per-gene PARPi response in ATM/CHEK2/NBN-altered prostate cancer with zygosity annotation, and whether ATR/WEE1 inhibition outperforms PARPi in ATM-null disease?","Does any credible clinical evidence support cGAS-STING agonism or zinc restoration in prostate cancer outside OVA-model artefacts?"],"leads":[{"id":"L1","title":"AKT inhibition in PTEN-deficient prostate cancer, biomarker-refined","mechanism":"Somatic PTEN loss (KG causal anchor; predominantly somatic/epigenetic in tumours) removes PIP3 phosphatase activity, driving AKT1-3 signalling and reciprocal AR/PI3K crosstalk that blunts ARPI monotherapy; capivasertib blocks the node downstream of PI3K.","approach":"Confirm PTEN-loss assay concordance (IHC vs genomic/CNV vs RNA signature) as an eligibility biomarker; extend capivasertib+ARPI into mCRPC and to PIK3CA/AKT1-mutant, PTEN-intact tumours; monitor hyperglycaemia (AKT2/insulin axis) as window-limiting. Expected resistance: PI3K/mTORC1 reactivation, SGK1 bypass, AR-V7 emergence, RB1/TP53 loss and lineage plasticity.","level":"LEAD","confidence":0.7,"citations":[{"kind":"PMID","id":"42359636","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04493853","verified":false,"isNew":false,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":135,"lastVisit":1,"lastNote":"New this visit: phase III rPFS benefit in PTEN-deficient mCSPC with FDA approval reported in P8; abstract gives no OS and no assay detail, so biomarker definition is the open risk.","history":[{"visit":1,"cycle":135,"status":"NEW","note":"New this visit: phase III rPFS benefit in PTEN-deficient mCSPC with FDA approval reported in P8; abstract gives no OS and no assay detail, so biomarker definition is the open risk."}]},{"id":"L2","title":"SLC3A1-dependent cystine uptake and ferroptosis evasion as an enzalutamide-resistance target","mechanism":"SLC3A1 (rBAT) upregulation in enzalutamide-resistant PCa raises cystine import/GSH capacity, suppresses ferroptosis and activates PI3K-AKT (knockdown lowers pAKT), coupling redox survival to the same AKT node as PTEN loss [INFERRED].","approach":"Test cyst(e)ine deprivation or xCT/SLC7A11-axis blockade (sulfasalazine-class) and GPX4 inhibition in combination with enzalutamide and with an AKT inhibitor in ARPI-resistant LNCaP/22Rv1 and PDX models; read out lipid peroxidation (C11-BODIPY, MDA) and GPX4/GSH. Normal-tissue window: rBAT is renal proximal tubule/intestinal, germline loss causes cystinuria [KNOWN][GERMLINE] — screen for nephrolithiasis/renal tubular toxicity. Resistance: SLC7A11 or MUFA/ACSL3 compensation, FSP1-CoQ10 axis.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42606826","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":135,"lastVisit":1,"lastNote":"Single new paper (bioinformatics plus LNCaP knockdown/overexpression and xenograft); no independent replication yet, so held at LEAD with low confidence.","history":[{"visit":1,"cycle":135,"status":"NEW","note":"Single new paper (bioinformatics plus LNCaP knockdown/overexpression and xenograft); no independent replication yet, so held at LEAD with low confidence."}]},{"id":"L3","title":"PSMA as delivery axis: alpha-emitter and CD28-costimulatory bispecific","mechanism":"PSMA/FOLH1 surface abundance permits targeted alpha-particle DNA double-strand break delivery (225Ac-J591) and T-cell costimulatory redirection (anti-PSMA x CD28) in immunologically cold prostate tumours.","approach":"Track dose-fractionation safety/efficacy of 225Ac-J591 and presurgical REGN5678 pathological response; prospectively test radioligand + PARP inhibitor or + PD-1 combinations given alpha-induced DSBs and cGAS-STING priming [SPECULATIVE]. Window: PSMA in salivary gland, kidney, duodenum, and CD28 agonism risks cytokine release. Resistance: PSMA-low/neuroendocrine transdifferentiation, heterogeneous uptake.","level":"LEAD","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT04506567","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT06085664","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42565339","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":135,"lastVisit":1,"lastNote":"New trials define the modality space; P3 is only a cost-consequence model and reiterates that TheraP OS (16.4 vs 19.4 mo) was not significant — recorded to prevent overclaiming radioligand survival benefit.","history":[{"visit":1,"cycle":135,"status":"NEW","note":"New trials define the modality space; P3 is only a cost-consequence model and reiterates that TheraP OS (16.4 vs 19.4 mo) was not significant — recorded to prevent overclaiming radioligand survival benefit."}]},{"id":"L4","title":"PARP inhibition beyond BRCA: ATM/CHEK2/NBN-mutant prostate cancer","mechanism":"Loss of homologous-recombination and checkpoint genes (BRCA2, ATM, CHEK2, NBN — KG anchors) creates PARP-inhibitor synthetic lethality, but non-BRCA alleles give shallower responses [KNOWN].","approach":"Use the talazoparib DNA-repair-variant basket to define per-gene response; require zygosity/biallelic calls and germline-vs-somatic annotation; test ATR or WEE1 inhibitors in ATM-null disease as a non-PARP route. Practical constraint: PARPi in transplant recipients on tacrolimus (CYP3A4 interaction, nephrotoxicity, marrow suppression).","level":"LEAD","confidence":0.4,"citations":[{"kind":"NCT","id":"NCT04550494","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42576962","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":135,"lastVisit":1,"lastNote":"Instantiated from KG anchors plus the new basket trial; P2 is a single case report contributing only a drug-interaction caveat, not efficacy evidence.","history":[{"visit":1,"cycle":135,"status":"NEW","note":"Instantiated from KG anchors plus the new basket trial; P2 is a single case report contributing only a drug-interaction caveat, not efficacy evidence."}]}],"retired":[],"nextQueries":["(\"prostate cancer\") AND (capivasertib OR ipatasertib OR \"AKT inhibitor\") AND (PTEN) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"prostate cancer\") AND (ferroptosis OR GPX4 OR SLC7A11 OR cystine) AND (enzalutamide OR \"androgen receptor\" OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"prostate cancer\") AND (\"225Ac\" OR \"actinium-225\" OR \"alpha therapy\" OR \"PSMA x CD28\" OR bispecific) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-19T21:55:22.884Z"},{"key":"colorectal cancer","name":"colorectal cancer","mondo":{"id":"MONDO:0005575","name":"colorectal cancer"},"genes":[{"label":"SRC","kind":"causal"},{"label":"BUB1","kind":"causal"},{"label":"DLC1","kind":"causal"},{"label":"FGFR3","kind":"causal"},{"label":"FLCN","kind":"causal"},{"label":"MCC","kind":"causal"},{"label":"NRAS","kind":"causal"},{"label":"PMS2","kind":"causal"},{"label":"PTPRJ","kind":"causal"},{"label":"RAD54B","kind":"causal"},{"label":"APC","kind":"causal"},{"label":"PDGFRL","kind":"causal"}],"visits":1,"openQuestions":["Is gambogenic acid's chemosensitisation genuinely LIG1-dependent (knockout/rescue, selectivity panel), and does any tool compound exist with a usable therapeutic index against crypt and marrow LIG1?","Does ZBP1 expression (or RIPK3/caspase-8 integrity) predict PANoptosis conversion and anti-PD-1 benefit in MSS CRC, and can it be scored in clinical specimens?","Do PARP1-selective inhibitors (AZD5305) have any CRC signal, and is BER-ligation blockade synthetically lethal with PARP1 loss or MUTYH-mutant [GERMLINE] background?","What CRC-specific response depth and resistance genotypes emerge from KRAS G12D degradation (ARV-806), and is upfront EGFR/MEK co-blockade required?","Are any microbiome interventions (SynComs, exercise-driven modulation) supported by controlled outcome data in CRC rather than review-level mechanism, i.e. worth opening a lead at all?","Is PI4K2B amplification in COAD reproducible in independent cohorts and does any PI4K inhibitor show CRC-selective dependency?"],"leads":[{"id":"L1","title":"LIG1 inhibition to break oxaliplatin resistance via ZBP1-dependent PANoptosis and immunogenic cell death","mechanism":"LIG1 [SOMATIC, overexpressed] completes base-excision/Okazaki ligation; its inhibition leaves unligated nicks, amplifying oxaliplatin-induced DNA damage response in bulk and drug-tolerant persister cells, driving ZBP1-dependent PANoptosis and ICD that raises anti-PD-1 sensitivity in MSS disease (PMID:42442130). Normal-tissue role: LIG1 is essential in replicating crypt epithelium and marrow, so window is the key unknown [KNOWN/INFERRED].","approach":"Validate gambogenic acid target engagement/selectivity (LIG1 CETSA, ligation assays, LIG1-knockout rescue); test GNA+oxaliplatin and GNA+FOLFOX+anti-PD-1 in MSS CRC organoids/syngeneic models; stratify by ZBP1 and LIG1 expression; probe synthetic lethality with PARP1-selective inhibition (AZD5305, NCT04644068) and in MUTYH-mutant [GERMLINE] BER-deficient backgrounds. Resistance routes: ZBP1 silencing, RIPK3/caspase-8 loss, XRCC1/LIG3 compensation, ABCB1-mediated efflux.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42442130","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04644068","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":136,"lastVisit":1,"lastNote":"New this visit: first mechanistic link from LIG1 blockade to PANoptosis/ICD and anti-PD-1 potentiation in CRC, including persister cells and organoids; abstract-only, no selectivity or PD data.","history":[{"visit":1,"cycle":136,"status":"NEW","note":"New this visit: first mechanistic link from LIG1 blockade to PANoptosis/ICD and anti-PD-1 potentiation in CRC, including persister cells and organoids; abstract-only, no selectivity or PD data."}]},{"id":"L2","title":"KRAS G12D targeted degradation with upfront vertical MAPK/RTK blockade in CRC","mechanism":"Catalytic degradation of KRAS G12D [SOMATIC driver] should suppress MAPK output more completely than occupancy inhibitors; wild-type RAS and normal tissue are spared, giving a genuine window (NCT07023731). Kinase-inhibitor experience in CRC predicts adaptive pathway redundancy (PMID:42539807).","approach":"Track ARV-806 phase 1/2 CRC-specific response and duration; pre-plan combinations with EGFR blockade or MEK/ERK inhibition; monitor ctDNA for KRAS amplification, secondary RAS allele switching, RTK reactivation and loss of E3-ligase components as resistance readouts.","level":"LEAD","confidence":0.4,"citations":[{"kind":"NCT","id":"NCT07023731","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42539807","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":136,"lastVisit":1,"lastNote":"New this visit: an active KRAS G12D degrader trial gives CRC a non-G12C direct-driver option; no efficacy data yet, level capped accordingly.","history":[{"visit":1,"cycle":136,"status":"NEW","note":"New this visit: an active KRAS G12D degrader trial gives CRC a non-G12C direct-driver option; no efficacy data yet, level capped accordingly."}]},{"id":"L3","title":"Innate-immune sensitisation of RAS-mutant MSS CRC by oncolytic reovirus on chemo-antiangiogenic backbone","mechanism":"Pelareorep replication in RAS-pathway-activated cells plus FOLFIRI/bevacizumab is intended to generate viral-sensing-driven inflammation and T-cell priming in immunologically cold MSS CRC (NCT07446322) — mechanistically parallel to the PANoptosis/ICD hypothesis but modality-independent.","approach":"Follow randomised second-line readout; if positive, compare immune-conversion biomarkers (interferon signature, CD8 influx) with those predicted for DNA-damage-driven ICD; treat as comparator/benchmark arm for cold-tumour conversion strategies.","level":"LEAD","confidence":0.3,"citations":[{"kind":"NCT","id":"NCT07446322","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":136,"lastVisit":1,"lastNote":"New this visit: randomised phase 2 recruiting; hypothesis is credible but historical oncolytic data in CRC are unimpressive [KNOWN], so confidence deliberately low.","history":[{"visit":1,"cycle":136,"status":"NEW","note":"New this visit: randomised phase 2 recruiting; hypothesis is credible but historical oncolytic data in CRC are unimpressive [KNOWN], so confidence deliberately low."}]},{"id":"L4","title":"Disrupt the 14-3-3sigma (SFN)-YY1 module to collapse UPR-dependent chemotolerance","mechanism":"SFN-encoded 14-3-3sigma sequesters/restricts YY1, sustaining the unfolded protein response and chemotherapy tolerance in CRC; the actionable unit is the stress-specific phospho-client complex, not total 14-3-3 expression (PMID:42507757).","approach":"Map the SFN-YY1 interaction under oxaliplatin/5-FU stress (proximity labelling, phosphosite mutants); test whether IRE1alpha/PERK inhibition or stapled-peptide disruption resensitises persister CRC cells; check overlap with the LIG1/persister axis. Normal-tissue role: SFN is broadly expressed in epithelium and keratinocytes, so window is a real concern.","level":"LEAD","confidence":0.22,"citations":[{"kind":"PMID","id":"42507757","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":136,"lastVisit":1,"lastNote":"New this visit but review-grade evidence only, no chemical matter; retained solely because the perturbation is concretely testable and links to persister biology.","history":[{"visit":1,"cycle":136,"status":"NEW","note":"New this visit but review-grade evidence only, no chemical matter; retained solely because the perturbation is concretely testable and links to persister biology."}]}],"retired":[],"nextQueries":["(LIG1 OR \"DNA ligase 1\") AND (inhibitor OR \"synthetic lethal\" OR PANoptosis) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"colorectal cancer\" AND (ZBP1 OR PANoptosis OR \"immunogenic cell death\") AND (\"microsatellite stable\" OR \"PD-1\") AND SRC:MED","(\"KRAS G12D\" AND (degrader OR PROTAC OR \"colorectal\")) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-19T21:58:32.219Z"},{"key":"endometrial cancer","name":"endometrial cancer","mondo":{"id":"MONDO:0011962","name":"endometrial cancer"},"genes":[{"label":"CDH1","kind":"causal"},{"label":"MSH3","kind":"causal"},{"label":"MLH3","kind":"correlated"},{"label":"MSH6","kind":"correlated"},{"label":"NUTM2A","kind":"correlated"},{"label":"YWHAE","kind":"correlated"},{"label":"JAZF1","kind":"correlated"},{"label":"SUZ12","kind":"correlated"},{"label":"NUTM2B","kind":"correlated"}],"visits":1,"openQuestions":["What is the prevalence of HER2 3+/ISH-amplified and HER2-low status by EC histotype and TCGA molecular class, and does T-DXd activity extend to HER2-low serous/carcinosarcoma?","Is CALB2 (calretinin) actually overexpressed in human progestin-refractory endometrial lesions versus responders, and does nuclear FOXO1 track response to metformin+progestin in trial specimens?","For pMMR/IO-refractory EC, what are the reported ORR and biomarker correlates of cabozantinib+nivolumab (NCT03367741) versus lenvatinib+pembrolizumab, and are there head-to-head or sequencing data?","Does endometrial cancer have a defensible PARP rationale (HRD scores, CCNE1 amplification, ARID1A/ATM loss) that would justify PARP1-selective AZD5305 plus ADC combinations (NCT04644068)?","Do JAZF1-SUZ12 or YWHAE-NUTM2A/B fusion uterine sarcomas show PRC2 dependency and EZH2-inhibitor sensitivity in any preclinical model?","Is there any EC-specific ferroptosis vulnerability (GPX4, SLC7A11, ACSL4 status) with an agent-level handle, or should the ferroptosis thread be closed?"],"leads":[{"id":"L1","title":"HER2-directed antibody and ADC therapy in serous/carcinosarcoma endometrial cancer","mechanism":"HER2 amplification/overexpression is enriched in p53-abnormal serous EC and carcinosarcoma; dual blockade (trastuzumab+pertuzumab) blocks HER2 dimerisation-driven MAPK/PI3K signalling, while trastuzumab deruxtecan exploits HER2 as a delivery antigen for topoisomerase-I payload with bystander effect in heterogeneous tumours.","approach":"Support/extend NCT05256225 (carbo-paclitaxel +/- Herceptin Hylecta or Phesgo, HER2+ serous/carcinosarcoma); test T-DXd in HER2-low serous EC; pre-specify PIK3CA/PTEN co-alteration as a stratifier. Normal-tissue window: HER2 in cardiomyocytes and GI epithelium -> echocardiographic monitoring; T-DXd interstitial lung disease [KNOWN]. Anticipated resistance: HER2 heterogeneity/antigen loss, PIK3CA-mutant bypass, payload efflux [INFERRED].","level":"LEAD","confidence":0.6,"citations":[{"kind":"NCT","id":"NCT05256225","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42125712","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":137,"lastVisit":1,"lastNote":"New this visit: a recruiting NCI phase 3 in exactly this histotype plus an ADC review reporting high ORR for T-DXd in HER2+ EC. Highest-maturity axis in the pack.","history":[{"visit":1,"cycle":137,"status":"NEW","note":"New this visit: a recruiting NCI phase 3 in exactly this histotype plus an ADC review reporting high ORR for T-DXd in HER2+ EC. Highest-maturity axis in the pack."}]},{"id":"L2","title":"Metformin + progestin to reverse progesterone resistance via AMPK-FOXO1-CALB2 and mitochondrial Ca2+ overload","mechanism":"Metformin promotes FOXO1 nuclear localisation; FOXO1 transcriptionally downregulates CALB2 (calretinin), removing cytosolic Ca2+ buffering and causing mitochondrial Ca2+ overload, membrane depolarisation and apoptosis. Effect is FOXO1-dependent and CALB2-rescuable, and operates in MPA-resistant as well as MPA-sensitive cells.","approach":"Repurposing combination: megestrol acetate/LNG-IUS + metformin in fertility-sparing early EC or atypical hyperplasia, with CALB2 IHC and nuclear FOXO1 as pharmacodynamic biomarkers. Compare against pure weight-loss interventions, which P2 suggests are not the effector (lifestyle 85% CR > semaglutide 73.9% > sleeve gastrectomy 60%). Normal tissue: FOXO1 is required for endometrial decidualisation, so fertility-preservation endpoints must be tracked [KNOWN]. Resistance: CALB2 re-expression, AMPK-independent mTORC1 reactivation [INFERRED].","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42163698","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42495930","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":137,"lastVisit":1,"lastNote":"New mechanistic chain with in vitro and xenograft rescue experiments; the observational weight-management study argues against GLP-1/bariatric weight loss as the active principle, sharpening the hypothesis onto AMPK-FOXO1.","history":[{"visit":1,"cycle":137,"status":"NEW","note":"New mechanistic chain with in vitro and xenograft rescue experiments; the observational weight-management study argues against GLP-1/bariatric weight loss as the active principle, sharpening the hypothesis onto AMPK-FOXO1."}]},{"id":"L3","title":"Salvage strategies for MMR-proficient, checkpoint-refractory endometrial cancer","mechanism":"With anti-PD-1 plus platinum now first line, the residual population is pMMR/IO-primary-resistant. VEGFR2/MET/AXL blockade (cabozantinib) normalises vasculature and reduces MDSC/Treg infiltration to restore PD-1 sensitivity; adoptive TIL transfer bypasses endogenous priming failure entirely.","approach":"Read out NCT03367741 (cabozantinib+nivolumab) by MMR status and prior-IO exposure; NCT01174121 TIL+pembrolizumab as an antigen-agnostic arm for pMMR/low-TMB disease. Resistance routes: MET/AXL-independent angiogenic escape, antigen-presentation loss (B2M/JAK1) [INFERRED]. Window: cabozantinib hypertension/GI perforation, aldesleukin capillary leak [KNOWN].","level":"LEAD","confidence":0.42,"citations":[{"kind":"NCT","id":"NCT03367741","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT01174121","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42535775","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":137,"lastVisit":1,"lastNote":"New this visit. P1 is only a budget-impact model but establishes dostarlimab+carbo-paclitaxel as an accepted first line, which relocates the unmet need to pMMR/post-IO disease. No efficacy data added by P1 - flagged.","history":[{"visit":1,"cycle":137,"status":"NEW","note":"New this visit. P1 is only a budget-impact model but establishes dostarlimab+carbo-paclitaxel as an accepted first line, which relocates the unmet need to pMMR/post-IO disease. No efficacy data added by P1 - flagged."}]},{"id":"L4","title":"PRC2/EZH2 inhibition in SUZ12- and YWHAE-fusion uterine mesenchymal tumours (lineage-separated from endometrial carcinoma)","mechanism":"JAZF1-SUZ12 and YWHAE-NUTM2A/B fusions generate aberrant PRC2 complexes with redistributed H3K27me3 and derepressed/repressed lineage programmes [KNOWN]; catalytic EZH2 inhibition may re-set this epigenetic state or, conversely, create a PRC2-dependency vulnerability.","approach":"Seek fusion-selected expansion within NCT04104776 (tulmimetostat, EZH2i) and profile H3K27me3 as pharmacodynamic marker. Explicit caveat: the Monarch anchor set conflates endometrial stromal sarcoma with endometrial carcinoma; this lead is sarcoma-only and must not be generalised. Window: EZH2 is required for haematopoiesis and germinal-centre B cells -> cytopenias, secondary T-cell malignancy risk [KNOWN]. Resistance: EZH2 gatekeeper mutations, EZH1 compensation [INFERRED].","level":"LEAD","confidence":0.3,"citations":[{"kind":"NCT","id":"NCT04104776","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":137,"lastVisit":1,"lastNote":"New but deliberately low confidence: the only clinical handle in the pack on the JAZF1/SUZ12/YWHAE/NUTM2 anchor genes, and the trial is histology-agnostic with no reported uterine sarcoma cohort in the abstract [SPECULATIVE].","history":[{"visit":1,"cycle":137,"status":"NEW","note":"New but deliberately low confidence: the only clinical handle in the pack on the JAZF1/SUZ12/YWHAE/NUTM2 anchor genes, and the trial is histology-agnostic with no reported uterine sarcoma cohort in the abstract [SPECULATIVE]."}]}],"retired":[],"nextQueries":["(\"endometrial\" AND (\"HER2\" OR \"trastuzumab deruxtecan\") AND (\"serous\" OR \"carcinosarcoma\" OR \"HER2-low\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"endometrial\" AND (\"progestin resistance\" OR \"progesterone resistance\") AND (\"FOXO1\" OR \"CALB2\" OR \"metformin\")) AND SRC:MED","((\"endometrial stromal sarcoma\" AND (\"JAZF1\" OR \"SUZ12\" OR \"YWHAE\" OR \"NUTM2\")) OR (\"endometrial cancer\" AND \"pMMR\" AND (\"resistance to immunotherapy\" OR \"lenvatinib\" OR \"cabozantinib\"))) AND SRC:MED AND PUB_YEAR:[2023 T"],"updatedAt":"2026-08-19T22:01:52.053Z"}]