[{"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":2,"openQuestions":["Does any LonP1 inhibitor with documented brain exposure exist, and does LONP1 loss sensitise MGMT-methylated as well as unmethylated orthotopic GBM to TMZ in vivo?","Is ATF4-driven LONP1/UPRmt induction the adaptive resistance route to TMZ and to OXPHOS inhibitors in GBM cells, and does ISR modulation phenocopy LONP1 loss?","Is there any primary in vivo GBM experiment (not review, not in silico) showing MCT1/MCT4 or LDHA blockade reverses bevacizumab resistance and lowers H3K18la at the BMAL1 promoter?","Does lactylation measurably support DNA repair in GBM specifically — i.e. does lactate or LDHA blockade alter SMUG1/LIG4/RAD51 and gammaH2AX resolution under hypoxia?","Is there experimental GBM evidence that CCL2/CCR2 or TIMP1/CD63 blockade improves PD-1 or LAG-3 efficacy, and does lactate-driven PD-L1 stabilisation offer a cleaner intervention on the same niche?","Which current GBM resistance targets have measurable intratumoral exposure by microdialysis or paired-tissue PK — which hypotheses are delivery-limited rather than biology-limited?"],"leads":[{"id":"L1","title":"LonP1 inhibition to resensitise glioblastoma to temozolomide (MGMT-independent)","mechanism":"LonP1 [SOMATIC] is elevated in TMZ- and O6-benzylguanine-resistant GBM lines irrespective of MGMT status, reprogrammes cells to OXPHOS, and its knockdown/inhibition restores TMZ sensitivity (PMID:42478633). New this visit: Lonp1 is an ATF4-dependent UPRmt effector induced by complex I inhibition, and ISRIB blocks that induction (PMID:42462827). [INFERRED] LonP1 is therefore likely a downstream adaptation node rather than a standalone driver — OXPHOS inhibitors may induce it and self-limit, making LonP1 blockade an anti-adaptation partner rather than a co-cytotoxin. Caveats: PMID:42462827 used 10 mM metformin in adipocytes, far above achievable plasma/CSF exposure [KNOWN].","approach":"Retire the biguanide-repurposing arm as written. Instead: in paired MGMT-methylated/unmethylated patient-derived GBM lines, test whether TMZ and complex I inhibition induce ATF4/LONP1/mtHSP70/FGF21, and whether LONP1 knockdown or ATF4 loss (or ISR modulation) converts adaptation into cytotoxicity; readouts Seahorse, mtDNA integrity, gammaH2AX persistence. Prerequisite before any in vivo claim: identify LonP1 chemical matter with measured brain exposure — none found in this visit's dedicated query. Normal tissue: LonP1 is essential for mitochondrial proteostasis in heart, muscle, neurons; germline LONP1 mutation causes CODAS syndrome [KNOWN][GERMLINE], so intermittent dosing keyed to TMZ days","level":"LEAD","confidence":0.42,"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}],"corrobVisits":2,"createdVisit":1,"createdCycle":1,"lastVisit":2,"lastNote":"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.","history":[{"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, strengthening TUBA1C binding and nuclear import; nuclear BMAL1 drives VEGFA and bevacizumab resistance across cell lines, PDX, mouse and five clinical cohorts (PMID:41995718). Independent 2026 syntheses now place this in a general framework: lactate/lactylation sustains tumour angiogenesis and the immunosuppressive vascular niche, and adaptive resistance plus worsened immunosuppression are the characteristic failure modes of conventional anti-angiogenics (PMID:41593811); lactylation additionally stabilises PD-L1 and supports DNA repair and stemness (PMID:42058190), and reshapes macro","approach":"Repurposing-first: bevacizumab plus MCT1/MCT4 blockade (AZD3965-class, syrosingopine [KNOWN]) or LDHA inhibition in orthotopic PDX; readouts H3K18la at the BMAL1 promoter, BMAL1 K123 lactylation, nuclear/cytoplasmic BMAL1, tumour VEGFA, vessel normalisation, and myeloid/CD8 composition. Target lactate supply, not BMAL1 itself — BMAL1 is the core clock TF in all tissues, a poor window. Expected resistance: MCT1/MCT4 redundancy (requires dual blockade), vessel co-option, invasive escape, systemic lactataemia/retinal toxicity of MCT1 inhibitors [KNOWN].","level":"CANDIDATE","confidence":0.48,"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}],"corrobVisits":2,"createdVisit":1,"createdCycle":1,"lastVisit":2,"lastNote":"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.","history":[{"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 simultaneously the most glycolytic and the most radioresistant compartment. Lactylation has been reported to support DNA-damage repair and stemness maintenance and to stabilise PD-L1 (PMID:42058190), while in GBM HIF-1alpha degradation lowered SMUG1 and LIG4 and potentiated DNA-damaging therapy (PMID:42523098). If lactate flux feeds both HIF-driven and lactylation-dependent repair capacity, then MCT1/MCT4 or LDHA blockade should act as a repair-capacity suppressor in exactly the compartment where RT fails, distinct from the angiogenic mechanism in L2.","approach":"Orthotopic GBM PDX and GL261/CT-2A: fractionated RT +/- LDHA or dual MCT1/4 inhibition; readouts pan-Kla and H3K18la by immunoblot/ChIP, SMUG1/LIG4/RAD51 abundance, 53BP1/gammaH2AX resolution kinetics, hypoxia mapping (pimonidazole/CAIX), clonogenic survival in normoxia vs 1% O2 to prove hypoxia-selectivity. Nest correlatives in the recurrent-GBM RT platform (NCT06860594) and use the microdialysis protocol (NCT04047264) to test whether intratumoral lactate falls on drug. Normal tissue: MCT1/4 are required by erythrocytes, muscle and neurons for lactate shuttling — neuronal lactate deprivation is the window risk, arguing for short peri-fraction dosing. Expected resistance: glutamine/fatty-aci","level":"LEAD","confidence":0.3,"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}],"corrobVisits":1,"createdVisit":2,"createdCycle":5,"lastVisit":2,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["(\"MCT1\" OR \"MCT4\" OR SLC16A1 OR SLC16A3 OR LDHA) AND (glioma OR glioblastoma) AND (orthotopic OR xenograft OR \"in vivo\" OR radiotherapy) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(LONP1 OR \"Lon protease\") AND (inhibitor OR CDDO OR obtusilactone OR \"blood-brain barrier\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(ATF4 OR \"integrated stress response\" OR ISRIB OR UPRmt) AND (glioblastoma OR glioma) AND (temozolomide OR radioresistance OR OXPHOS) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T14:23:33.894Z"},{"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":2,"openQuestions":["What fraction of human PDAC resections carry cdd/cdd_L+ Gammaproteobacteria, and does carriage predict neoadjuvant gemcitabine non-response?","Does tumour-restricted antibiotic delivery (GSH-cleavable antibiotic–drug conjugate) achieve the same gemcitabine rescue as systemic Gram-negative antibiotics with less microbiome-wide perturbation, and is the immune activation (DC maturati","Are preclinical antibiotic-potentiation effect sizes inflated by non-physiological SPF mouse microbiomes, and do they persist in environmentally colonised or humanised-microbiome PDAC models?","For KRAS G12D, does PI3K/AKT rather than MAPK rebound dominate on-treatment escape, and does adding a PI3K/AKT inhibitor to degradation deepen pERK/pS6 suppression without crypt toxicity?","Does pan-RAS(ON) tri-complex inhibition outperform mutant-selective degradation on duration of response and resistance-clone spectrum, and at what cost to the wild-type-RAS-dependent window?","Does LIF blockade lower intratumoral pSTAT3 in PDAC patients on gemcitabine/nab-paclitaxel, and is IL-6/OSM redundancy the escape?"],"leads":[{"id":"L1","title":"cdd_L+ intratumoral Enterobacter as an antibiotic-reversible driver of gemcitabine inactivation","mechanism":"Intratumoral E. hormaechei cdd_L (Km 0.22 mM, kcat 194 s-1) deaminates gemcitabine to dFdU in situ; cdd_L ablation fully restores sensitivity and bacterial depletion permits 50% gemcitabine dose reduction (PMID:42099454). Independently, tobramycin–SS–gemcitabine conjugates cleaved by high tumour-microenvironment GSH reduce intratumoral bacterial burden and improve gemcitabine response in bacteria-colonised Panc02 tumours, with DC maturation and increased CD8+ infiltration — so the bacterium is both a drug sink and an immunosuppressive input (PMID:42302584). Reviews frame microbial metabolic inactivation of antimetabolites as a general, causation-unproven axis needing human biomarkers (PMID:4","approach":"(1) Human prevalence first: cdd/cdd_L qPCR + culturomics + 16S on banked neoadjuvant gemcitabine-treated resections, nested into NCT07226154, testing cdd_L carriage vs pathologic response. (2) LC-MS intratumoral gemcitabine:dFdU ratio as pharmacodynamic endpoint. (3) Prefer tumour-restricted delivery (GSH-cleavable antibiotic–drug conjugate, or tetrahydrouridine-class deaminase inhibition) over systemic ciprofloxacin to avoid microbiome-wide ablation. Resistance: outgrowth of other cdd+ taxa (Klebsiella, Citrobacter), aminoglycoside resistance genes, fungal/anaerobic compartment unaffected, conjugate premature cleavage in circulation.","level":"CANDIDATE","confidence":0.65,"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}],"corrobVisits":2,"createdVisit":1,"createdCycle":2,"lastVisit":2,"lastNote":"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.","history":[{"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 is the dominant PDAC allele and lacks a covalent handle; degradation removes the protein pool rather than blocking one nucleotide state (PMID:41423807, PMID:41598808). New emphasis from the pack: G12D preferentially routes to PI3K/AKT and enforces an immunosuppressive, immune-excluded microenvironment (PMID:41423807, PMID:41924551), so downstream rebound may be PI3K- as much as MAPK-driven. Window argument remains mutant-selectivity, since wild-type KRAS is required in intestinal crypt and haematopoietic renewal.","approach":"Follow NCT07023731 for depth/duration of pERK suppression and mutant selectivity. Reprioritise combinations: PI3K/AKT or mTOR inhibition alongside SHP2/SOS1 (wild-type RAS/RTK reactivation) and CDK4/6 in CDKN2A-null tumours. Serial ctDNA for KRAS amplification and secondary/alternate RAS-BRAF mutations; paired-biopsy pERK/pAKT/pS6. Resistance: KRAS amplification, NRAS/BRAF acquisition, YAP1 MAPK-independent bypass, CRBN/VHL loss.","level":"LEAD","confidence":0.5,"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}],"corrobVisits":2,"createdVisit":1,"createdCycle":2,"lastVisit":2,"lastNote":"Review-only corroboration, so no promotion; substantive change is elevating PI3K/AKT as a co-target for G12D specifically.","history":[{"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":"Allele-selective G12D agents are escaped by wild-type RAS/RTK-driven reactivation and by secondary RAS alterations; tri-complex pan-RAS(ON) agents (RMC-9805 class) suppress mutant RAS signalling broadly, with early reports of tumour-microenvironment remodelling and delayed resistance (PMID:41924551, PMID:41423807, PMID:41598808). [INFERRED] Because bypass via wild-type RAS is pre-empted, on-treatment ctDNA should show fewer RAS-pathway escape events and more non-RAS routes (PI3K, YAP1, MYC). Normal tissue: wild-type RAS is required in intestinal crypt and marrow, so unlike a mutant-selective degrader this strategy spends its window deliberately — dermatologic/GI toxicity and intermittent dos","approach":"Head-to-head preclinical comparison in KPC and G12D PDX: pan-RAS(ON) vs G12D degrader vs MRTX1133 for depth/duration of pERK and pAKT suppression, crypt proliferation index as a window readout, and resistance-clone sequencing at relapse. Test whether pan-RAS(ON)-induced TME remodelling converts PD-1 refractoriness (paired CD8/Treg immunophenotyping). Resistance: RAS amplification, RTK-independent PI3K activation, YAP1, MYC.","level":"LEAD","confidence":0.4,"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}],"corrobVisits":1,"createdVisit":2,"createdCycle":6,"lastVisit":2,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["(\"pancreatic ductal adenocarcinoma\" AND (\"pan-RAS\" OR \"RMC-6236\" OR \"RMC-9805\" OR \"tri-complex\") AND (resistance OR trial OR response)) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"pancreatic\" AND (\"cytidine deaminase\" OR cdd OR Gammaproteobacteria) AND (\"human\" OR resection OR cohort OR biomarker) AND gemcitabine) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"pancreatic\" AND (LIF OR \"leukemia inhibitory factor\" OR STAT3) AND (durvalumab OR \"immune checkpoint\" OR stroma)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T14:27:00.178Z"},{"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":2,"openQuestions":["Does adding a CDK4/6 inhibitor to pemigatinib or futibatinib restore PFS in FGFR2-fusion CCA with CDKN2A/CDKN2B loss, and is CDKN2A loss prognostic or genuinely predictive of FGFRi failure?","In post-FGFRi FGFR2-fusion CCA, what fraction of progression is kinase-domain-mutant (covalent-inhibitor-addressable) versus bypass/EMT, and does tinengotinib's activity segregate by that split?","Can azacitidine-induced HR impairment (DNMT3B/OGFR axis) be reproduced in BTC organoids/PDX with a functional RAD51 readout, and is priming-then-PARPi superior to concurrent dosing?","Are the DDR (BRCA2/ATM/FANCA) and IDH1 subgroup signals from BilT-02 reproducible in a prospective biomarker-selected PARPi cohort, and were those BRCA2 events germline or somatic?","Does the multiomic CCA cluster assignment and its TNK1 dependency replicate in an independent cohort, and is there an FFPE-deployable classifier?","Do the KG correlated anchors ROS1 (fusion) and PTPN3 represent recurrent druggable events in CCA, or small-series artefacts — still unresolved after two visits?"],"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 kinase activity into RAS-MAPK/PI3K; futibatinib's covalent binding retains activity against much of the kinase-domain resistance spectrum (PMID:41869869). New evidence relocates a large share of resistance to primary co-alterations: 44.4% of pemigatinib-treated FGFR2+ CCA carry concomitant GAs, and CDKN2A mutation halves PFS (4.79 vs 8.66 mo), with BAP1 11.1%, TP53 9.5%, CDKN2B 7.9%, PTEN 4.7% (PMID:42494243). CDKN2A/B deletion releases CDK4/6-cyclin D restraint downstream of FGFR-MAPK, so FGFR blockade alone leaves the cell cycle engaged [INFERRED]; PTEN loss sustains PI3K-AKT independent of FGFR2 [INFERRED]. Fusions remain the best-responding FGFR alt","approach":"Mandate baseline DNA/RNA NGS co-alteration panel (CDKN2A/B, PTEN, BAP1, TP53) as a stratification factor in NCT06439485 and any futibatinib cohort; test futibatinib or pemigatinib + palbociclib/abemaciclib in CDKN2A/B-null fusion tumours and + PI3K/AKT inhibitor in PTEN-null, with paired ctDNA to separate kinase-domain alleles (gatekeeper/molecular brake) from bypass (MET, EGFR, PIK3CA) at progression. Reserve covalent futibatinib for post-reversible-FGFRi patients with a demonstrated sensitive kinase-domain allele rather than all comers. Window constraints: FGFR1-driven hyperphosphataemia, class nail toxicity (40-50%), which anecdotally improved on switching pemigatinib to futibatinib (PMID","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}],"corrobVisits":2,"createdVisit":1,"createdCycle":3,"lastVisit":2,"lastNote":"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'.","history":[{"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 G12D is an activated oncogene requiring direct pharmacology; a heterobifunctional degrader eliminates the protein rather than occupying the switch-II pocket, which should blunt the RTK-driven RAS-reactivation rebound and nucleotide-cycling escape that limits reversible G12D inhibitors [INFERRED]. CCA carries a KRAS-mutant subset enriched in extrahepatic/gallbladder disease [KNOWN].","approach":"Seek CCA-specific enrolment and response data from NCT07023731; pre-plan combination logic with SHP2 or EGFR/MET inhibition to suppress wild-type RAS bypass, and MAPK-reactivation ctDNA surveillance. Normal-tissue window: KRAS is required in normal epithelium, so allele-selective degradation, not pan-RAS depletion, is the argument.","level":"LEAD","confidence":0.4,"citations":[{"kind":"NCT","id":"NCT07023731","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42146765","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":3,"lastVisit":1,"lastNote":"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.","history":[{"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":"Actionable BRCA1/2 alterations are rare in BTC, so HRD must be induced rather than selected. In TFK-1 and RBE BTC lines, azacitidine or siRNA knockdown of DNMT3B impaired homologous recombination — mechanistically attributed to opioid growth factor receptor (OGFR)-mediated signalling with supporting whole-genome bisulfite and RNA-seq data — and sensitised cells to niraparib, with increased apoptosis and lowered IC50 (PMID:41463187). This is a repurposing combination of two approved drug classes that converts the PARPi hypothesis from a rare-genotype play into a broadly applicable one [INFERRED].","approach":"Confirm in BTC PDX/organoids: does azacitidine (or decitabine) pretreatment produce a functional HRD phenotype (loss of RAD51 foci, RAD51 gene-conversion assay) and does the schedule matter — priming then PARPi versus concurrent? Validate DNMT3B and OGFR dependency by CRISPR rather than siRNA alone. Test whether the effect is confined to specific molecular clusters (see TNK1/multiomic lead). Normal-tissue window: DNMT inhibitors and PARPi both hit haematopoiesis, so myelosuppression is the dose-limiting axis and intermittent low-dose azacitidine priming is the rational design [SPECULATIVE]. Resistance routes: HR restoration on drug withdrawal, SLFN11 loss, ABCB1 efflux.","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"41463187","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":7,"lastVisit":2,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["(\"cholangiocarcinoma\" OR \"biliary tract cancer\") AND (\"CDKN2A\" OR \"CDK4/6\" OR palbociclib OR abemaciclib) AND (FGFR2 OR pemigatinib OR futibatinib) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"biliary tract cancer\" OR cholangiocarcinoma) AND (azacitidine OR decitabine OR DNMT OR \"induced BRCAness\") AND (\"PARP inhibitor\" OR niraparib OR olaparib) AND SRC:MED","cholangiocarcinoma AND (TNK1 OR \"proteogenomic\" OR \"phosphoproteome\" OR \"molecular subtype\" OR ROS1 fusion OR PTPN3) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T14:30:48.793Z"},{"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":2,"openQuestions":["Is the YAP1-positive persister state (PMID:42019833) pharmacologically preventable or reversible, or only avoidable by antigen switching - and does any citable SCLC experiment show restoration of DLL3/SEZ6 after LSD1/EZH2 or Notch modulatio","In relapsed SCLC, do DLL3+ and YAP1+/B7-H3+ compartments coexist spatially in the same lesion (mandating concurrent DLL3-engager + B7-H3 ADC) or replace each other temporally (permitting sequencing)?","Does the NCT07203053 PS 2 read-out show efficacy loss or toxicity-driven discontinuation - i.e. is the engager ceiling in unfit patients set by cytokine toxicity/T-cell fitness (CD28-null, CD58 loss) or by tumour biology?","What is the CD58 expression status of SCLC and of the YAP1-emergent state, and is CD58 loss an independent engager-resistance route in this disease?","Is there any citable synthetic-lethal handle for RB1/TP53-null SCLC (Aurora A/B, CHK1, WEE1, PARP+temozolomide) - still wholly unaddressed after two visits?","What is AZD6750's molecular target, and does NCT07115043 (with rilvegostomig) enrol SCLC at all?"],"leads":[{"id":"L1","title":"DLL3xCD3 T-cell engagers as lineage-restricted therapy in neuroendocrine SCLC","mechanism":"ASCL1/NEUROD1-driven NE SCLC aberrantly surface-expresses DLL3, a normally Golgi-retained inhibitory Notch ligand near-absent from adult somatic tissue, allowing an MHC-independent cytolytic synapse that is agnostic to the RB1/TP53-null genotype [KNOWN/INFERRED]. Window rests on lineage/compartmental restriction. New this visit: the resistance ceiling is now mechanistically specified - an emergent YAP1-positive persister population at relapse abandons SCLC identity for an LCNEC-like state and loses DLL3 and SEZ6 (PMID:42019833), so escape is state drift with coordinate antigen loss rather than isolated DLL3 downregulation.","approach":"Follow NCT07203053 (pretreated ES-SCLC, ECOG PS 2) and NCT07472517 (obrixtamig + atezolizumab/carbo/etoposide vs standard chemoimmunotherapy, first line). Mandate paired pre/post biopsies plus CTC/ctDNA to quantify DLL3, SEZ6, B7-H3, TROP2 and YAP1 at progression; test whether cytokine burden rather than efficacy caps benefit in PS 2; treat DLL3 loss as the primary correlative endpoint, not an exploratory one.","level":"CANDIDATE","confidence":0.62,"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}],"corrobVisits":2,"createdVisit":1,"createdCycle":4,"lastVisit":2,"lastNote":"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","history":[{"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 contains an emergent YAP1-positive drug-tolerant persister population with senescence, stemness and plasticity features that evolves toward an LCNEC-like phenotype; these cells lack DLL3 and SEZ6 but are enriched for B7-H3 and TROP2 (PMID:42019833). Antigen switching, not target mutation, is therefore the escape currency, and the escape state carries its own druggable surfaceome. B7-H3 (CD276) is minimally expressed on normal adult tissue at protein level and TROP2 is broadly epithelial - the window for TROP2 ADCs is payload-driven and narrower [KNOWN].","approach":"Design DLL3-engager trials with pre-specified crossover or concurrent addition of a B7-H3-directed ADC at progression, selected by post-progression biopsy/CTC antigen profile rather than by baseline subtype. Assays: multiplex IF for DLL3/SEZ6/B7-H3/TROP2/YAP1 on paired biopsies; CTC surfaceome as a non-invasive surrogate (feasible per PMID:42019833 methods). Anticipated failure mode: spatial coexistence of DLL3+ and YAP1+ compartments demanding concurrent rather than sequential coverage, plus overlapping myelosuppression/ILD from ADC payloads on a chemo-exposed marrow [INFERRED]. Subtype-plasticity reviews (PMID:41411619, PMID:41824576, PMID:41220942) support treatment-induced state transiti","level":"LEAD","confidence":0.55,"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}],"corrobVisits":1,"createdVisit":2,"createdCycle":8,"lastVisit":2,"lastNote":"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.","history":[{"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 in solid tumours are limited by dose-limiting cytokine toxicity and absent costimulation. A non-blocking CD2-agonist bispecific delivers tumour-dependent costimulation, restores full cytotoxicity of a sub-efficacious low engager dose, compensates for tumour CD58 loss (a documented escape route), and uniquely recruits CD28-negative CD8 T cells that are prevalent in elderly patients (PMID:42271190). In SCLC this predicts efficacy at engager doses below the CRS/ICANS threshold - the specific constraint in ECOG PS 2 populations. CD2/CD58 signalling is a normal T-cell adhesion/costimulation axis, so systemic agonism risks off-tumour T-cell activation; tumour-dependency of the bispeci","approach":"Preclinical: build a DLL3xCD3 engager plus DLL3- or SEZ6-anchored CD2-costimulatory bispecific pair in SCLC PDX/humanised models; read out CD58 status of SCLC lines and of relapsed biopsies, and CD28-negativity of patient T cells as predictive covariates. Clinically, this is the mechanistic hypothesis to 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 agonism (PMID:41645963) is the alternative costimulatory axis but carries a worse hepatotoxicity legacy; CD28 formats carry the TGN1412 legacy [KNOWN].","level":"LEAD","confidence":0.35,"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}],"corrobVisits":1,"createdVisit":2,"createdCycle":8,"lastVisit":2,"lastNote":"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.","history":[{"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":"L5","title":"Epigenetic blockade of subtype plasticity to prevent, not chase, antigen loss","mechanism":"SCLC master transcription factor identity (ASCL1/NEUROD1/POU2F3/YAP1) is epigenetically maintained and switches under therapeutic pressure; reviews converge on chromatin regulators as the machinery enabling subtype transition and chemoresistance (PMID:41824576, PMID:41220942, PMID:41411619), and cisplatin-resistance mechanisms include explicit subtype transition and epigenetic reprogramming (PMID:41869709). If the YAP1-emergent persister state is epigenetically licensed, a plasticity-blocking agent given with a DLL3 engager would preserve the NE state and thus the antigen, converting acquired antigen loss into a preventable event [INFERRED/SPECULATIVE]. LSD1 and EZH2 are the plausible nodes ","approach":"Preclinical only for now: in DLL3-engager-treated SCLC models, ask whether LSD1 or EZH2 inhibition suppresses emergence of YAP1-positive/DLL3-negative persisters and maintains DLL3 surface density (flow + ChIP/ATAC at the DLL3 and YAP1 loci). Read-out must be persister emergence frequency, not bulk growth inhibition. Liabilities: myelosuppression stacking on chemoimmunotherapy, and the risk that plasticity is stochastic and multi-node so single-agent epigenetic blockade merely delays drift.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"41824576","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41220942","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41411619","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41869709","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":8,"lastVisit":2,"lastNote":"New but review-level evidence only - no SCLC experiment in this pack shows pharmacological reversal or prevention of subtype switching. Deliberately low confidence; exists to keep the 'reversibility' half of open question 1 alive and to give the desk a falsifiable preclinical experiment.","history":[{"visit":2,"cycle":8,"status":"NEW","note":"New but review-level evidence only - no SCLC experiment in this pack shows pharmacological reversal or prevention of subtype switching. Deliberately low confidence; exists to keep the 'reversibility' half of open question 1 alive and to give the desk a falsifiable preclinical experiment."}]}],"retired":[],"nextQueries":["(\"SCLC\" OR \"small cell lung\") AND (\"B7-H3\" OR CD276 OR \"ifinatamab\" OR TROP2 OR \"sacituzumab\") AND (relapsed OR resistance OR \"antibody-drug conjugate\") AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"small cell lung\" AND (LSD1 OR KDM1A OR EZH2 OR \"Notch\") AND (\"DLL3\" OR plasticity OR \"subtype switch\" OR persister)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","((\"RB1\" AND \"TP53\") AND (\"synthetic lethal\" OR AURKA OR AURKB OR CHK1 OR WEE1 OR \"PARP\") AND (\"small cell lung\" OR SCLC)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T14:34:22.060Z"},{"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":1,"openQuestions":["Which pharmacological agent induced KLF4 in PMID:42493491, at what exposure, and is the MHC-I/CD8 rescue strictly KLF4-dependent (KLF4-null and B2M-null controls)?","Does KLF4-low / MHC-I-low status prospectively predict PD-1 failure in esophageal cohorts, and is it enriched in ESCC vs EAC?","Is there a genotype that confers SHP2 dependency in esophageal cancer (EGFR/ERBB2 amplification, NF1 loss, KEAP1/NFE2L2), and does SHP2i + anti-ERBB2/EGFR give synergy rather than additivity?","What fraction of ESCC tumours carry Lactobacillus/D-lactate-high niches, and does decolonisation or ldhD blockade restore GPX4-inhibitor or chemoradiation-induced ferroptosis in immunocompetent models?","Is STAT3 K631 lactylation detectable as a clinical-grade biomarker, and does it overlap with the KLF4-low immune-cold phenotype?","What is B7-H3/CD276 prevalence and intensity in ESCC vs EAC, and does it co-segregate with antigen-presentation loss?"],"leads":[{"id":"L1","title":"KLF4 re-induction to reopen MHC-I chromatin and rescue PD-1 blockade in esophageal cancer","mechanism":"KLF4 downregulation during esophageal carcinogenesis reduces chromatin accessibility at MHC class I loci and blocks enhanceosome assembly, lowering surface MHC-I, forming CD8-poor immunosuppressive niches and conferring immunotherapy resistance; pharmacological KLF4 induction restores antigen presentation, CD8+ T-cell activity and anti-PD-1 efficacy in mouse allografts, and low KLF4 tracks with immunotherapy failure across human cancers (PMID:42493491).","approach":"Identify and characterise the KLF4-inducing pharmacology used in PMID:42493491 (agent unnamed in abstract); benchmark against [KNOWN] KLF4-raising epigenetic agents (HDAC/BET inhibitors, APTO-253) in ESCC/EAC lines and organoids with HLA-ABC flow cytometry, B2M/TAP1/NLRC5 transcript readout and ATAC-seq at MHC-I loci; require CD8-dependence (anti-CD8 depletion, B2M-null control) before combination. Translational slot: add-on arm to established PD-1 backbones such as the pembrolizumab umbrella (NCT06780111) or nivolumab/paclitaxel (NCT06203600), with pre/post-treatment MHC-I IHC as the pharmacodynamic endpoint.","level":"LEAD","confidence":0.55,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":9,"lastVisit":1,"lastNote":"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","history":[{"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 receptor tyrosine kinases to RAS-ERK; the KG anchor set offers ERBB2 as the only correlated/[SOMATIC] actionable driver while DCC, LZTS1, WWOX, TGFBR2 and RNF6 are [GERMLINE]-leaning tumour suppressors that are not directly druggable. BGC1201, a fragment-derived allosteric SHP2 inhibitor (SHP2-WT IC50 2.47 nM), suppressed p-ERK and produced dose-dependent growth inhibition in the ESCC line KYSE-520 xenograft while sparing normal HUVEC and showing low hERG liability (PMID:42388521); P10 frames TKIs and MAPK-axis agents as the main unmet targeted-therapy need in EC (PMID:42425097).","approach":"Test SHP2i as a vertical-combination partner rather than monotherapy: pair with anti-ERBB2/EGFR agents in RTK-amplified ESCC/EAC lines; stratify by EGFR/ERBB2 copy number, PIK3CA and KEAP1/NFE2L2 status. [INFERRED] resistance routes to pre-empt: RAS-GTP reloading, MEK/ERK reactivation, PTPN11 allosteric-pocket mutations, bypass via FGFR or MET. Monitor on-target haematologic and edema toxicity, since SHP2 is required for normal cytokine signalling and haematopoiesis [KNOWN].","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42388521","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42425097","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":9,"lastVisit":1,"lastNote":"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.","history":[{"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":"Tumour-resident L. reuteri-derived D-lactate (distinct from host L-lactate) drives site-specific STAT3 lactylation at K631, promoting STAT3 dimerisation/nuclear translocation and upregulating the ferroptosis suppressors GPX4 and FTH1, reducing ferroptotic vulnerability and enhancing ESCC growth; ldhD-deficient bacteria and STAT3-K631R reconstitution abolish the effect in vitro and in vivo (PMID:42281240). Cancer GSH/antioxidant reprogramming is the broader context for exploiting this axis (PMID:42275298).","approach":"Stratify ESCC by intratumour Lactobacillus load (16S/qPCR on biopsies) and test whether Lactobacillus-high tumours are refractory to GPX4 inhibition or cyst(e)ine deprivation and are resensitised by targeted decolonisation or ldhD blockade; validate STAT3 K631-lactylation as an IHC/MS pharmacodynamic biomarker and check whether the axis also modulates chemoradiation-induced lipid peroxidation. Confounder to control: antibiotic exposure alters immunotherapy response independently [KNOWN].","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42281240","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42275298","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":9,"lastVisit":1,"lastNote":"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.","history":[{"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":"Payload delivery to B7-H3-expressing tumour cells with a topoisomerase-I deruxtecan warhead, combined with pembrolizumab; DNA-damage-driven immunogenic cell death is the [INFERRED] rationale for synergy with checkpoint blockade. Under active clinical test as an esophageal-specific umbrella substudy arm (I-DXd + pembrolizumab, NCT06780111).","approach":"Track the KEYMAKER-U06 substudy 06E readout; in parallel establish CD276/B7-H3 expression distribution in ESCC vs EAC and whether it correlates with MHC-I-low, KLF4-low immune-cold phenotypes, which would make ADC-induced immunogenic cell death and KLF4 re-induction complementary. Expected resistance: antigen downregulation, payload efflux (ABCG2/ABCB1), SLFN11 loss.","level":"LEAD","confidence":0.3,"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":1,"lastNote":"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","history":[{"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"}]}],"retired":[],"nextQueries":["(\"KLF4\" AND (\"MHC class I\" OR \"antigen presentation\" OR \"immune evasion\")) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"esophageal squamous cell carcinoma\" AND (SHP2 OR PTPN11 OR \"ERBB2 amplification\") AND (inhibitor OR combination OR resistance)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","((lactylation OR \"D-lactate\" OR \"intratumor microbiota\") AND (ferroptosis OR GPX4) AND (esophageal OR ESCC)) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T14:37:49.771Z"},{"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":1,"openQuestions":["Is RPRD1B expression low enough in normal gastric/marrow/crypt epithelium to give a therapeutic window, and does RPRD1B loss sensitise GC to ATR inhibitors and PARP1-selective agents as well as to 5-FU?","Does the FAO/CAV1 oxaliplatin-resistance axis replicate in independent GC models, and is CPT1 inhibition additive with platinum in PDX at tolerable cardiac exposure?","Is there gastric-specific evidence that the G3BP1-14-3-3zeta complex (not total 14-3-3) governs Bax localisation and BH3-mimetic sensitivity?","Does chemoimmunotherapy benefit in MSS colorectal cancer (PMID:42322272) extend to MSS/immune-cold gastric cancer, and what does PARAMUNE (NCT06203600) predict for taxane+PD-1 in that subset?","Which gastric molecular subsets are enriched in CDK12/MSH2 alterations (fast-growing PDX signature), and do they define a PARP- or ICI-tractable stratum?","Is SIRT1 loss a reproducible stage biomarker of H. pylori-driven intestinal metaplasia in independent human cohorts, and can eradication plus SIRT1 agonism reverse OLGIM stage?"],"leads":[{"id":"L1","title":"RPRD1B(CREPT)-TOPBP1 axis as the druggable node of 5-FU resistance in gastric cancer","mechanism":"RPRD1B is overexpressed in GC and recruits RNA Pol II to the TOPBP1 promoter, transcriptionally upregulating TOPBP1 and amplifying ATR-dependent DNA damage response/repair; high RPRD1B tumours respond poorly to 5-FU. Lowering RPRD1B collapses TOPBP1-mediated repair and restores 5-FU sensitivity (AAV knockdown in resistant AGS/MGC803 lines).","approach":"Two arms: (i) knock down/degrade RPRD1B (siRNA-LNP, AAV, or PROTAC campaign) plus fluoropyrimidine; (ii) exploit the induced repair dependency pharmacologically with ATR inhibition or PARP1-selective AZD5305 combinations already in clinic (NCT04644068 includes paclitaxel/carboplatin/T-DXd arms). Stratify by RPRD1B/TOPBP1 IHC. Test in intramuscular PDX (71.7% engraftment) with Ki-67/necrosis pharmacodynamic read-outs. Expected resistance: ATR-independent repair via POLQ/TMEJ, SLFN11 loss, drug-efflux (ABCB1), or restoration of DDR by CDK12-associated transcriptional bypass. Normal tissue: TOPBP1/ATR signalling is required in proliferating crypt and marrow compartments [KNOWN], so window favou","level":"LEAD","confidence":0.5,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":10,"lastVisit":1,"lastNote":"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.","history":[{"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":"lncRNA SNHG15 (high in GC) sponges miR-451a (low in GC), de-repressing Caveolin-1; CAV1 gain drives proliferation, blocks apoptosis, relieves G0-G1 arrest and increases fatty-acid beta-oxidation, and the axis controls oxaliplatin resistance in vivo.","approach":"Test CPT1A/FAO blockade (etomoxir-class, or repurposed ranolazine/perhexiline [SPECULATIVE]) or ACC/ETC-linked metabolic agents in combination with oxaliplatin in SNHG15-high, CAV1-high PDX; use miR-451a mimics or SNHG15 ASO as mechanistic controls. Biomarkers: CAV1 IHC, SNHG15 qRT-PCR, tumour palmitate oxidation flux. Expected resistance: glycolytic/glutamine switch, lipid-droplet buffering, GPX4-dependent ferroptosis avoidance. Normal tissue caution: FAO is essential in cardiomyocytes, hepatocytes and fasting states, so intermittent dosing and cardiac monitoring frame the window.","level":"LEAD","confidence":0.33,"citations":[{"kind":"PMID","id":"41972796","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":10,"lastVisit":1,"lastNote":"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.","history":[{"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":"L3","title":"YWHAZ(14-3-3zeta)-G3BP1 stress-granule module sequesters Bax and sets apoptotic resistance in gastric cancer","mechanism":"Under stress, G3BP1-nucleated granules cooperate with 14-3-3zeta to retain pro-apoptotic Bax in the cytoplasm, preventing mitochondrial permeabilisation; the clinically meaningful unit is the stress-specific complex, not total 14-3-3 levels.","approach":"Quantify G3BP1:14-3-3zeta:Bax proximity (PLA/co-IP) in chemo-treated GC lines and PDX; test whether disrupting the complex (14-3-3 phosphopeptide/difopein-like tools, G3BP1 depletion) restores Bax mitochondrial translocation and sensitises to platinum/taxane and to BH3 mimetics (venetoclax/navitoclax-class) [SPECULATIVE]. Expected resistance: MCL1 dependence, BAK compensation. Normal tissue: 14-3-3 and G3BP1 are ubiquitous stress adaptors, so only stress-conditional targeting is plausible.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42507757","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":10,"lastVisit":1,"lastNote":"New but review-grade evidence only (PMID:42507757 grades this module without primary gastric perturbation data in the abstract); entered at low confidence as an assay-first lead.","history":[{"visit":1,"cycle":10,"status":"NEW","note":"New but review-grade evidence only (PMID:42507757 grades this module without primary gastric perturbation data in the abstract); entered at low confidence as an assay-first lead."}]},{"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":"MUTYH [GERMLINE] is a base-excision repair glycosylase, not an HR gene, so the BRCA/PARP synthetic-lethal logic does not transfer a priori; conversely CDK12 and MSH2 alterations enriched in fast-growing GC grafts imply an HR-defective/hypermutant subset that could be PARP- or ICI-tractable.","approach":"Use ongoing basket data as the arbiter rather than assuming: talazoparib in DNA-repair-variant tumours (NCT04550494) and AZD5305 combinations (NCT04644068) for gastric-specific signal; pre-specify MUTYH mono/biallelic, CDK12, BRCA1/2, ATM strata; pair with WES-annotated PDX (PMID:42466845). Do not re-propose MUTYH-to-PARPi as established.","level":"LEAD","confidence":0.2,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":10,"lastVisit":1,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["(\"gastric cancer\" OR \"gastric adenocarcinoma\") AND (RPRD1B OR CREPT OR TOPBP1 OR \"ATR inhibitor\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"gastric cancer\" AND (\"fatty acid oxidation\" OR CPT1A OR CAV1 OR \"lipid metabolism\") AND (oxaliplatin OR cisplatin OR resistance) AND SRC:MED","\"gastric cancer\" AND (\"microsatellite stable\" OR \"immune cold\") AND (\"chemoimmunotherapy\" OR \"PD-1\" OR nivolumab OR paclitaxel) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]"],"updatedAt":"2026-08-19T14:41:19.623Z"},{"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":1,"openQuestions":["Is the ABHD17C lenvatinib-resistance effect hydrolase-activity dependent, and which palmitoylated substrates (N-RAS? MET? EGFR?) mediate it — i.e. is there a druggable enzyme step rather than an expression biomarker?","Does ABHD17C-high status also cause the CD8-poor microenvironment it correlates with, making ABHD17C inhibition a TKI-plus-IO sensitiser in immunocompetent models?","For the DNAJB1-PRKACA fusion [SOMATIC] in fibrolamellar HCC, what current evidence exists for direct PKA-catalytic or downstream (e.g. Aurora, mTOR) inhibition, and can the desk cite it?","Does AXIN1/CTNNB1-mutant [SOMATIC] Wnt activation predict resistance to PD-L1xVEGF bispecifics as it does to PD-1+VEGF, and is there a tractable co-target (Porcupine, TCF/beta-catenin, TEAD)?","In GPC3-directed cell therapy, what is the observed on-target hepatic toxicity and the GPC3 expression floor for activity, and do GPC3-negative subclones drive relapse?","Are TSC1/TSC2-altered [SOMATIC] HCCs an mTORC1-inhibitor-sensitive subset with any recent clinical or organoid evidence?"],"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":"Simultaneous PD-L1 blockade and VEGF neutralisation in one molecule is intended to concentrate VEGF-dependent vascular normalisation and Treg/MDSC reduction within PD-L1+ tumour tissue, with CTLA-4 blockade added for priming (NCT07291076). Context: an existing anti-PD-1+bevacizumab regimen (finotonlimab+bevacizumab) delivered 0.93 QALYs over sorafenib but at an ICER of $51,899/QALY with negative net monetary benefit in China (PMID:42505057).","approach":"Watch ROSETTA HCC-206 for hepatic and bleeding/perforation toxicity from combined VEGF plus dual checkpoint blockade, and for whether a bispecific improves depth of response over atezolizumab+bevacizumab-class regimens rather than only tolerability. Any future first-line nomination from this desk must state the incremental-benefit-per-cost case and treatment duration, not the hazard ratio alone. Resistance routes: VEGF-independent angiogenesis (ANG2, FGF), alternative checkpoints (TIM-3, LAG-3), Wnt/CTNNB1-driven immune exclusion.","level":"LEAD","confidence":0.35,"citations":[{"kind":"NCT","id":"NCT07291076","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42505057","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":11,"lastVisit":1,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["(\"DNAJB1-PRKACA\" OR \"fibrolamellar\") AND (inhibitor OR target OR \"protein kinase A\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"hepatocellular carcinoma\") AND (CTNNB1 OR AXIN1 OR \"Wnt\") AND (\"immune evasion\" OR \"immunotherapy resistance\" OR \"checkpoint\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"hepatocellular carcinoma\") AND (palmitoylation OR depalmitoylation OR ZDHHC OR ABHD17) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T14:44:52.617Z"},{"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":2,"openQuestions":["Does the IL-6/MCP-1 decision tree of PMID:42121891 validate in an independent DMR cohort, and does the counterintuitive low-cytokine/high-relapse direction survive adjustment for treatment duration and prior interferon exposure?","Is the CD56+CD57+CD8dim NK-like effector clone of PMID:42377752 detectable at population scale in durable-TFR versus relapsing patients, and does peg-IFN-alpha or a TKI switch (dasatinib-driven large granular lymphocytosis) induce it?","Do results exist yet from NCT03906292 (frontline asciminib + ATP-site TKI) on MR4.5 depth, TFR eligibility and the compound-mutation spectrum at relapse?","Has NCT02689440 (dasatinib + venetoclax) reported CD34+CD38- LSC clearance, and does BH3 profiling implicate MCL1/BCL-xL switching in non-responders?","Are TRIM28/SETDB1 regulons experimentally enriched in TKI-persistent CML LSCs, and does their disruption spare normal CD34+ HSPCs?","In myeloid blast crisis, do RUNX1 [SOMATIC] and HOX/MEIS-driven transcriptional states create a menin-inhibitor-sensitive subset analogous to KMT2A-r/NPM1-mutant AML?"],"leads":[{"id":"L1","title":"Orthosteric + myristoyl-pocket dual BCR-ABL1 blockade (asciminib + ATP-site TKI) for deeper response and treatment-free remission","mechanism":"BCR-ABL1 [SOMATIC] fusion kinase constitutively activates STAT5/PI3K/RAS; ATP-competitive TKIs are escaped by kinase-domain mutation, while asciminib binds the myristate pocket to restore autoinhibition. Simultaneous occupancy of both sites should require compound mutations for escape [INFERRED].","approach":"Read out NCT03906292 frontline asciminib+imatinib/nilotinib/dasatinib for MR4.5 depth, BCR-ABL1 kinetics, and TFR eligibility; pair with deep sequencing for compound mutants (T315I+A337V/P465S) and for off-target myristoyl-pocket variants.","level":"LEAD","confidence":0.7,"citations":[{"kind":"NCT","id":"NCT03906292","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42517020","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":12,"lastVisit":1,"lastNote":"New lead this visit; fresh trial NCT03906292 supplies the clinical vehicle. Normal-tissue note: ABL1 is broadly expressed (cytoskeletal/DNA-damage signalling), but decades of imatinib-class exposure define an acceptable window [KNOWN].","history":[{"visit":1,"cycle":12,"status":"NEW","note":"New lead this visit; fresh trial NCT03906292 supplies the clinical vehicle. Normal-tissue note: ABL1 is broadly expressed (cytoskeletal/DNA-damage signalling), but decades of imatinib-class exposure define an acceptable window [KNOWN]."}]},{"id":"L2","title":"BCL2 co-dependence of the TKI-persistent CML clone: dasatinib + venetoclax","mechanism":"BCR-ABL1-driven STAT5 sustains BCL2/MCL1 expression; TKI monotherapy suppresses proliferative signalling but leaves apoptotically primed quiescent leukaemic stem cells alive, a BCR-ABL1-independent survival mechanism [KNOWN/INFERRED]. Adding a BH3 mimetic should convert priming into death.","approach":"Track NCT02689440 (dasatinib+venetoclax, early chronic phase) for MR4.5/undetectable-transcript rates and LSC (CD34+CD38-) clearance; BH3 profiling to test MCL1/BCL-xL switching as the predicted escape route.","level":"LEAD","confidence":0.55,"citations":[{"kind":"NCT","id":"NCT02689440","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":12,"lastVisit":1,"lastNote":"New lead. Window argument: venetoclax's normal-tissue cost is neutropenia/tumour lysis, mitigable by short pulsed exposure rather than continuous dosing [SPECULATIVE].","history":[{"visit":1,"cycle":12,"status":"NEW","note":"New lead. Window argument: venetoclax's normal-tissue cost is neutropenia/tumour lysis, mitigable by short pulsed exposure rather than continuous dosing [SPECULATIVE]."}]},{"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; whether they re-expand after TKI cessation appears to be set by host immune surveillance rather than by leukaemic burden alone. Lower plasma IL-6 and MCP-1 predicted molecular relapse in a real-world discontinuation cohort (PMID:42121891), read here as a marker of a hypofunctional myeloid/T-cell surveillance compartment rather than a licence to block IL-6 [INFERRED]; a durable TFR >7 years after only 9 months of dasatinib was accompanied by a persistent clonal CD56+CD57+CD8dim NK-like T-cell population (PMID:42377752), and NK gene-regulatory signatures separated early-relapse from durable-remission patients in a small sing","approach":"Prospectively assay, at the moment of planned cessation, plasma IL-6/MCP-1 by multiplex plus flow/TCR-seq quantification of CD56+CD57+CD8dim NK-like clones and NK maturation subsets; test the PMID:42121891 decision tree in an independent DMR cohort for specificity/PPV. Then a biomarker-stratified pilot: 6-12 months peg-IFN-alpha added to TKI before discontinuation in patients scoring immune-unready, primary endpoint 12-month molecular relapse-free survival, secondary endpoints effector clone expansion and BCR-ABL1 kinetics at 1-2 log below MR4.5. Explicitly do NOT test IL-6 blockade peri-cessation: the observed direction of effect argues against it.","level":"LEAD","confidence":0.55,"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}],"corrobVisits":1,"createdVisit":2,"createdCycle":24,"lastVisit":2,"lastNote":"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","history":[{"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":"L6","title":"TIF1beta/TRIM28-SETDB1 chromatin node as a BCR-ABL1-kinase-independent LSC-state dependency","mechanism":"Single-cell/multi-omic work reframes TKI persistence as a conserved chronic-phase LSC transcriptional state governed by distinct gene regulatory networks with lineage skewing, altered metabolic/environmental responsiveness and epigenetic dysregulation, rather than purely as mutational clonal selection (PMID:41952641). TIF1beta/TRIM28/KAP1, acting through SETDB1-dependent H3K9 methylation and SETDB1-independent co-activation, enforces such a leukaemic chromatin state, sustaining self-renewal programmes while repressing lineage-differentiation regulators (PMID:41601208). Predicted consequence of disruption: differentiation of the persistent clone plus endogenous retroelement derepression, gene","approach":"In CD34+CD38- primary chronic-phase CML LSCs cultured +/- imatinib/asciminib, knock down TRIM28 and SETDB1 (and apply available SETDB1 methyltransferase tool inhibitors / TRIM28 degrader chemistry) and score long-term culture-initiating cell and serial-replating capacity, differentiation markers, ERV/interferon-stimulated gene induction, and TKI IC50 shift; compare with normal CD34+ HSPCs from the same donors to define the therapeutic window. Cross-reference GRN inference from published CML single-cell atlases to confirm TRIM28/SETDB1 regulon activity is enriched in the persistent LSC state before committing to chemistry.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"41601208","verified":true,"isNew":true,"addedVisit":2},{"kind":"PMID","id":"41952641","verified":true,"isNew":true,"addedVisit":2}],"corrobVisits":1,"createdVisit":2,"createdCycle":24,"lastVisit":2,"lastNote":"New but deliberately low confidence: both citations are reviews, neither is CML-LSC-specific at the experimental level, and the TIF1beta data cited are largely from other leukaemia contexts. Normal-tissue caveat is severe - TRIM28/SETDB1 are required for HSC maintenance, imprinting and ERV silencing, so a window must be demonstrated, not assumed.","history":[{"visit":2,"cycle":24,"status":"NEW","note":"New but deliberately low confidence: both citations are reviews, neither is CML-LSC-specific at the experimental level, and the TIF1beta data cited are largely from other leukaemia contexts. Normal-tissue caveat is severe - TRIM28/SETDB1 are required for HSC maintenance, imprinting and ERV silencing, so a window must be demonstrated, not assumed."}]}],"retired":[],"nextQueries":["\"chronic myeloid leukemia\" AND (\"interferon alfa\" OR peginterferon) AND (\"treatment-free remission\" OR discontinuation OR \"deep molecular response\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"chronic myeloid leukemia\" AND (asciminib) AND (combination OR \"compound mutation\" OR MR4.5 OR resistance) AND SRC:MED AND PUB_YEAR:[2024 TO 2026]","(\"blast crisis\" OR \"blast phase\") AND \"chronic myeloid leukemia\" AND (RUNX1 OR menin OR KMT2A OR venetoclax) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T15:27:45.350Z"},{"key":"mesothelioma","name":"mesothelioma","mondo":{"id":"MONDO:0005065","name":"mesothelioma"},"genes":[{"label":"WT1","kind":"causal"},{"label":"BAP1","kind":"correlated"},{"label":"BCL10","kind":"correlated"}],"visits":1,"openQuestions":["Which TEAD inhibitor, dose and route were used in PMID:42208538, and does the effect require tumour-cell-intrinsic YAP/TAZ or macrophage-intrinsic Hippo signalling?","Do NF2 copy-number loss and BAP1 loss co-occur or are they mutually exclusive in pleural mesothelioma cohorts, and does BAP1 status modify CAR-T/anti-PD-1 resistance?","Which specific chemokine(s) and retinoic-acid receptor isoform mediate CRIg+ macrophage recruitment, and is there an approved antagonist (e.g. a CCR2/CCR5 or RARalpha agent) to repurpose?","Does EZH2 inhibition alter the pleural myeloid niche or MHC-I/antigen presentation in BAP1-null mesothelioma, i.e. is an EZH2i + PD-1 or EZH2i + CAR-T combination mechanistically supported?","Is WT1 [GERMLINE-likely per KG anchor] tractable as a mesothelioma immunotherapy target (vaccine or TCR) in current literature, and what is the somatic-versus-predisposition split?","Does LAG-3 blockade (fianlimab, NCT07234058) address the same macrophage-mediated resistance or a distinct T-cell-intrinsic mechanism?"],"leads":[{"id":"L1","title":"TEAD inhibition to reverse NF2-loss-driven resistance to mesothelin CAR T cells in pleural mesothelioma","mechanism":"NF2 [SOMATIC] copy-number loss de-represses YAP/TAZ-TEAD, driving tumour secretion of chemokines and retinoic acid that recruit immunosuppressive CRIg+ macrophages specifically within the pleural cavity; this blunts CAR T cell and anti-PD-1 efficacy. Pharmacologic TEAD inhibition (or chemokine ablation / retinoic-acid inhibition) restored CAR-T sensitivity in immunocompetent DPM models, and NF2 CNV loss (not point mutation) tracked with higher myeloid infiltration in two patient cohorts.","approach":"Add a TEAD palmitoylation-site inhibitor, intermittently or intracavitarily dosed, to anti-mesothelin TNaive/SCM hYP218 CAR T cells (NCT06885697) in NF2-CNV-loss-selected pleural disease; readouts = intratumoural CRIg+ macrophage fraction, CAR-T persistence/expansion, YAP target genes (CTGF/CYR61). Expected resistance routes: YAP-independent TAZ activation, TEAD palmitoylation-site mutation, mesothelin antigen loss/shedding, alternative myeloid chemokine axes. Normal-tissue window: YAP1/TEAD1 sustains SLC7A5-leucine-mTOR and guards renal tubular epithelium from ferroptosis, plus known Hippo roles in intestinal/skin regeneration [KNOWN] - so schedule and route, not target choice, are the safe","level":"LEAD","confidence":0.55,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":13,"lastVisit":1,"lastNote":"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.","history":[{"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 the BAP1 tumour predisposition syndrome) leaves PRC2/EZH2-mediated H3K27me3 unopposed, silencing tumour suppressors; EZH2 also has non-canonical effects on DNA repair, apoptosis and immune evasion. High EZH2 correlates with BAP1 loss and aggressiveness.","approach":"Test EZH2 inhibitors (tazemetostat, valemetostat, tulmimetostat via NCT04104776) in BAP1-deficient mesothelioma only in combination - with platinum-pemetrexed or PD-1 blockade - given that [KNOWN] single-agent tazemetostat produced disease control but few objective responses. Resistance routes: EZH1 compensation (argues for dual EZH1/2 agents), PRC2 subunit (EED/SUZ12) mutation, and BAP1-restored/BAP1-wild-type subclones. Normal tissue: EZH2 is required for haematopoietic and germinal-centre B-cell function, predicting cytopenias and secondary T-cell malignancy risk.","level":"LEAD","confidence":0.4,"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":1,"lastNote":"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.","history":[{"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":"Pleural (but not subcutaneous) mesothelioma tumours accumulate CRIg+ macrophages in a manner dependent on tumour-secreted chemokines and retinoic acid; this site-specific myeloid niche, rather than the tumour cell itself, is the proximate cause of immunotherapy failure in NF2-low disease.","approach":"Rather than blocking Hippo tumour-cell-intrinsically, target the niche: RAR antagonism or ATRA-pathway inhibition, plus blockade of the implicated chemokine-receptor axis, as pre-conditioning before CAR T or anti-PD-1 in pleural/peritoneal mesothelioma (cf. NCT05001880 for the peritoneal chemo-immunotherapy backbone). Assays: serial pleural-fluid immunophenotyping for CRIg+/CD206+ macrophages, single-cell RNA-seq of the cavity niche. Normal tissue: retinoic acid is essential for mucosal tolerance and haematopoiesis, so systemic RAR blockade risks gut immunopathology - argues for local instillation.","level":"LEAD","confidence":0.35,"citations":[{"kind":"PMID","id":"42208538","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05001880","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":13,"lastVisit":1,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["(\"mesothelioma\" OR \"diffuse pleural mesothelioma\") AND (\"NF2\" OR \"TEAD\" OR \"YAP\") AND (inhibitor OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"mesothelioma\" AND (\"BAP1\" AND (\"EZH2\" OR tazemetostat OR \"synthetic lethal\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"mesothelioma\" AND (mesothelin AND (\"CAR T\" OR \"chimeric antigen receptor\")) AND (macrophage OR \"tumor microenvironment\" OR resistance) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T14:51:15.174Z"},{"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":1,"openQuestions":["Is there any clinical or preclinical footprint for E6*(aa49-110)-directed TCR-T or TCR-mimic bispecifics in HPV+ OPSCC, and has the E7_11-19 TCR-T trial reported outcomes that corroborate or refute the avidity/persistence hypothesis?","Does any HNSCC-specific dataset support AKT or PI3K inhibition plus platinum, and does PTEN-null status stratify response - i.e. is there a synthetic-lethal partner (PI3Kbeta, SGK1, PARP) for PTEN loss in this disease?","TNFRSF10B (DR5) and ING1 are the Monarch causal/germline-likely anchors and have zero citable support in this pack - is DR5 agonism (with a caspase-8-intact requirement) a real HNSCC lead, and does ING1 loss create any exploitable dependenc","What resistance mechanisms are reported for the pembrolizumab neoadjuvant backbone (KEYNOTE-689), since every combination lead must now be layered onto it?","Which myeloid-axis or CD47 combination has actually shown ADCP-dependent responses in EGFR-driven tumours, and does cetuximab remain necessary given HPV status?","Is LAMC2/laminin-332-integrin alpha6beta4 signalling independently druggable in HNSCC, separate from the PI3K/AKT readout?"],"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, giving a near-ideal therapeutic window; patient-derived TCRs recognising an alternatively spliced E6 region (E6*, aa49-110) were high-avidity and persisted in an oligoclonally expanded exhausted CD8 compartment within a lung metastasis three years after curative therapy, whereas lower-avidity clones including an E7_11-19 TCR under clinical investigation were lost, implicating avidity and epitope isoform as determinants of durable control.","approach":"Retroviral/lentiviral TCR-T or TCR-mimic bispecific built on the validated E6*-specific high-avidity TCRs, HLA-matched, with NFAT-reporter avidity ranking as the selection assay; monitor with HPV DNA gargle/rinse (rule-in only, pooled sensitivity 0.68, specificity 0.91) plus plasma ctHPV; anticipate HLA-A LOH, B2M loss, E6 splice-isoform loss and exhaustion, so pair with a pembrolizumab backbone.","level":"LEAD","confidence":0.55,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":14,"lastVisit":1,"lastNote":"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.","history":[{"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 was the only cisplatin-resistance gene significantly associated with poor survival in TCGA-HNSCC and directly transactivates LAMC2 (ChIP + luciferase promoter binding), with transcriptomic enrichment of PI3K/AKT signalling; LAMC2 (laminin-332 gamma2) engages integrin alpha6beta4/FAK at the invasive front [INFERRED]. PTEN loss [SOMATIC, correlated in the Monarch anchor] is an independent route to the same node, so PI3K/AKT is a convergent chemoresistance hub rather than a single-gene finding.","approach":"Repurposing first: capivasertib or alpelisib plus cisplatin (or plus cetuximab-RT) in FOXA2-high/LAMC2-high or PTEN-null biopsies; validate in the reported patient-derived organoid system; readouts pAKT/pS6, LAMC2 protein, apoptotic fraction. Normal-tissue window is the limiter - PI3K/AKT is required in glucose homeostasis and immune cells, hence hyperglycaemia, rash, diarrhoea [KNOWN]. Resistance routes: PIM/SGK bypass, mTORC1 reactivation, RTK feedback upregulation.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42319071","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":14,"lastVisit":1,"lastNote":"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.","history":[{"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 antitumour phagocytosis is restrained by the CD47-SIRPalpha 'don't eat me' axis and by tumour-associated macrophage reprogramming; MTDH-driven CCL18 paracrine signalling to macrophages and MMP1-selective NF-kB output provide a disease-specific rationale that the HNSCC myeloid compartment is actively immunosuppressive.","approach":"Two live arms already in the clinic: anti-CD47 AK117 + cetuximab (and AK117 + PD-1/CTLA-4 bispecific AK104) second line, and BI 770371 + pembrolizumab with or without cetuximab. Correlatives to demand: CD47/SIRPalpha IHC, CD68/CD163 density, CCL18 in plasma, FcgammaR polymorphisms. On-target risk is RBC/platelet clearance and anaemia with CD47 blockade [KNOWN]; MTDH itself is a scaffold with no asserted ligandable pocket and is not nominated as a direct target.","level":"LEAD","confidence":0.35,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":14,"lastVisit":1,"lastNote":"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.","history":[{"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, increasing its flexibility and RAN-dependent nuclear import; nuclear IRF9 then drives JAK-STAT and basal-cell-carcinoma pathway programmes, i.e. the drug itself creates its own bypass. Higher IRF9 protein predicted resistance in patient material.","approach":"Test Oroxin B (HY-N1435) or a RAN-import blocker as a resensitiser in apatinib-resistant HNSCC lines and PDX; validate IRF9 nuclear/cytoplasmic ratio as a pharmacodynamic biomarker. IRF9 is an obligate ISGF3 component in normal interferon signalling, so systemic inhibition risks blunting antiviral and possibly anti-tumour IFN responses - the window is the weak point of this lead [INFERRED].","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42540626","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":14,"lastVisit":1,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["(\"head and neck\" OR oropharyngeal) AND (\"TCR-T\" OR \"T cell receptor\" OR \"adoptive cell therapy\") AND (HPV16 OR E6 OR E7) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"head and neck squamous cell carcinoma\" AND (PTEN OR \"PIK3CA\" OR capivasertib OR alpelisib OR \"AKT inhibitor\") AND (cisplatin OR platinum OR \"synthetic lethality\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"head and neck squamous cell carcinoma\" AND (TNFRSF10B OR \"death receptor 5\" OR TRAIL OR ING1 OR \"caspase-8\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"updatedAt":"2026-08-19T14:54:39.171Z"},{"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":1,"openQuestions":["Is the OTSSP167 effect genuinely RSK1-dependent, or MELK/off-target polypharmacology — and does any clinically developable agent reproduce the WEE1-induction phenotype in TP53-mutant ACC?","Does cortisol-secreting status (or GNAS/HSD11B2 alteration) predict failure of PD-1-based therapy in ACC cohorts larger than n=1?","Do published single-cell/spatial ACC datasets show WEE1, RSK1 or CDK1 pathway dependency confined to particular molecular subtypes (steroid-high vs proliferative)?","The KG anchors ZNRF3 and CTNNB1 (WNT activation) generated no leads this visit — is there any 2023-2026 evidence for tractable WNT-pathway or porcupine/TNKS targeting in ACC, and does WNT activation drive T-cell exclusion here?","Which resistance mechanism dominates after VEGFR-TKI/PD-1 combination in ACC, and are there on-treatment biopsy data from NCT06900595 or its predecessors?","Does concurrent glucocorticoid administration (as in NCT05286814) measurably blunt immunotherapy efficacy in ACC?"],"leads":[{"id":"L1","title":"Adaptive WEE1 induction as the actionable vulnerability of TP53-mutant ACC after RSK1/multikinase inhibition","mechanism":"OTSSP167 (MELK-directed; RSK1 identified as direct in vitro target) causes caspase-dependent apoptosis and G2/M arrest independent of TP53 status, plus DNA damage and translational suppression selectively in TP53-mutant ACC lines; tumours respond by inducing the G2/M gatekeeper WEE1. In p53-deficient cells the G1/S checkpoint is absent, so survival after DNA damage depends on WEE1-mediated CDK1 restraint [KNOWN] — WEE1 blockade should force premature mitosis and mitotic catastrophe.","approach":"Confirm on-target contribution of RSK1 vs MELK vs off-target kinases by isoform-selective RSK inhibitors and degrader/CRISPR rescue in H295R, CUACC1, CUACC9; then dose-fractionate OTSSP167 + adavosertib (AZD1775) in TP53-mutant PDX with pharmacodynamic readouts (pCDK1-Y15, gamma-H2AX, pHH3). Given OTSSP167's promiscuity and unclear clinical developability, in parallel test whether a clinic-ready DNA-damage inducer (cisplatin/etoposide, the ACC backbone) or ATR inhibition substitutes for OTSSP167 upstream of WEE1. Expected resistance: PKMYT1 compensation, CCNE1/CDC25 rewiring, SLFN11 loss, drug efflux.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42601067","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT03583710","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":15,"lastVisit":1,"lastNote":"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.","history":[{"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 and responds poorly to single-agent checkpoint blockade [KNOWN]; anti-angiogenic kinase inhibition (cabozantinib, lenvatinib) reduces VEGF-driven myeloid suppression and normalises vasculature to permit T-cell infiltration [INFERRED]. MET/AXL inhibition by cabozantinib may additionally blunt an ACC survival axis.","approach":"Follow NCT06900595 (cabozantinib + cemiplimab) for response rate and correlative biopsies; contrast with basket-level single-agent pembrolizumab (NCT02721732) and nivolumab/ipilimumab (NCT03333616). Prespecify biomarkers: TMB, MMR-gene mutation (MSH6), steroid-secretion status, TOP2A. Resistance routes: HGF/MET bypass, Treg re-expansion, WNT/CTNNB1-driven T-cell exclusion.","level":"LEAD","confidence":0.4,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":15,"lastVisit":1,"lastNote":"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.","history":[{"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":"Steroidogenic ACC cell populations sit in ecotypes with a distinctive immune interface (PMID:42590935); locally secreted cortisol acting through GR on T cells and myeloid cells is a plausible intrinsic driver of checkpoint resistance [INFERRED/SPECULATIVE]. In PMID:42158873, tumour response coincided with resolution of Cushing's syndrome and induction of adrenal insufficiency.","approach":"Retrospectively stratify existing ACC immunotherapy cohorts by cortisol secretion; test selective GR antagonist relacorilant (safety database NCT03604198) or steroidogenesis inhibition combined with PD-1 blockade in immunocompetent ACC models. Flag a live contradiction to resolve: NCT05286814 gives systemic dexamethasone alongside PDS01ADC (IL-12 immunocytokine) and hepatic-artery floxuridine, which should antagonise the immune arm if this hypothesis holds.","level":"LEAD","confidence":0.3,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":15,"lastVisit":1,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["(\"adrenocortical carcinoma\" AND (WEE1 OR adavosertib OR RSK1 OR MELK OR \"cell cycle checkpoint\")) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"adrenocortical carcinoma\" AND (cortisol OR hypercortisolism OR glucocorticoid) AND (immunotherapy OR \"PD-1\" OR \"checkpoint\" OR \"T cell\")) AND SRC:MED","(\"adrenocortical carcinoma\" AND (ZNRF3 OR CTNNB1 OR \"Wnt\" OR beta-catenin) AND (inhibitor OR target OR dependency)) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"updatedAt":"2026-08-19T14:57:42.730Z"},{"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":1,"openQuestions":["What is the quantitative single-cell co-expression of GD2 (ST8SIA1), GPC2, B7-H3 and SLC6A2/NET across ADRN versus MES neuroblastoma states, and does any pair cover both states?","Does EZH2 or DNMT inhibition restore MHC-I and GD2 synthase expression in MYCN-amplified models, i.e. can one epigenetic agent enable both immunotherapy and re-differentiation?","Is there controlled (beyond n=2) or randomised evidence that adoptive NK infusion adds benefit over anti-GD2 alone, and does FCGR3A-158V/F genotype predict it?","What ALK-inhibitor (lorlatinib) data exist in ALK-mutant/amplified neuroblastoma and what are the reported resistance mutations? No ALK evidence appeared in this pack despite ALK being a KG anchor.","Which myeloid-directed intervention (CSF1R, CD47, adenosine axis) most reliably reverses MDSC/TAM-mediated anti-GD2 resistance in neuroblastoma models?","Are LIN28B, LMO1, HACE1 or PHOX2B tractable as anything other than lineage/predisposition markers, and are any germline versus somatic?"],"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] is associated with MHC-I downregulation and neuroblastoma has low tumour mutational burden, so classical MHC-restricted T-cell recognition and checkpoint monotherapy are structurally disadvantaged; MHC-independent CAR targeting of GPC2 and B7-H3 bypasses this, while a dominant-negative TGF-beta receptor (dTBRII) neutralises the dominant immunosuppressive node of the neuroblastoma TME.","approach":"Track GPC2 CAR-T (NCT05650749) and B7-H3 CAR-T combined with dTBRII-expressing antigen-specific T cells (NCT07172958); propose dual/tandem GD2+GPC2 or GD2+B7-H3 constructs armoured with dTBRII to pre-empt single-antigen escape. Normal-tissue window: GPC2 is fetal/neural-restricted with minimal adult expression [KNOWN]; B7-H3 is broadly expressed on some normal tissue, so on-target off-tumour toxicity is the key risk to model. Expected resistance: antigen downregulation during ADRN-to-MES switching, CAR exhaustion, myeloid exclusion.","level":"LEAD","confidence":0.5,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":16,"lastVisit":1,"lastNote":"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.","history":[{"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":"meta-astatobenzylguanidine ([211At]MABG) enters tumour cells via the norepinephrine transporter (SLC6A2), an adrenergic-lineage gene; alpha emission delivers high-LET, short-range double-strand breaks less dependent on oxygenation than beta emitters. Because NET expression is part of the ADRN programme, mesenchymal/therapy-resistant states are predicted to be intrinsically low-uptake, making state plasticity an on-target escape route; SSTR2-directed alpha therapy is a lineage-orthogonal hedge.","approach":"Follow the first-in-human [211At]MABG dose-finding study (NCT07767630) and the [212Pb]VMT-alpha-NET programme (NCT06479811, currently non-neuroblastoma indications); pair with quantitative SLC6A2 and SSTR2 profiling across ADRN/MES states and test whether epigenetic re-differentiation (Lead 3) raises NET-mediated uptake. Expected resistance: MES-state NET loss, marrow dose-limiting toxicity, thyroid/salivary uptake.","level":"LEAD","confidence":0.4,"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":1,"lastNote":"New lead; trial-anchored with no efficacy data yet (early phase 1, recruiting) - explicitly speculative on the NET/ADRN coupling.","history":[{"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."}]}],"retired":[],"nextQueries":["\"neuroblastoma\" AND (ALK OR lorlatinib OR crizotinib) AND (resistance OR mutation OR trial) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"neuroblastoma\" AND (\"adrenergic\" OR \"mesenchymal\" OR \"ADRN\" OR \"plasticity\") AND (\"GD2\" OR \"MHC class I\" OR \"antigen loss\" OR \"EZH2\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"neuroblastoma\" AND (\"GPC2\" OR \"B7-H3\" OR \"CAR T\" OR \"NK cell\") AND (\"clinical trial\" OR \"phase 1\" OR \"phase 2\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T15:00:59.454Z"},{"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":1,"openQuestions":["Is there primary evidence that ELP1-mutant [GERMLINE] SHH-MB carries a tRNA-modification/proteostasis or translational-stress vulnerability that could be drugged (e.g. ISR, GCN2, HSP90)?","Which MYC-amplified Group 3 dependency is more tractable — replication stress (TOP1/ATR/PARP/CHK1) or transcription-CDK (CDK7/CDK9/CDK12) — and does any dataset compare them head-to-head in vivo?","Do the in-silico-nominated FDA/EMA-approved brefeldin-A mimetics have named identities, CNS penetration and orthotopic activity, and is the target GBF1/ARF1 rather than CD133?","Are the immunotherapy strategies reviewed in the pack (CAR-T/NK, DC-RNA vaccines, ICI) backed by any primary MB efficacy data, and what antigens (GD2, B7-H3, HER2) are actually validated in MB rather than glioma?","Does molecular subgroup predict measurable intratumoural drug exposure/BBB permeability in MB, and can Group 3/4 exposure be raised without generalised barrier disruption?","Which radiosensitisers besides atovaquone have been tested under fractionated CSI rather than focal irradiation, and did any show spinal-relapse control?"],"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 replication-fork collapse, a synthetic-lethal dependency the trial design explicitly gates on amplification status [INFERRED]","approach":"PEGylated SN-38 prodrug PLX038 in biomarker-selected CNS tumours (NCT06161519); oral irinotecan VAL-413 + temozolomide (NCT04337177) as pediatric tolerability/comparator arm; test in orthotopic D425/D283 MYC-amplified models with SLFN11 and ABCG2 as pre-specified resistance biomarkers","level":"LEAD","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT06161519","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04337177","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":17,"lastVisit":1,"lastNote":"New this visit; opened because NCT06161519 is amplification-gated rather than histology-gated, making it the most mechanistically interpretable active trial in the pack.","history":[{"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":"L5","title":"Subgroup-differential BBB integrity as the determinant of CNS drug exposure in MB","mechanism":"WNT7a/b-beta-catenin signalling with GPR124/RECK/SOX17 co-regulators drives CNS endothelial barrier differentiation and is epigenetically suppressed in the mature BBB; somatic CTNNB1 activation in WNT-MB is associated with an aberrant, permeable tumour vasculature, predicting higher intratumoural drug concentrations in WNT-MB than in SHH/Group 3/4 [INFERRED/SPECULATIVE]","approach":"Measure paired plasma/tumour drug concentrations and DCE-MRI permeability by molecular subgroup in xenografts; test whether transient pharmacological WNT/beta-catenin modulation of tumour endothelium alters payload delivery in Group 3 models; caution — the same pathway maintains normal BBB, so systemic WNT agonism risks generalised barrier disruption","level":"LEAD","confidence":0.2,"citations":[{"kind":"PMID","id":"42007489","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":17,"lastVisit":1,"lastNote":"New this visit; based on a BBB review with no MB-specific data, opened as an explicitly speculative delivery hypothesis that also frames CTNNB1 from the KG anchor.","history":[{"visit":1,"cycle":17,"status":"NEW","note":"New this visit; based on a BBB review with no MB-specific data, opened as an explicitly speculative delivery hypothesis that also frames CTNNB1 from the KG anchor."}]}],"retired":[],"nextQueries":["(\"medulloblastoma\") AND (ELP1 OR SUFU OR \"germline predisposition\") AND (vulnerability OR dependency OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"medulloblastoma\" AND (\"Group 3\" OR MYC)) AND (\"replication stress\" OR ATR OR CHK1 OR PARP OR CDK7 OR \"transcriptional addiction\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"medulloblastoma\") AND (\"CAR T\" OR \"CAR-NK\" OR GD2 OR B7-H3 OR \"immune checkpoint\") AND (xenograft OR \"clinical trial\" OR \"first-in-human\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T15:04:28.694Z"},{"key":"retinoblastoma","name":"retinoblastoma","mondo":{"id":"MONDO:0008380","name":"retinoblastoma"},"genes":[{"label":"RB1","kind":"causal"},{"label":"MYCN","kind":"correlated"}],"visits":1,"openQuestions":["Do RB1-null retinoblastoma models show genuine selective sensitivity to CDK7 (vs CDK9/CDK12) inhibition, and are there primary data from RB1-negative tumours in NCT07633756 or preclinical RB1-loss panels?","Is the P1 claim that CDK4/6 inhibitors were 'validated' in CRISPR retinoblastoma organoids reconcilable with RB1 loss causing CDK4/6i resistance — were those organoids RB1-proficient/MYCN-amplified?","What is GPC2 surface expression frequency and density in retinoblastoma primaries, vitreous seeds and metastatic deposits, and does it track with MYCN amplification?","What is the immune landscape of retinoblastoma (MHC-I level, T-cell infiltration, ocular immune privilege) that would gate any CAR-T or checkpoint-combination strategy?","Which specific PTM enzyme (E3 ligase, DUB, SUMO E1/E2) is a validated genetic dependency in RB1-null retinoblastoma rather than a review-level suggestion?","Which agents achieve tumoricidal intravitreal/intra-arterial exposure in retinoblastoma, and can transcriptional-CDK inhibitors be delivered locally to widen the window?"],"leads":[{"id":"L1","title":"CDK7 / transcriptional-CDK inhibition as synthetic lethality with RB1 loss and MYCN amplification in retinoblastoma","mechanism":"Biallelic RB1 inactivation [GERMLINE first hit / SOMATIC second hit] collapses the RB-E2F checkpoint, and the minority RB1-proficient subtype is MYCN-amplified; both create E2F/MYC-driven transcriptional addiction (P1, P10). CDK7 phosphorylates RNA Pol II CTD and activates cell-cycle CDKs, so its inhibition should preferentially kill cells that have lost the RB brake and depend on high-output E2F/MYCN transcription [INFERRED]. Normal tissue: CDK7 is essential for basal transcription broadly, so the window is dose/schedule and local (intravitreal/intra-arterial) delivery, not target restriction.","approach":"Test selective CDK7 inhibitors (REC-617 class) and CDK9/12 comparators in RB1-null retinoblastoma lines (WERI-Rb1, Y79) and CRISPR RB1-/- cone-precursor retinal organoids versus RB1-proficient MYCN-amplified models; read out E2F/MYCN target-gene collapse and apoptosis; combine with the topotecan/carboplatin backbone (NCT01783535) and model ocular exposure. Anticipated resistance: ABCB1/ABCG2 efflux, CDK12/13 or cyclin-C/CDK8 compensation.","level":"LEAD","confidence":0.45,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":18,"lastVisit":1,"lastNote":"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].","history":[{"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 cell-surface glycoprotein with restricted postnatal normal expression outside developing CNS [KNOWN]; MYCN dysregulation is documented in retinoblastoma pathogenesis (P1), providing a rationale for GPC2 surface expression in a subset of tumours [INFERRED]. CAR T engagement gives antigen-dependent cytolysis independent of RB1 status, which matters because the driver lesion is a tumour-suppressor loss.","approach":"Quantify GPC2 surface density by IHC/flow on retinoblastoma primaries, vitreous seeds and metastatic/CSF samples (specimen sources: NCT01109394, NCT03050268) and correlate with MYCN amplification; follow safety/response in the open GPC2 CAR T arm that includes metastatic retinoblastoma. Resistance/failure modes to pre-specify: antigen-low escape, poor T-cell trafficking into vitreous and subretinal sanctuary sites, on-target CNS toxicity.","level":"LEAD","confidence":0.4,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":18,"lastVisit":1,"lastNote":"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.","history":[{"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":"L3","title":"PTM-enzyme pharmacology (ubiquitin/SUMO/acetylation circuits) around the RB-E2F axis, with immunotherapy combination","mechanism":"Post-translational modification circuits — phosphorylation and ubiquitination centrally, with SUMOylation, lactylation and glycosylation underexplored — rewire RB-centred signalling, chromatin control, metabolic adaptation and therapy resistance in retinoblastoma; PTM state is also proposed to shape immune visibility, motivating PTM-enzyme inhibitor or degrader plus immunotherapy combinations (P10).","approach":"Nominate specific enzymes before advancing: CRISPR/degrader screens for E3 ligase, DUB and SUMO-pathway dependencies in RB1-null retinoblastoma organoids; profile MHC-I/antigen-presentation machinery under PTM-enzyme inhibition to test the immunosensitisation claim.","level":"LEAD","confidence":0.2,"citations":[{"kind":"PMID","id":"42212122","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":18,"lastVisit":1,"lastNote":"New but deliberately low-confidence: review-level only, no named enzyme, no genetic dependency data. Will be retired next visit unless a specific PTM enzyme with a retinoblastoma dependency appears.","history":[{"visit":1,"cycle":18,"status":"NEW","note":"New but deliberately low-confidence: review-level only, no named enzyme, no genetic dependency data. Will be retired next visit unless a specific PTM enzyme with a retinoblastoma dependency appears."}]},{"id":"L4","title":"Sunitinib repurposing (multi-RTK inhibition) validated in CRISPR retinal organoid retinoblastoma models","mechanism":"Organoid-based validation identified sunitinib as active alongside CDK4/6 inhibitors in CRISPR-engineered cone-precursor retinoblastoma models; candidate axes are PDGFR/VEGFR/KIT-driven survival and PI3K/AKT/mTOR signalling reported as dysregulated in RB (P1). Target attribution is not resolvable from the abstract.","approach":"Re-derive the organoid finding with target deconvolution (which RTK dependency?), then evaluate feasibility of local ocular delivery given systemic sunitinib toxicity in infants; benchmark against intravitreal topotecan/melphalan standards [KNOWN].","level":"LEAD","confidence":0.18,"citations":[{"kind":"PMID","id":"41782059","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":18,"lastVisit":1,"lastNote":"New, weak: single review abstract, no primary data seen, no dose or target attribution. Logged mainly so the desk does not treat it as established and to force target deconvolution before escalation.","history":[{"visit":1,"cycle":18,"status":"NEW","note":"New, weak: single review abstract, no primary data seen, no dose or target attribution. Logged mainly so the desk does not treat it as established and to force target deconvolution before escalation."}]}],"retired":[],"nextQueries":["(\"retinoblastoma\" OR \"RB1-deficient\" OR \"RB1 loss\") AND (\"CDK7\" OR \"CDK9\" OR \"CDK12\" OR \"transcriptional addiction\" OR \"synthetic lethal\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"retinoblastoma\" AND (\"GPC2\" OR \"glypican-2\" OR \"CAR T\" OR \"immune microenvironment\" OR \"HLA class I\") AND SRC:MED AND PUB_YEAR:[2021 TO 2026]","\"retinoblastoma\" AND (\"MYCN amplification\" AND \"RB1 wild-type\") AND SRC:MED AND PUB_YEAR:[2018 TO 2026]"],"updatedAt":"2026-08-19T15:07:51.214Z"},{"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":1,"openQuestions":["What are the HER2 expression criteria and any reported WT responses in NCT04616560 (trastuzumab deruxtecan), and is HER2 genuinely expressed in WT epithelial components?","What is GPC3 and B7-H3 protein prevalence across WT histologic subtypes (blastemal vs epithelial vs stromal, anaplastic vs favourable) in primary human series?","Is there any preclinical or clinical evidence that TRIM28-mutant or DIS3L2/CTR9-mutant WT has a distinct exploitable dependency, and are these germline or somatic in the reported cases?","Does germline BRCA2 in WT predisposition translate into any somatic HR deficiency (PARP-inhibitor rationale) or is it purely a predisposition signal?","What primary data (not review-level) support ATRA-induced differentiation in WT models, and has ATRA plus a DNMT inhibitor ever been tested in WT?","What are the current dominant relapse mechanisms after standard COG/SIOP chemotherapy in high-risk WT, and which are drug-addressable?"],"leads":[{"id":"L1","title":"IL-15/IL-21-armored GPC3 CAR-T against onco-fetal GPC3 in Wilms tumor","mechanism":"GPC3 is a KG causal gene (germline LoF causes Simpson-Golabi-Behmel with WT predisposition [KNOWN]) but the tumour-maintenance-relevant fact is somatic onco-fetal re-expression of the GPI-anchored protein on blastemal/epithelial WT cells; cytokine-armored CAR-T overcomes the poor persistence seen with unarmored GPC3 CAR products [INFERRED]. Normal-tissue window: GPC3 is near-absent in postnatal tissues except placenta/fetal liver [KNOWN].","approach":"Enrol WT cohort within/alongside NCT04715191; screen archival WT for GPC3 IHC by histology subtype; pre-specify escape monitoring for GPC3-low outgrowth and soluble GPC3 antigen sink.","level":"LEAD","confidence":0.5,"citations":[{"kind":"NCT","id":"NCT04715191","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":19,"lastVisit":1,"lastNote":"New lead; GPC3 KG anchor plus an actively recruiting pediatric solid-tumour CAR-T trial with a cytokine-armoring design.","history":[{"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 broadly expressed on pediatric embryonal tumours [KNOWN]; blastemal WT stroma is TGF-beta rich, so dominant-negative TGF-beta receptor II expression should protect effector T cells from paracrine suppression [INFERRED]. Predicted resistance: antigen-low subclones, CAR-T exhaustion, myeloid-derived suppression independent of TGF-beta.","approach":"Track NCT07172958 (SABRE) WT-specific subgroup; correlate B7-H3 IHC intensity with response; assay tumour TGF-beta1 and pSMAD2 in pre/post biopsies.","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT07172958","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":19,"lastVisit":1,"lastNote":"New lead from an actively recruiting phase 1 explicitly in relapsed/refractory embryonal tumours.","history":[{"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."}]}],"retired":[],"nextQueries":["\"Wilms tumor\" AND (GPC3 OR \"glypican-3\" OR B7-H3 OR CD276 OR \"CAR T\") AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","\"Wilms tumor\" AND (TRIM28 OR DIS3L2 OR CTR9 OR \"IGF2\" OR \"loss of imprinting\") AND (dependency OR vulnerability OR inhibitor) AND SRC:MED","\"Wilms tumor\" AND (relapse OR refractory OR \"anaplastic\") AND (\"patient-derived xenograft\" OR organoid OR \"drug screen\") AND SRC:MED AND PUB_YEAR:[2021 TO 2026]"],"updatedAt":"2026-08-19T15:11:22.950Z"},{"key":"osteosarcoma","name":"osteosarcoma","mondo":{"id":"MONDO:0009807","name":"osteosarcoma"},"genes":[{"label":"CHEK2","kind":"causal"},{"label":"RB1","kind":"causal"},{"label":"TP53","kind":"correlated"}],"visits":1,"openQuestions":["Does KIF18A-inhibitor sensitivity in osteosarcoma track quantitatively with WGD/CIN burden and SAC gene integrity across PDX panels, rather than with a single isogenic pair?","What are the p53-independent USP7 substrates in TP53-null osteosarcoma, and is any selective USP7 inhibitor active in that context?","Does 68Ga-B7-H3 immunoPET uptake correlate with tissue antigen density and predict response to B7-H3-directed cell therapy or ADC in bone sarcoma?","Is the macrophage CCL3/CCL4/CXCL2/IL-1beta to lung-colonisation circuit (shown in TNBC, PMID:42319344) operative in osteosarcoma pulmonary metastasis, making maraviroc/navarixin/anakinra repurposing testable?","Is METTL3-m6A stabilisation of CACNA1E and WNT7B/Ca2+ signalling a genuine, targetable chemoresistance node in osteosarcoma, and can calcium-channel or METTL3 inhibitors reverse doxorubicin/cisplatin resistance?","What is the mature efficacy signal for antiangiogenic backbones in relapsed osteosarcoma (cabozantinib, NCT02243605; losartan+sunitinib, NCT03900793) and are they suitable partners for immune or mitotic-targeted agents?"],"leads":[{"id":"L1","title":"KIF18A inhibition as CIN/whole-genome-doubling-selective synthetic lethality in osteosarcoma","mechanism":"TP53 [SOMATIC] and RB1 loss permit whole-genome doubling and chromosomal instability [KNOWN]; KIF18A-dependent kinetochore microtubule dynamics become essential in WGD/CIN cells, and its loss triggers aberrant spindle assembly, SAC activation and mitotic arrest, with SAC deficiency rescuing growth (PMID:42328720). KIF18A is dispensable in normal diploid tissues [KNOWN], giving a therapeutic window.","approach":"Test AM-1882-class KIF18A inhibitors across ploidy-annotated osteosarcoma PDX/cell panels; stratify by WGD status, CIN score and SAC gene integrity; combine with taxane-free mitotic stressors; profile resistance via MAD1/MAD2/BUB1B loss and near-diploid reversion.","level":"LEAD","confidence":0.6,"citations":[{"kind":"PMID","id":"42328720","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":20,"lastVisit":1,"lastNote":"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.","history":[{"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":"Osteosarcoma has low TMB and few targetable surface antigens (PMID:42366590); B7-H3 is a broadly expressed sarcoma surface antigen [KNOWN]. Quantitative in vivo antigen mapping by 68Ga-B7-H3 nanobody PET/CT (NCT07774533) could define which lesions carry sufficient antigen density for CAR-T, ADC or radioligand engagement, including metastatic heterogeneity.","approach":"Use B7-H3 immunoPET SUV thresholds as an enrolment/stratification biomarker in B7-H3-directed cell-therapy or ADC trials; test lesion-level PET-vs-IHC concordance and whether low-uptake lung metastases predict antigen-escape relapse.","level":"LEAD","confidence":0.45,"citations":[{"kind":"NCT","id":"NCT07774533","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42366590","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":20,"lastVisit":1,"lastNote":"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.","history":[{"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":"Bone sarcoma TME is myeloid-rich and T-cell-poor with static outcomes in relapsed disease (PMID:42366590); anchoring tumour-targeted IL-12 to the T-cell membrane concentrates a potent myeloid-repolarising, IFN-gamma-inducing cytokine intratumourally, circumventing the systemic toxicity of free IL-12 [KNOWN].","approach":"Track first-in-human attIL12-T and attIL12-TIL trials (NCT05621668, NCT06474676) for bone-sarcoma-specific responses; request paired biopsies for intratumoural IFN-gamma, TAM phenotype, Treg fraction; hypothesise baseline T-cell infiltrate as response predictor and IFN-gamma-driven PD-L1/IDO1 upregulation as the resistance route needing checkpoint combination.","level":"LEAD","confidence":0.4,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":20,"lastVisit":1,"lastNote":"New: two MDACC trials give a concrete clinical vehicle for the cold-TME problem articulated in the immunotherapy review; osteosarcoma-specific efficacy unreported.","history":[{"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."}]}],"retired":[],"nextQueries":["\"osteosarcoma\" AND (KIF18A OR \"whole genome doubling\" OR \"chromosomal instability\" OR \"spindle assembly checkpoint\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"osteosarcoma\" OR \"bone sarcoma\") AND (\"B7-H3\" OR CD276 OR \"CAR T\" OR \"antibody-drug conjugate\" OR IL12) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"osteosarcoma\" AND (USP7 OR deubiquitinase OR \"lung metastasis\" AND macrophage) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T15:14:41.720Z"},{"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":1,"openQuestions":["Which ATR inhibitor trials currently enrol EWSR1/FUS/TAF15-fusion sarcomas, and are any ES-specific response or pATM/pCHK1 pharmacodynamic data published?","Is ATM hypofunction in ES quantitative and fusion-dose dependent, and does it predict ATR-inhibitor sensitivity better than SLFN11 or STAG2 status?","Does genetic (ATG5/ATG7) rather than pharmacologic autophagy ablation restore PARPi killing in ES, and does the same autophagy axis blunt ATR inhibitors?","What is B7-H3 antigen density and heterogeneity across ES primaries versus metastases, and has any ES patient responded to a B7-H3 CAR construct?","Is there ES-specific evidence that DFMO/AMXT 1501 depletes tumour polyamines and suppresses the EWSR1::FLI1 transcriptional programme in vivo?","Can DWI-ADC and FDG-SUV (PMID:42208702, PMID:42314618) serve as early pharmacodynamic response endpoints for DDR-directed agents in phase 1/2 ES cohorts?"],"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 fusion oncoproteins are recruited to DNA double-strand breaks and impair activation and downstream signalling of ATM; the compensatory ATR axis becomes a collateral dependency, validated in PDX models of multiple FET-rearranged cancers (PMID:41811428). Analogous to BRCA/PARP synthetic lethality but with the fusion oncoprotein, not a tumour-suppressor deletion, as the DDR lesion.","approach":"Basket-style early-phase testing of an ATR inhibitor (e.g. elimusertib/ceralasertib/camonsertib class [KNOWN]) in EWSR1/FUS/TAF15-fusion sarcomas, with fusion-status and pATM/pCHK1/gammaH2AX pharmacodynamics on serial biopsies; rational combinations with topoisomerase-I poisons (irinotecan/topotecan, cf. NCT04337177) or gemcitabine to amplify replication stress, dose-limited by marrow toxicity since ATR is essential in normal proliferating tissue [KNOWN]. Anticipated resistance: restored ATM signalling, checkpoint bypass, SLFN11 loss, fusion-low mesenchymal state [SPECULATIVE].","level":"LEAD","confidence":0.6,"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":1,"lastNote":"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.","history":[{"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":"Olaparib showed preclinical activity but failed to produce substantial clinical responses in Ewing sarcoma; in WE-68 and SK-ES-1, olaparib and veliparib induce autophagy alongside cell death, and cells sorted for high autophagy (Cyto-ID) are significantly less killed, implicating autophagy as a resistance mechanism (PMID:42215796). Abstract does not include genetic autophagy ablation, so causality vs. co-marker status is unresolved.","approach":"Do not re-propose single-agent PARPi. Test PARPi plus lysosomal/autophagy inhibition (hydroxychloroquine, or ULK1/VPS34 inhibitors) with ATG5/ATG7 knockout controls to establish causality, and benchmark head-to-head against ATR inhibition before any clinical proposal.","level":"LEAD","confidence":0.3,"citations":[{"kind":"PMID","id":"42215796","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":21,"lastVisit":1,"lastNote":"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.","history":[{"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":"Pediatric bone sarcomas have low TMB, few targetable surface antigens and a TGF-beta-rich immunosuppressive microenvironment that limits checkpoint blockade and unmodified adoptive cells (PMID:42366590). B7-H3 (CD276) is highly expressed on Ewing sarcoma with restricted normal-tissue expression [KNOWN], and co-infusion of dominant-negative TGF-beta receptor II-expressing antigen-specific T cells with B7-H3 CAR T cells is designed to neutralise the dominant TME resistance axis (NCT07172958).","approach":"Track NCT07172958 for ES-specific responses and persistence; require paired pre/post biopsies for B7-H3 antigen density, T-cell infiltration and TGF-beta pathway activity. Expected resistance: antigen downregulation/heterogeneity, CAR exhaustion, myeloid-mediated exclusion.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42366590","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT07172958","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":21,"lastVisit":1,"lastNote":"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.","history":[{"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 transcriptional target of EWSR1::FLI1 and Ewing cells are polyamine-dependent [KNOWN]; DFMO alone is escaped by upregulated polyamine uptake, which AMXT 1501 blocks, making the combination a candidate metabolic synthetic lethality in fusion-driven sarcomas (NCT06465199).","approach":"Follow NCT06465199 sarcoma cohorts for ES-specific signal; preclinically confirm ODC1/polyamine flux dependence in ES lines and PDX, and test combination with the ATR lead given polyamine involvement in chromatin and DDR [SPECULATIVE]. Normal-tissue window: ODC1 activity in gut epithelium and hearing toxicity of DFMO [KNOWN].","level":"LEAD","confidence":0.35,"citations":[{"kind":"NCT","id":"NCT06465199","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":21,"lastVisit":1,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["\"Ewing sarcoma\" AND (\"ATR inhibitor\" OR elimusertib OR ceralasertib OR camonsertib OR berzosertib) AND SRC:MED","(\"Ewing sarcoma\" OR \"FET fusion\") AND (SLFN11 OR STAG2 OR \"replication stress\" OR \"ATM\") AND PUB_YEAR:[2023 TO 2026]","(\"Ewing sarcoma\" OR sarcoma) AND (\"B7-H3\" OR CD276) AND (\"CAR T\" OR \"chimeric antigen receptor\") AND SRC:MED"],"updatedAt":"2026-08-19T15:18:00.402Z"},{"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":1,"openQuestions":["Is L1CAM surface expression transcriptionally driven by PAX3/PAX7-FOXO1, and what molecules-per-cell threshold does the CD28-based L1CAM.III CAR require for lysis?","Does L1CAM-CAR add anything over B7-H3-CAR in matched fusion-negative RMS PDX, or is its value confined to fusion-positive disease?","What did the phase 3 temsirolimus-plus-chemotherapy arm in intermediate-risk RMS (NCT02567435) show — if negative, record mTOR-plus-VAC/VI as retired ground?","Do RMS tumours express SSTR2 at densities that would justify Lu-177 edotreotide radioligand therapy (NCT06441331), and is there any RMS IHC/expression dataset to support it?","Is MYLK4 a genuine genetic dependency in RMS lines, and does osimertinib achieve MYLK4 inhibition at clinically attainable free concentrations without cardiomyocyte toxicity?","Which armouring modality (dnTGFBRII vs IL-15/IL-21) is limiting in RMS specifically, and can they be combined on one CAR without unacceptable cytokine toxicity in a paediatric population?"],"leads":[{"id":"L1","title":"CD28-costimulated L1CAM-CAR T cells for moderate-/low-antigen-density, fusion-positive RMS","mechanism":"L1CAM is expressed with relative tissue restriction across RMS lines, PDXs and healthy tissue, and more prominently in fusion-positive (PAX3/PAX7-FOXO1) RMS; CAR hinge/costimulatory architecture sets the antigen-density threshold, with a CD28-based L1CAM.III construct exceeding the clinical 4-1BB CE7 configuration in cytotoxicity, IFN-gamma release, in vivo expansion and tumour control, including partial activity in a low-L1CAM model. [INFERRED] fusion-driven neural/adhesion transcriptional programme may set L1CAM density; [SPECULATIVE] L1CAM as a direct PAX3-FOXO1 target gene.","approach":"Advance L1CAM.III (CD28) CAR T in orthotopic fusion-positive and fusion-negative RMS PDX with paired B7-H3 CAR benchmarking; quantify surface L1CAM molecules/cell versus lysis threshold; test PAX3-FOXO1 knockdown/degradation for L1CAM modulation; profile CNS, adrenal medulla and renal tubule cross-reactivity as the window argument. Named resistance routes: antigen-density downshift/L1CAM loss, exhaustion under chronic CD28 signalling, TGF-beta-rich stroma, tumour clonal L1CAM-negative outgrowth.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42336095","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41709231","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":22,"lastVisit":1,"lastNote":"New this visit: first dataset in the programme giving construct-resolved L1CAM CAR potency with a B7-H3 comparator and healthy-tissue profiling.","history":[{"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":"Soft-tissue sarcoma including RMS is predominantly immune-cold and refractory to single-agent checkpoint blockade; RMS CAR failure modes are antigen heterogeneity plus TME-mediated suppression. Counter-engineering: dominant-negative TGFBR2 to blunt stromal TGF-beta signalling, and IL-15/IL-21 co-expression to sustain stem-like memory CAR persistence.","approach":"Composite platform arms in RMS PDX: (i) B7-H3 CAR + dnTGFBRII-expressing antigen-specific T cells (clinical precedent NCT07172958), (ii) IL-15/IL-21-armoured CAR backbone (NCT04715191) transplanted onto L1CAM.III or FGFR4/CD276 binders, (iii) dual-antigen L1CAM+B7-H3 CAR to pre-empt single-antigen escape. Resistance routes: cytokine-driven T-cell dysfunction/CRS toxicity, IL-15-independent immunosuppression via MDSC/TAM, antigen-negative escape despite dual targeting.","level":"LEAD","confidence":0.38,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":22,"lastVisit":1,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["\"rhabdomyosarcoma\" AND (\"PAX3-FOXO1\" OR \"PAX7-FOXO1\") AND (\"surface\" OR \"immunotherapy target\" OR \"transcriptional target\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"rhabdomyosarcoma\" AND (\"L1CAM\" OR \"B7-H3\" OR \"CD276\" OR \"FGFR4\" OR \"somatostatin receptor\" OR SSTR2) AND SRC:MED","(\"rhabdomyosarcoma\" OR \"soft tissue sarcoma\") AND (temsirolimus OR mTOR OR \"maintenance therapy\") AND (\"randomized\" OR \"phase 3\" OR \"survival\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]"],"updatedAt":"2026-08-19T15:21:09.646Z"},{"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":1,"openQuestions":["Does corin (or another LSD1/HDAC1-2 bifunctional agent) achieve pharmacologically active CNS exposure, and what is its neurodevelopmental toxicity profile in infant models — the actual gating question for translation?","Which combination partner most potentiates CoREST inhibition in ATRT: EZH2 (tazemetostat), Aurora A (alisertib), retinoids, or radiation dose-sparing?","What is quantitative B7-H3 surface density across ATRT-MYC/SHH/TYR, and did the 5 ATRT patients in BrainChild-03 Arm B show any objective response or CSF CAR persistence?","Is there any ATRT-specific evidence that SMARCB1 loss derepresses interferon/ERV programmes and thereby rationalises checkpoint blockade, or is NCT06622941 empirical?","Can any regimen plausibly beat 4-year EFS 49% while omitting or deferring craniospinal irradiation, given documented late systolic dysfunction after CSI?","Are differentiation-inducing epigenetic agents synergistic with CAR T by raising target antigen density in ATRT?"],"leads":[{"id":"L1","title":"CoREST complex inhibition (corin; bifunctional LSD1/HDAC1-2) to restore differentiation programmes in SMARCB1-deficient ATRT","mechanism":"Biallelic SMARCB1 loss cripples SWI/SNF activity at enhancers/promoters that are held closed by the CoREST (RCOR/LSD1/HDAC1-2) repressor complex; pharmacologic CoREST inhibition substitutes for lost SWI/SNF opposition, increasing chromatin accessibility at neuronal differentiation and synaptic genes, driving differentiation and apoptosis. RCOR2 knockdown phenocopies corin and desensitises cells to it, confirming on-target dependency (PMID:42479134). Efficacy was subgroup-agnostic (MYC/SHH/TYR), which is unusual and attractive given ATRT heterogeneity (PMID:41289204).","approach":"Confirm corin CNS exposure/BBB penetration in orthotopic models; dose-response across ATRT-MYC/SHH/TYR lines with ATAC-seq/RNA-seq differentiation readouts as pharmacodynamic biomarkers; test rational epigenetic combinations (EZH2 inhibitor tazemetostat, HDAC inhibitor, Aurora A inhibitor alisertib per PMID:41289204) and combination with radiation as a dose-sparing strategy given CSI cardiotoxicity (PMID:42296837). Normal-tissue window: LSD1 and HDAC1/2 are required for normal neurogenesis and haematopoiesis [KNOWN], so an infant population (median age 18 months, PMID:42453193) demands explicit neurodevelopmental and marrow toxicity endpoints. Expected resistance: CoREST-independent repressi","level":"LEAD","confidence":0.55,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":23,"lastVisit":1,"lastNote":"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.","history":[{"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 on many paediatric CNS embryonal tumours; locoregional ICV delivery bypasses the blood-brain barrier and limits systemic antigen exposure. ATRT is genomically quiet, so a surface-antigen-directed cellular therapy is mechanistically better matched than mutation-dependent approaches [INFERRED].","approach":"BrainChild-03 Arm B (NCT04185038) established feasibility, no DLTs, and an MTD regimen of 10x10^7 CAR T/dose across 181+ infusions, including 5 ATRT patients (PMID:42503899); the published abstract is truncated so ATRT-specific response/survival is not verifiable from this pack. Next: obtain ATRT-subgroup B7-H3 expression quantification (MYC vs SHH vs TYR), CSF cytokine/CAR persistence data, and consider combining with differentiation-inducing epigenetic therapy to raise antigen density. Normal tissue: B7-H3 is low in normal CNS parenchyma but present in some normal epithelia [KNOWN]; ICV route mitigates. Expected resistance: antigen loss/low-density escape, T cell exhaustion, myeloid-rich i","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42503899","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04185038","verified":false,"isNew":false,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":23,"lastVisit":1,"lastNote":"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.","history":[{"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":"SMARCB1-deficient tumours have been proposed to be immunologically engageable despite low mutational burden, via derepression of endogenous retroviral/interferon programmes on SWI/SNF loss [SPECULATIVE]; a dedicated rhabdoid-tumour phase 2 is now running (NCT06622941).","approach":"Track NCT06622941 readout; require correlative PD-L1 IHC, T cell infiltration and interferon-signature data stratified by ATRT-MYC/SHH/TYR before proposing combinations. Window: checkpoint blockade risks immune-related toxicity in infants and hypophysitis in irradiated survivors [KNOWN]. Expected resistance: low neoantigen load, absent MHC class I, myeloid exclusion phenotype.","level":"LEAD","confidence":0.3,"citations":[{"kind":"NCT","id":"NCT06622941","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41289204","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":23,"lastVisit":1,"lastNote":"New this visit; deliberately low confidence — trial existence is the only evidence, no ATRT response data in the pack.","history":[{"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":"L4","title":"Polyamine depletion (DFMO + AMXT 1501) targeting the MYC-driven ATRT subgroup","mechanism":"ODC1 is a canonical MYC transcriptional target [KNOWN]; DFMO inhibits ODC1 while AMXT 1501 blocks compensatory polyamine uptake, closing the salvage escape route that has historically limited DFMO monotherapy. ATRT-MYC is the subgroup with the worst outcome, including spinal presentations (PMID:41869689).","approach":"NCT06465199 (phase 1/2) already enrols CNS tumours; required next steps are ATRT-specific: ODC1/MYC expression and polyamine flux in ATRT-MYC vs SHH/TYR lines, CNS pharmacokinetics of AMXT 1501, and orthotopic efficacy. Window: DFMO causes reversible ototoxicity and affects rapidly dividing gut epithelium [KNOWN]. Expected resistance: SLC transporter-independent uptake, MYC-independent proliferative rewiring.","level":"LEAD","confidence":0.25,"citations":[{"kind":"NCT","id":"NCT06465199","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"41869689","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":23,"lastVisit":1,"lastNote":"New this visit as a repurposing hypothesis only; no ATRT preclinical data in this pack, so it stays at the bottom of the ranking and must be killed or supported next visit.","history":[{"visit":1,"cycle":23,"status":"NEW","note":"New this visit as a repurposing hypothesis only; no ATRT preclinical data in this pack, so it stays at the bottom of the ranking and must be killed or supported next visit."}]}],"retired":[],"nextQueries":["(\"rhabdoid tumor\" OR \"atypical teratoid\") AND (LSD1 OR KDM1A OR CoREST OR RCOR2 OR HDAC1) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"atypical teratoid rhabdoid\" OR \"rhabdoid tumor\") AND (B7-H3 OR CD276 OR \"CAR T\" OR PD-L1 OR \"immune microenvironment\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","SMARCB1 AND (\"synthetic lethal\" OR EZH2 OR \"Aurora A\" OR CDK4 OR \"MYC\" OR polyamine) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T15:24:28.085Z"},{"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":1,"openQuestions":["Does the IL-17A/NLRP3/PTGS2 axis operate in non-PTPN11 JMML genotypes (NRAS/KRAS/NF1/CBL), and does it differ between somatic PTPN11 JMML and germline Noonan-associated myeloproliferative disease?","Which single agent in the P6 triplet is dispensable — is IL-1beta blockade (anakinra/canakinumab) sufficient downstream of NLRP3, allowing an all-approved combination with trametinib?","In the pooled pre-HSCT HMA data, what are the JMML-only CR and post-HSCT survival rates for decitabine vs azacitidine, and do they track with JMML methylation class?","Is venetoclax resistance in JMML actually MCL-1/BCL2L1-driven, and does MEK or SHP2 pre-treatment re-prime BCL2 dependence in primary samples?","What dependencies emerge from synthetic-lethal screens in the humanized NF1-LOF HSPC model, and does vertical MEK+PI3K blockade extend survival there?","Do JMML clinical trials of MEK inhibitors (trametinib) report inflammatory-cytokine pharmacodynamics that could serve as the biomarker for the triplet?"],"leads":[{"id":"L1","title":"IL-17A/NLRP3/PTGS2 inflammatory axis blockade combined with MEK inhibition in PTPN11-mutant JMML","mechanism":"Shp2E76K/+ mutant macrophages upregulate IL-17A, triggering NLRP3 inflammasome activation, caspase-1 cleavage, IL-1beta maturation and PTGS2 induction; this remodels the marrow niche toward Treg expansion and CD4/CD8 exhaustion, sustaining myeloproliferation independently of, but cooperatively with, RAS/MAPK signalling in the leukemic clone [SOMATIC PTPN11]","approach":"Repurposing triplet: anti-IL-17A mAb (secukinumab/ixekizumab) or downstream IL-1 blockade (anakinra/canakinumab) + celecoxib (PTPN11-independent PTGS2 arm) + an NLRP3 inhibitor (MCC950-class, clinical-stage), each layered on trametinib; validate in Shp2E76K/+ mice and ex vivo primary JMML CFU/immunophenotype assays as done in the source study; endpoints = GM-CSF-independent colony output, marrow IL-1beta, Treg fraction, CD8 cytotoxicity. Normal-tissue window: IL-17A = mucosal antifungal defence (candidiasis), PTGS2 = GI/renal prostaglandins, NLRP3 = innate sensing; MEK inhibition sets the toxicity ceiling. Anticipated resistance: MAPK reactivation via CRAF/PI3K, IL-1beta-independent NF-kB in","level":"LEAD","confidence":0.62,"citations":[{"kind":"PMID","id":"42233403","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":25,"lastVisit":1,"lastNote":"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.","history":[{"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 originating in granulocyte-monocyte progenitors drive monocytic differentiation and shift apoptotic dependence from BCL2 to MCL-1/BCL2L1, conferring venetoclax resistance; JMML is definitionally RAS-pathway-driven and monocytic, so the same dependency shift is predicted [INFERRED]","approach":"Profile BH3 dependencies (BH3 profiling, MCL1/BCL2L1/BCL2 protein) in primary JMML by genotype (PTPN11/NRAS/KRAS/NF1/CBL); test MEK or SHP2 inhibitor pre-treatment to re-prime BCL2 dependence, then venetoclax; compare direct MCL-1 inhibition (cardiotoxicity is the window-limiting normal-tissue role) [KNOWN]. Watch adult CMML read-out NCT05600894 for venetoclax+decitabine/cedazuridine activity in a monocytic RAS-enriched disease.","level":"LEAD","confidence":0.42,"citations":[{"kind":"PMID","id":"42087923","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT05600894","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":25,"lastVisit":1,"lastNote":"New from P10; framed primarily as a de-risking/negative-prediction lead (naked venetoclax should fail in JMML) rather than a ready combination.","history":[{"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 reduce pre-transplant disease burden; pooled pediatric data show agent-specific response patterns, with complete remission strongly associated with decitabine in MDS and improved post-HSCT survival in responders, suggesting non-interchangeable pharmacology (deoxy- vs ribonucleoside incorporation, RNA effects of azacitidine) [KNOWN]","approach":"Extract JMML-only stratified outcomes from the pooled cohort and prospective registries; correlate CR with methylation subgroup (high-methylator JMML), genotype, and post-HSCT relapse; design a JMML-specific DAC-vs-AZA comparison or ASTX727 arm as a bridge, with methylation class as the pre-specified biomarker.","level":"LEAD","confidence":0.4,"citations":[{"kind":"PMID","id":"42393761","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":25,"lastVisit":1,"lastNote":"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.","history":[{"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":"L5","title":"CD69 blockade to reverse Treg-dominated marrow niche in RAS-mutant myelomonocytic leukemia","mechanism":"Nras-G12D CMML mice accumulate CD69+ T cells and Tregs in marrow (not blood); anti-CD69 mAb reduced GMP generation, decreased marrow Tregs and prolonged survival, implicating CD69 as a niche immune-suppression node in RAS-mutant myelomonocytic disease [SOMATIC NRAS]","approach":"Cross-read to JMML: quantify marrow CD69+/Treg compartments in NRAS/KRAS-mutant JMML, then test anti-CD69 in a JMML model; converges with the IL-17A/NLRP3 lead on Treg reversal, so co-test with MEK inhibition.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"42330053","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":25,"lastVisit":1,"lastNote":"New from P3 but disease- and species-mismatched (mouse CMML, no human JMML data); kept only because it corroborates the Treg/niche theme independently. Retire if next visit yields no JMML-specific CD69 data.","history":[{"visit":1,"cycle":25,"status":"NEW","note":"New from P3 but disease- and species-mismatched (mouse CMML, no human JMML data); kept only because it corroborates the Treg/niche theme independently. Retire if next visit yields no JMML-specific CD69 data."}]}],"retired":[],"nextQueries":["(\"juvenile myelomonocytic leukemia\" OR \"Noonan syndrome\" ) AND (trametinib OR \"MEK inhibitor\" OR SHP2 OR \"SHP099\" OR \"RMC-4630\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"juvenile myelomonocytic leukemia\" AND (methylation OR \"hypomethylating\" OR azacitidine OR decitabine OR relapse) AND SRC:MED AND PUB_YEAR:[2021 TO 2026]","(\"juvenile myelomonocytic leukemia\" OR \"chronic myelomonocytic leukemia\") AND (venetoclax OR MCL1 OR \"BH3 profiling\" OR NLRP3 OR \"IL-1beta\" OR \"IL-17\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T15:31:03.944Z"},{"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":1,"openQuestions":["Do darovasertib combinations (with MET/ALK, MEK, or TEAD/YAP inhibitors) retain activity in patient-derived organoids, and does BAP1 status stratify that response?","What are the mechanisms of acquired resistance after tebentafusp (HLA class I/B2M loss, gp100 downregulation, T-cell exhaustion), and is PRAME-directed brenetefusp active in that setting?","Is there a validated synthetic-lethal vulnerability for SF3B1-mutant UM (splicing modulators, PARP/ATR, neoantigen load from mis-splicing) and for BAP1-null UM beyond HDAC inhibition?","Did NCT01587352 (vorinostat) and NCT01979523 (trametinib +/- uprosertib) report results, and do they close out the epigenetic-differentiation and MEK/AKT branches definitively?","Does immunogenic ablation of the primary tumour (bel-sar) alter metastasis-free survival, and is there any measurable systemic immune priming?","Which liver-metastasis-specific microenvironmental features (macrophage/CAF, ECM stiffness, YAP/TAZ mechanotransduction) explain UM's resistance to checkpoint blockade, and are any pharmacologically addressable?"],"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":"GNAQ/GNA11/CYSLTR2 mutations drive constitutive Gq->PLCbeta->DAG->PKC signalling with downstream RASGRP3/MAPK and Gq-independent YAP/TAZ activation [SOMATIC; KNOWN]. PKC inhibition targets the proximal node rather than the MEK bypass-prone distal node; expected resistance is ERK rebound, YAP/TAZ mechanotransduction and MITF-type non-genetic phenotype switching (PMID:42290218). Normal-tissue role: PKC isoforms are broadly expressed (immune, CNS, cardiac), so isoform selectivity and the reported neoadjuvant tolerability define the window.","approach":"Organoid-anchored triage of darovasertib plus (a) a YAP/TAZ-TEAD palmitoylation inhibitor, (b) a MET/ALK inhibitor as per the neoadjuvant precedent, in BAP1-wildtype vs BAP1-loss patient-derived organoids; explicitly exclude MEK+AKT/PI3K combinations from further consideration.","level":"LEAD","confidence":0.6,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":26,"lastVisit":1,"lastNote":"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.","history":[{"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 (soluble affinity-enhanced TCR vs gp100(280-288)/HLA-A*02:01 fused to anti-CD3 scFv) redirects polyclonal T cells to lyse melanocyte-lineage cells, validated by OS benefit in IMCgp100-202 (PMID:42163062). The modality is HLA-restricted and antigen-restricted; escape routes are HLA class I / B2M loss, gp100 downregulation, and the T-cell-poor liver metastatic niche. Alternative pHLA targets (PRAME via brenetefusp) and other HLA alleles extend reach; TLR7/8 agonism supplies the missing innate priming for cold liver lesions [INFERRED]. Normal tissue: gp100 is melanocyte-restricted, hence rash/vitiligo as predictable on-target toxicity.","approach":"Prioritise PRAME-directed and non-A*02:01 ImmTACs in the HLA-A*02:01-negative population; test engager plus TLR7 agonist (MBS8) or anti-PD-1 for liver-met conversion, with paired biopsies for HLA class I, PRAME and gp100 expression at progression.","level":"LEAD","confidence":0.55,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":26,"lastVisit":1,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["\"uveal melanoma\" AND (darovasertib OR IDE196 OR \"protein kinase C inhibitor\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"uveal melanoma\" AND (tebentafusp OR ImmTAC OR PRAME OR brenetefusp) AND (resistance OR \"HLA loss\" OR biomarker) AND SRC:MED","\"uveal melanoma\" AND (SF3B1 OR BAP1) AND (\"synthetic lethal\" OR splicing OR PARP OR HDAC) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T15:34:18.836Z"},{"key":"chordoma","name":"chordoma","mondo":{"id":"MONDO:0008978","name":"chordoma"},"genes":[{"label":"BRCA2","kind":"correlated"},{"label":"PALB2","kind":"correlated"},{"label":"TBXT","kind":"correlated"}],"visits":1,"openQuestions":["Do the C1/C2/C7/C9 copy-number clusters predict drug sensitivity in cluster-annotated chordoma lines/PDX, specifically CDK4/6i in C9 and GLI/BET inhibition in C2?","Is the C2 SHH signature ligand/SMO-dependent or driven by non-canonical GLI activation, which would make SMO inhibitors futile?","Are BRCA2/PALB2 alterations in chordoma germline predisposition, somatic, or artefacts of small-cohort correlation — and is there any functional HR deficiency (RAD51 foci, HRDetect) in chordoma tumours?","What chordoma-specific response rates emerge from the INI1/SMARCB1-deficient checkpoint baskets (NCT05286801, NCT04416568, NCT02834013), and does poorly differentiated chordoma differ from conventional?","Which TBXT-targeting modality has actual in vivo tumour regression data — degrader, covalent binder, or peptide-centric CAR-T — and what is the first documented resistance mechanism?","Do the CN clusters differ between skull-base and sacral/mobile-spine chordoma, given the near-equal site distribution in US incidence data?"],"leads":[{"id":"L1","title":"TBXT (brachyury) lineage addiction: degraders, covalent binders, peptide-centric CAR-T","mechanism":"TBXT is the pathognomonic notochordal T-box transcription factor sustaining chordoma identity and proliferation; as an undruggable-by-orthosteric-means TF it is approached by covalent ligands, targeted protein degradation, and TCR-mimic/peptide-centric CAR-T against intracellular TBXT-derived HLA-presented epitopes. Adult normal tissue expression is essentially absent, giving the window.","approach":"Prioritise TBXT degrader chemistry and peptide-centric CAR-T constructs in TBXT-high patient-derived lines/PDX; pre-specify resistance readouts (TBXT-low mesenchymal drift, HLA-I loss, TBX2/4 paralogue compensation) and pair with CDK4/6 or SHH-axis agents per CN cluster.","level":"LEAD","confidence":0.55,"citations":[{"kind":"PMID","id":"42571860","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42448412","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":27,"lastVisit":1,"lastNote":"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.","history":[{"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":"Skull-base chordoma resolves into four reproducible CN clusters across two independent cohorts and platforms; C9 carries chr9/CDKN2A loss and C2/C9 are cell-cycle-gene enriched (predicting CDK4/6-cyclin D dependence after p16 loss [KNOWN]), while C2 uniquely up-regulates Sonic Hedgehog signalling, nominating GLI/SMO-axis dependence. Clusters explain 31-33% of transcriptomic variance and are FISH-assayable (84-89% concordance), so stratification is deployable with existing pathology tools.","approach":"FISH/methylation-array cluster assignment as a trial biomarker: palbociclib or abemaciclib arm for C9 (CDKN2A-deleted, RB1-intact); GLI-directed agent (rather than SMO inhibitor, since ligand dependence is unproven) or BET inhibitor arm for C2. Validate in cluster-annotated PDX/organoid panels first; expected resistance = RB1 loss, CCNE1 gain, non-canonical GLI activation.","level":"LEAD","confidence":0.5,"citations":[{"kind":"PMID","id":"42284679","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":27,"lastVisit":1,"lastNote":"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.","history":[{"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":"Poorly differentiated chordoma is defined by SMARCB1/INI1 loss [KNOWN, SOMATIC]; SWI/SNF-deficient tumours are being tested for responsiveness to PD-L1/TIGIT and CTLA-4/PD-1 co-blockade in dedicated baskets. Chordoma's immune microenvironment is described as functionally dynamic and immunosuppressive, implying macrophage/checkpoint-mediated evasion rather than antigen absence.","approach":"Extract chordoma-specific arm-level outcomes from NCT05286801 (tiragolumab+atezolizumab, SMARCB1/SMARCA4-deficient), NCT04416568 (nivolumab+ipilimumab, INI1-negative) and NCT02834013 (rare tumours); if signal exists, test EZH2 inhibition as a SWI/SNF-loss synthetic-lethal partner to checkpoint blockade.","level":"LEAD","confidence":0.3,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":27,"lastVisit":1,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["\"chordoma\" AND (brachyury OR TBXT) AND (degrader OR PROTAC OR \"CAR-T\" OR covalent) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","\"chordoma\" AND (CDKN2A OR \"CDK4/6\" OR palbociclib OR hedgehog OR GLI OR SMARCB1 OR EZH2) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","\"chordoma\" AND (\"patient-derived xenograft\" OR organoid OR \"drug screen\") AND (sensitivity OR resistance) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T15:37:36.314Z"},{"key":"chondrosarcoma","name":"chondrosarcoma","mondo":{"id":"MONDO:0008977","name":"chondrosarcoma"},"genes":[{"label":"EXT1","kind":"causal"}],"visits":1,"openQuestions":["Has any clinical readout been published for mutant-IDH inhibition (LY3410738, ivosidenib) in chondrosarcoma, and what is the 2-HG-independent resistance spectrum?","Is the REGγ-WDR6-STK11/AMPK ferroptosis axis reproduced by any independent group, and does RLY01 (or genetic REGγ loss) have a tolerable normal-tissue profile?","Do IDH1/2-mutant chondrosarcomas show a distinct ferroptosis or GPX4/SLC7A11 dependency that could be co-targeted with mutant-IDHi?","Does Grb10/pAKT status stratify platinum response in primary chondrosarcoma tissue, or is the circHMGB2 axis a cell-line artefact?","What is the actual efficacy record of Hedgehog inhibition (NCT01267955 vismodegib) in chondrosarcoma, and is EXT1/heparan-sulfate loss a maintenance dependency in secondary peripheral disease or purely germline predisposition?","Which immune-editing strategy (combination checkpoint, adoptive cell therapy, radiation priming) has any chondrosarcoma-specific signal given the immune-cold phenotype?"],"leads":[{"id":"L1","title":"Mutant IDH1/IDH2 inhibition plus hypomethylating/HDAC therapy in conventional central chondrosarcoma","mechanism":"IDH1 R132/IDH2 R172 [SOMATIC] neomorphic 2-hydroxyglutarate production inhibits alpha-KG-dependent TET and KDM demethylases, producing a DNA/histone hypermethylator state that blocks chondrocyte differentiation; covalent mutant-selective IDH inhibition removes the epigenetic block, and DNMT/HDAC inhibition should collapse the residual methylation programme [INFERRED]","approach":"Enrol IDH1/2-mutant chondrosarcoma into NCT04521686 (LY3410738 monotherapy and chemo/durvalumab arms); test sequential or concurrent mutant-IDHi with the belinostat + guadecitabine/ASTX727 backbone of NCT04340843; readouts = serum/tumour 2-HG, 5hmC restoration, differentiation markers. Expected resistance: dimer-interface second-site IDH mutations, IDH1-to-IDH2 isoform switching, 2-HG-independent bypass [KNOWN]. Normal tissue: wild-type IDH1/2 spared by mutant-selective covalent binders; HMA/HDACi toxicity is haematologic","level":"LEAD","confidence":0.6,"citations":[{"kind":"NCT","id":"NCT04521686","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04340843","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":28,"lastVisit":1,"lastNote":"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.","history":[{"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 is overexpressed in chondrosarcoma and degrades WDR6 via a ubiquitin-independent 20S proteasome route; WDR6 loss suppresses STK11/AMPK signalling and lipid peroxidation, blocking ferroptosis and conferring chemoresistance (PMID:42360152)","approach":"REGγ-20S inhibitor RLY01 + cisplatin in patient-derived chondrosarcoma models; combine with SLC7A11/GPX4 axis agents (sulfasalazine, GPX4 inhibitors) to deepen lipid peroxidation [SPECULATIVE]; stratify by REGγ-high/WDR6-low IHC. Expected resistance: SLC7A11/GPX4 upregulation, ACSL4 loss, FSP1-CoQ10 bypass [KNOWN]. Normal tissue: REGγ is broadly expressed in immune and neural tissue and regulates proteostasis, so therapeutic window is unproven and must be measured before advancing","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42360152","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":28,"lastVisit":1,"lastNote":"Single-paper mechanism with a tool inhibitor and in vivo chemosensitisation; needs independent replication and tolerability data before promotion.","history":[{"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":"Recurrent CDKN2A/B deletion and CDK4 amplification [SOMATIC] remove p16 restraint on CDK4/6-cyclin D, driving RB1 phosphorylation and G1-S transit; tumour-suppressor loss is not directly druggable, so the dependency is addressed downstream at the kinase [KNOWN]","approach":"Genotype-selected enrolment into NCT04040205 (abemaciclib for bone/soft tissue sarcoma with CDK pathway alteration); require RB1 intact; explore combination with mutant-IDHi in co-altered tumours [SPECULATIVE]. 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":0.4,"citations":[{"kind":"NCT","id":"NCT04040205","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":28,"lastVisit":1,"lastNote":"Trial-anchored only; no chondrosarcoma-specific response data in this pack, so it stays a low-confidence LEAD pending the biomarker-selected readout.","history":[{"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."}]}],"retired":[],"nextQueries":["(\"chondrosarcoma\" AND (IDH1 OR IDH2 OR \"2-hydroxyglutarate\" OR ivosidenib OR vorasidenib) AND SRC:MED AND PUB_YEAR:[2022 TO 2026])","(\"chondrosarcoma\" AND (ferroptosis OR GPX4 OR SLC7A11 OR \"lipid peroxidation\" OR PSME3 OR \"REG gamma\") AND SRC:MED)","(\"chondrosarcoma\" AND (CDKN2A OR CDK4 OR \"hedgehog\" OR EXT1 OR \"heparan sulfate\" OR \"immune checkpoint\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026])"],"updatedAt":"2026-08-19T15:40:51.843Z"},{"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":1,"openQuestions":["What are the published resistance mechanisms in afami-cel/lete-cel-treated synovial sarcoma - antigen downregulation, HLA-A*02 LOH, TCR-T exhaustion, or stromal exclusion - and which is dominant?","What fraction of SS tumours co-express MAGE-A4 and NY-ESO-1 at TCR-T-qualifying intensity, and can hypomethylating agents or EZH2 inhibition raise antigen density in antigen-low tumours?","Is there any SS-specific preclinical or clinical data for BRD9 degraders or other ncBAF/PRC2-directed agents, and does it show fusion-selective dependency?","Can SPP1/OPN blockade (or CD44/integrin receptor blockade) be shown in vivo to restore CD8 function in SS, and does it synergise with PD-1 blockade or TCR-T?","Are there prospective randomised data for antiangiogenic TKIs (anlotinib, pazopanib) specifically in SS with lung metastases, and how does the retrospective OS gain hold up?","Beyond NTRK, which other 'actionable' co-mutations have failed in SS18::SSX tumours, so the desk can generalise the driver-versus-passenger rule?"],"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 chromatin rewiring derepresses testis-restricted antigens MAGE-A4 and CTAG1B/NY-ESO-1, giving homogeneous surface HLA-I presentation in an otherwise immune-cold, checkpoint-refractory histology; engineered TCRs (or TCR-transduced IL-15-armoured NK cells) bypass the absent endogenous T-cell priming.","approach":"Clinical-stage assets: afami-cel (NCT05642455, paediatric extension), lete-cel (NCT03967223), NY-ESO-1 TCR/IL-15 NK (NCT06083883), NY-ESO-1 TIL with dominant-negative TGF-betaRII +/- decitabine (NCT02650986). Read out antigen-loss vs HLA-LOH vs TGF-beta-mediated exclusion as resistance routes; decitabine arm tests epigenetic antigen re-induction. Normal tissue: antigens testis-restricted, so window depends on TCR cross-reactivity, not on-target expression.","level":"LEAD","confidence":0.7,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":29,"lastVisit":1,"lastNote":"Created this visit; four independent NEW trials converge on the same antigen class, and the review confirms SS is otherwise checkpoint-cold.","history":[{"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":"L3","title":"Degrader-based attack on SS18::SSX chromatin dependencies (BRD9, PRC2)","mechanism":"SS18::SSX acts as a master epigenetic driver whose dominance overrides other actionable lesions, implying the fusion-containing ncBAF/PRC2 machinery is the maintenance dependency; targeted protein degradation can remove scaffolding subunits that small molecules cannot inhibit.","approach":"Seek SS-specific data for BRD9 or PRC2-subunit PROTACs/molecular glues in SS18::SSX models; combine with CTA-directed TCR-T on the hypothesis that degrader-induced chromatin reset alters antigen presentation. Normal tissue: BRD9/ncBAF has roles in haematopoiesis and neural development - dose-limiting risk.","level":"LEAD","confidence":0.25,"citations":[{"kind":"PMID","id":"41885448","verified":true,"isNew":true,"addedVisit":1},{"kind":"PMID","id":"42376758","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":29,"lastVisit":1,"lastNote":"Placeholder lead: pack contains only a generic PROTAC review plus the 'master epigenetic driver' framing. Must find SS-specific degrader data next visit or retire.","history":[{"visit":1,"cycle":29,"status":"NEW","note":"Placeholder lead: pack contains only a generic PROTAC review plus the 'master epigenetic driver' framing. Must find SS-specific degrader data next visit or retire."}]},{"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."}]}],"retired":[],"nextQueries":["\"synovial sarcoma\" AND (\"MAGE-A4\" OR \"NY-ESO-1\" OR afamitresgene OR letetresgene) AND (resistance OR relapse OR \"antigen loss\") AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"SS18-SSX\" OR \"SS18::SSX\") AND (BRD9 OR ncBAF OR PRC2 OR EZH2 OR degrader OR PROTAC) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(SPP1 OR osteopontin) AND (sarcoma OR \"synovial sarcoma\") AND (\"PD-L1\" OR CD44 OR \"immune evasion\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T15:44:05.952Z"},{"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":1,"openQuestions":["Does the G4/HRD GIST subtype carry demonstrable biallelic loss or mutation of BRCA1/2, PALB2, RAD51C/D, or is the HRD signature purely transcriptional - and has any second cohort reproduced olaparib sensitivity in GIST?","In SDH-deficient GIST, is HIF-2alpha inhibition (belzutifan) or FGFR inhibition (rogaratinib) the dominant dependency, and are there data on combining them or on olverembatinib's actual mechanism of benefit in SDHx-null disease?","Which resistance mechanisms have been documented after ripretinib/avapritinib failure - KIT-independent bypass (FGFR, AXL, MAPK, cell-cycle) versus new KIT mutations - and do any support autophagy or MAPK-directed combinations?","Is velzatinib (IDRX-42) supported by published phase 1/2 response and ctDNA clonal-suppression data, or is NCT07585266 running ahead of the biology?","What is the current evidence-based option set for the KIT/PDGFRA wild-type, SDH-proficient niches - NF1-associated [GERMLINE], BRAF V600E, NTRK/FGFR-fusion GIST (plixorafenib NCT05503797)?","Does PDGFRA D842V-mutant GIST show avapritinib resistance mechanisms distinct from KIT-mutant disease that would justify a separate lead?"],"leads":[{"id":"L1","title":"PARP inhibition in the HRD-signature G4 (metabolic) GIST subtype","mechanism":"Multi-omics of 106 primary GISTs defines a metabolic subtype (G4; non-gastric, poor neoadjuvant imatinib response, synchronous metastasis) with HRD mutational signatures, reduced homologous recombination activity and compensatory NHEJ upregulation; PARP trapping of unrepaired SSBs becomes lethal in HR-incompetent cells. [SOMATIC]","approach":"Prospective transcriptomic/HRD-score stratification of imatinib-refractory or non-gastric GIST; olaparib monotherapy window study with RAD51 foci and functional HR assays as pharmacodynamic readout; consider olaparib + temozolomide or + OXPHOS inhibition given the aerobic-metabolism phenotype [SPECULATIVE]. Expected resistance: HR restoration, 53BP1/Shieldin loss, ABCB1 efflux. Window: PARP1 is dispensable in most normal tissue; dose-limiting toxicity is haematologic.","level":"LEAD","confidence":0.45,"citations":[{"kind":"PMID","id":"42384257","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":30,"lastVisit":1,"lastNote":"New from P9. Held at LEAD deliberately: [KNOWN] GIST is genomically quiet and BRCA-mutant GIST is rare, and the abstract does not identify the genetic lesion generating the HRD signature, so the biomarker may be transcriptional rather than mutational.","history":[{"visit":1,"cycle":30,"status":"NEW","note":"New from P9. Held at LEAD deliberately: [KNOWN] GIST is genomically quiet and BRCA-mutant GIST is rare, and the abstract does not identify the genetic lesion generating the HRD signature, so the biomarker may be transcriptional rather than mutational."}]},{"id":"L2","title":"Pseudohypoxia-axis blockade in SDH-deficient (KIT/PDGFRA wild-type) GIST","mechanism":"Biallelic loss of SDHA/SDHB/SDHC [GERMLINE, with somatic second hit] stabilises HIF-1/2alpha via succinate-mediated PHD inhibition and drives FGF4/FGFR-dependent growth plus global DNA hypermethylation; the tumour-suppressor loss itself is undruggable, so target the downstream nodes. Matches 3 of 5 KG anchors.","approach":"Three converging trials to track: belzutifan (HIF-2alpha, NCT04924075), rogaratinib (FGFR1-4, NCT04595747), olverembatinib (phase 3, NCT06640361). Rational test of combined HIF-2alpha + FGFR blockade in SDHx-null models. Expected resistance: HIF2A gatekeeper mutations, HIF-1alpha switch, MAPK reactivation. Window: belzutifan suppresses renal EPO (anaemia, hypoxia); FGFR inhibition causes hyperphosphataemia.","level":"LEAD","confidence":0.6,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":30,"lastVisit":1,"lastNote":"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.","history":[{"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, 17/18 activation-loop) across separate metastases, making sequential monotherapy structurally unwinnable; a single agent covering primary exon 11 plus the secondary spectrum should suppress emergence rather than chase it. [SOMATIC]","approach":"Phase 3 velzatinib vs imatinib, treatment-naive metastatic/unresectable GIST (NCT07585266). Key correlative ask: serial ctDNA clonal tracking to test whether the resistance spectrum is suppressed or merely shifted (e.g. to KIT-independent FGFR/AXL/MAPK or KIT amplification). Window: on-target KIT inhibition affects mast cells, melanocytes, germ cells, haematopoiesis; cross-agent AE profiles now catalogued in FAERS.","level":"LEAD","confidence":0.55,"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}],"corrobVisits":1,"createdVisit":1,"createdCycle":30,"lastVisit":1,"lastNote":"New. Registrational-stage test of the field's central resistance hypothesis; graded LEAD only because no efficacy data are in the pack.","history":[{"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."}]}],"retired":[],"nextQueries":["(\"gastrointestinal stromal tumor\" OR GIST) AND (\"homologous recombination\" OR \"HRD\" OR PARP OR olaparib) AND SRC:MED AND PUB_YEAR:[2020 TO 2026]","(\"SDH-deficient\" OR SDHA OR SDHB OR succinate) AND (GIST OR \"gastrointestinal stromal\") AND (HIF2 OR belzutifan OR FGFR OR pseudohypoxia OR methylation) AND SRC:MED","(GIST OR \"gastrointestinal stromal tumor\") AND (ripretinib OR avapritinib OR \"IDRX-42\" OR velzatinib OR \"KIT-independent\" OR \"bypass resistance\" OR autophagy OR ULK1) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T15:47:40.970Z"},{"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":1,"openQuestions":["In prior-¹⁷⁷Lu-DOTATATE PPGL, is failure driven by SSTR2 antigen loss or insufficient absorbed dose — what do paired ⁶⁸Ga-DOTATATE / [²⁰³Pb]VMT-alpha-NET scans show?","Which molecular cluster (VHL, SDHx, EPAS1 vs RET/NF1/HRAS) predicts belzutifan response in PPGL, and what are the acquired-resistance genotypes?","Is there exploitable synthetic lethality in SDHx-deficient PPGL (PARP inhibition, MGMT-low temozolomide, 2-HG/TET-driven hypermethylation, glutamine or NAD dependency)?","Does RET-mutant (MEN2) pheochromocytoma respond to selective RET inhibitors (selpercatinib/pralsetinib), or is the evidence confined to medullary thyroid carcinoma?","Do TMEM127 and MAX lesions [SOMATIC-likely per anchor] converge on an mTORC1/MYC-MAX axis that is druggable (rapalogs, MYC-MAX dimerisation, aurora/CDK)?","Has MBTA or any intratumoral innate-agonist regimen been tested in a PPGL model, and can catecholamine-crisis risk be managed?"],"leads":[{"id":"L1","title":"HIF-2α inhibition (belzutifan) in cluster-1 pseudohypoxic PPGL","mechanism":"VHL [GERMLINE, causal per Monarch anchor] loss, and by extension SDHx/EPAS1 lesions, produce constitutive HIF-2α stabilisation and a pseudohypoxic transcriptional programme (VEGF, PDGF, GLUT1); the tumour suppressor itself is undruggable so the addiction node downstream is targeted instead. [INFERRED] cluster-1 PPGL should be the enriched responder subset.","approach":"Belzutifan (MK-6482) monotherapy in advanced PPGL/PGL is already open (NCT04924075); the desk's proposed refinement is prospective stratification by molecular cluster (VHL/SDHx/EPAS1 vs RET/NF1/HRAS) and by pseudohypoxic methylation signature, with on-treatment plasma metanephrine and VEGF as pharmacodynamic readouts. Normal-tissue window: HIF-2α governs EPO and duodenal iron handling, so anaemia and hypoxia-mimicry are the expected dose-limiting toxicities [KNOWN]. Expected resistance: EPAS1 gatekeeper mutation, HIF-1α isoform switching, MYC/mTOR bypass [SPECULATIVE].","level":"LEAD","confidence":0.6,"citations":[{"kind":"NCT","id":"NCT04924075","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT00001238","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":31,"lastVisit":1,"lastNote":"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.","history":[{"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."}]}],"retired":[],"nextQueries":["(\"pheochromocytoma\" OR \"paraganglioma\") AND (SDHB OR SDHx) AND (\"synthetic lethality\" OR PARP OR temozolomide OR MGMT) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\") AND (belzutifan OR \"HIF-2\" OR EPAS1) AND (response OR resistance) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\") AND (SSTR2 OR DOTATATE OR \"radioligand\") AND (expression OR cluster OR dosimetry OR outcome) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T15:51:04.739Z"},{"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":1,"openQuestions":["What are the actual response rates, duration and genotype breakdown (SDHB vs SDHD vs EPAS1 vs VHL) for belzutifan in the PPGL cohort of NCT04924075, and are there published on-treatment biopsies showing HIF2α PAS-B mutation or HIF1α switchi","Is there any citable synthetic-lethality axis for SDHx loss — PARP inhibition, PARP+temozolomide with MGMT promoter methylation, NAMPT/NAD+ dependence, or glutamine/reductive carboxylation — with in vivo data in SDH-deficient models?","What is the quantitative prevalence and intensity of DLK1 protein in PPGL by genotype, and does ectodomain shedding compromise ADC targeting?","Do 177Lu-DOTATATE and 212Pb-VMT-alpha-NET produce durable responses in SDHB-mutant metastatic PGL, and is post-radioligand progression driven by SSTR2 loss or by uptake heterogeneity?","Does succinate-driven DNA/histone hypermethylation (TET/KDM inhibition) create an exploitable dependency — e.g. hypomethylating agents or EZH2/LSD1 inhibitors — and does it explain the immune-cold phenotype of SDHx tumours?","Is there any evidence for MBTA or other intratumoral innate agonists in paraganglioma or pheochromocytoma models specifically?"],"leads":[{"id":"L1","title":"HIF2α antagonism in pseudohypoxic (cluster 1) paraganglioma","mechanism":"SDHx loss [GERMLINE] causes succinate accumulation that competitively inhibits α-KG-dependent prolyl hydroxylases, stabilising HIF2α; VHL loss and EPAS1 gain-of-function [SOMATIC] converge on the same transcription factor, driving VEGF/EPO/GLUT1 programmes. Allosteric PAS-B pocket ligands block HIF2α–ARNT dimerisation.","approach":"Belzutifan monotherapy in advanced PPGL (T7); stratify response by cluster-1 genotype (SDHB vs SDHD vs EPAS1 vs VHL) and by baseline plasma succinate/succinate:fumarate ratio as a candidate pharmacodynamic biomarker. Monitor on-target anaemia/hypoxia. Rational combinations to test: belzutifan + VEGFR TKI (sunitinib/cabozantinib) to close the angiogenic escape route.","level":"LEAD","confidence":0.68,"citations":[{"kind":"PMID","id":"42050152","verified":true,"isNew":true,"addedVisit":1},{"kind":"NCT","id":"NCT04924075","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":32,"lastVisit":1,"lastNote":"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","history":[{"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":"L4","title":"MBTA intratumoral innate-immune agonist cocktail for locally accessible or recurrent paraganglioma","mechanism":"Mannan-BAM anchors a phagocytosis-promoting mannan to tumour cell membranes, opsonising them for complement/lectin-pathway recognition, while resiquimod (TLR7/8), poly(I:C) (TLR3/RIG-I), LTA (TLR2) and agonistic anti-CD40 license myeloid cells and drive antigen presentation — converting an injected lesion into an in situ vaccine.","approach":"Test the optimised 5×2 intratumoral schedule reported for Panc02 in SDHB-deficient allograft PGL models; endpoints = abscopal control of non-injected lesions and catecholamine burden. Only then consider image-guided intratumoral delivery to accessible metastases.","level":"LEAD","confidence":0.22,"citations":[{"kind":"PMID","id":"42318705","verified":true,"isNew":true,"addedVisit":1}],"corrobVisits":1,"createdVisit":1,"createdCycle":32,"lastVisit":1,"lastNote":"New but weak: P1 reports 87.5% survival in pancreatic and confirmatory colon adenocarcinoma models, NOT in paraganglioma. Extrapolation to PGL is [INFERRED] and rests on my [KNOWN] recollection that this platform originated in pheochromocytoma models — unsupported by anything citable in this pack. Retire next visit unless PGL-model data appear. Key liabilities: requires injectable lesions, systemi","history":[{"visit":1,"cycle":32,"status":"NEW","note":"New but weak: P1 reports 87.5% survival in pancreatic and confirmatory colon adenocarcinoma models, NOT in paraganglioma. Extrapolation to PGL is [INFERRED] and rests on my [KNOWN] recollection that this platform originated in pheochromocytoma models — unsupported by anything citable in this pack. Retire next visit unless PGL-model data appear. Key liabilities: requires injectable lesions, systemi"}]}],"retired":[],"nextQueries":["(\"pheochromocytoma\" OR \"paraganglioma\") AND (\"succinate\" OR \"SDHB\") AND (\"synthetic lethality\" OR PARP OR temozolomide OR NAD OR glutamine) AND SRC:MED AND PUB_YEAR:[2022 TO 2026]","belzutifan AND (pheochromocytoma OR paraganglioma OR \"HIF2\" ) AND (resistance OR \"response rate\" OR biomarker) AND SRC:MED AND PUB_YEAR:[2023 TO 2026]","(\"pheochromocytoma\" OR \"paraganglioma\") AND (\"DOTATATE\" OR \"radioligand\" OR \"MIBG\" OR \"212Pb\" OR \"alpha emitter\") AND (outcome OR \"progression-free\") AND SRC:MED AND PUB_YEAR:[2022 TO 2026]"],"updatedAt":"2026-08-19T15:54:22.691Z"},{"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":1,"openQuestions":[],"leads":[],"retired":[],"nextQueries":[],"updatedAt":null}]