For research use by qualified professionals. Not for clinical decision-making or medical advice. Associations are not causation. Evidence-confidence is not a truth probability.
CureGraph CureGraph.FutureTranz.ai · Biomedical Evidence
Open PDAC Demo Start Workspace
Workspace ID: ws_pdac_demo · Role: Principal Investigator (Demo)

Pancreatic Cancer Target Discovery — Demo Workspace

Labeled demonstration workspace for organizing PDAC evidence, a KRAS G12D hypothesis, and follow-up experiments. Associations are not causation. Not for clinical decisions.

1. Evidence (7) 2. Trials (3) 3. Knowledge Graph 4. Hypothesis Scorer 5. Ethics Gate

Stage 1 & 2 · Discover & Screen

PubMed / NCBI Evidence Explorer

PMID: 18772397 · Science (2008) supporting

Core signaling pathways in human pancreatic cancers revealed by global genomic analyses

Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P

KRASTP53CDKN2ASMAD4 MAPK genomic cohort

Screening Note: Establishes KRAS, TP53, CDKN2A, SMAD4 as core PDAC pathways. Association in tumors is not proof of causal dependence on any single target.

PMID: 25719666 · Nature (2015) supporting

Whole genomes redefine the mutational landscape of pancreatic cancer

Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P

KRASBRCA2CDKN2A DNA damage repair whole-genome sequencing

Screening Note: Replicates core drivers and adds DNA-repair subsets that may modify therapeutic hypotheses.

PMID: 26909576 · Nature (2016) supporting

Genomic analyses identify molecular subtypes of pancreatic cancer

Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC

KRASTP53 expression subtypes integrated genomic analysis

Screening Note: Subtype context (squamous vs progenitor) may stratify MAPK dependence hypotheses.

PMID: 28803728 · Cancer Cell (2017) methodological concern

Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

Cancer Genome Atlas Research Network

KRASTP53CDKN2ASMAD4 MAPK TCGA genomic characterization

Screening Note: Low neoplastic cellularity can confound genomic calls. Interpret KRAS wild-type calls cautiously.

PMID: 23159449 · Nature (2012) supporting

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB

KRASTP53ROBOSLIT axon guidance exome sequencing

Screening Note: Exome sequencing and copy-number analysis of 142 primary PDAC tumors confirmed frequent KRAS, TP53, CDKN2A, and SMAD4 alterations.

ClinicalTrials.gov APIv2 Registry

Three-Study Clinical Trial Comparator

Registry presence is for translational context only and is not proof of clinical safety or efficacy.

NCT ID Title & Sponsor Phase & Status Interventions Primary Outcomes
NCT05737706

Study of MRTX1133 in Patients With Advanced Solid Tumors Harboring a KRAS G12D Mutation

Mirati Therapeutics Inc. · Start 2023-03

 PHASE1, PHASE2
RECRUITING (n=304) 		MRTX1133 Dose-limiting toxicities; Objective response rate
NCT02184195

Olaparib in gBRCA Mutated Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum-Based Chemotherapy (POLO)

AstraZeneca · Start 2015-01

 PHASE3
COMPLETED (n=154) 		Olaparib, Placebo Progression-free survival
NCT02562716

S1505: Combination Chemotherapy or Gemcitabine Hydrochloride and Paclitaxel Albumin-Stabilized Nanoparticle Formulation Before Surgery in Treating Patients With Pancreatic Cancer

SWOG · Start 2016-01

 PHASE2
COMPLETED (n=147) 		mFOLFIRINOX, Gemcitabine, Nab-paclitaxel Overall survival; Resection rate

Stage 3 · Synthesize

Interactive Biomedical Knowledge Graph (PDAC)

Click any entity node below to inspect its biological description, connected edges, and literature provenance.

Selected Node Inspector

KRAS G12D

protein

Constitutively active KRAS oncoprotein; candidate direct target.

Provenance: Waters & Der 2018 PMID 29229669

Provenance Edges

  • PDAC → associated_with → KRAS (PMID 18772397)
  • PDAC → associated_with → TP53 (PMID 18772397)
  • PDAC → associated_with → CDKN2A (PMID 18772397)
  • PDAC → associated_with → SMAD4 (PMID 18772397)
  • KRAS → associated_with → KRAS G12D (PMID 29229669)
  • KRAS G12D → activates → MAPK/ERK (PMID 29229669)
  • MRTX1133 → targets → KRAS G12D (NCT05737706)
  • CDKN2A → associated_with → p16INK4a (PMID 18772397)
  • p16INK4a → inhibits → G1/S cell cycle (PMID 18772397)
  • SMAD4 → associated_with → TGF-β/SMAD (PMID 18772397)
  • MAPK/ERK → studied_in → MAPK PD assay (exp_1)

Stage 4 · Hypothesize

Interactive Hypothesis Evidence-Confidence Scorer

This score is a transparent weighted summary of evidence properties (source quality, replication, relevance, plausibility, recency, and contradiction burden). It is not a probability of truth, clinical validity, treatment effect, or that a hypothesis is correct.

KRAS G12D dependence of MAPK output in PDAC models

Mechanism: Mutant KRAS G12D constitutively GTP-binds and activates RAF-MEK-ERK (MAPK) signaling. Selective inhibition of KRAS G12D is hypothesized to reduce MAPK output and PDAC cell viability in G12D-mutant models, provided the models remain MAPK-dependent.

Model System: KRAS G12D PDAC cell lines and patient-derived organoids, with KRAS WT controls

Expected Observation: Decreased phospho-ERK within 6–24 h and reduced viability over 72–120 h in G12D-mutant models, with limited effect in KRAS WT models.

Falsification Criteria: If phospho-ERK and viability are unchanged in validated G12D-mutant models at exposures that engage KRAS G12D, the hypothesized MAPK dependence is falsified for those models.

Key Unanswered Questions

  • Which PDAC subtypes retain MAPK dependence after KRAS G12D blockade?
  • Does CDKN2A loss modify the apoptotic response to KRAS G12D inhibition?
  • What adaptive resistance programs emerge in organoids?
Live Weighted Calculator 78 / 100

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Stage 5 · Validate & Ethics Governance

Interactive Ethics Gate Simulator

Verify all 5 required ethics & governance items below to unlock transition from Ready to Running.

Experiment: PDX MAPK Pathway Engagement Study (exp_4)

Ethics gate blocked: complete all 5 Required checks before moving to Running.

Experiment Board Queue

In vitro KRAS G12D inhibition panel Priority 84

A. Chen, PI · Stage: ready · 8/8 ethics checks

No human subjects. Cell-line work under institutional biosafety.

Organoid phospho-proteomics after KRAS G12D blockade Priority 72

J. Okonkwo, Computational · Stage: design · 5/8 ethics checks

De-identified organoids; confirm IRB coverage before Running.

Combination screen: KRAS G12D + CDK4/6 inhibition Priority 65

M. Reyes, Translational · Stage: idea · 0/8 ethics checks

Ethics checklist not started — Running stage blocked.

PDX MAPK pathway engagement study Priority 56

A. Chen, PI · Stage: ready · 2/8 ethics checks

IACUC not yet filed — Running is blocked until remaining ethics checks complete.