Overview
We deploy genetic and small-molecule screens to systematically interrogate pancreatic ductal adenocarcinoma (PDAC) biology at scale. The goal is to move beyond single-gene hypotheses and let unbiased functional data nominate the targets, combinations, and resistance mechanisms that matter clinically.
Approach
CRISPR-based functional genomics screens identify genetic dependencies and synthetic lethal interactions across PDAC models.
Small-molecule and combination screens map which therapeutic pairings overcome adaptive resistance, informing rational trial design.
Computational pipelines integrate screen hits with clinical genomics so candidate targets are prioritised by translational relevance.
Platforms & methods
Genome-wide and focused CRISPR knockout, CRISPRi, and CRISPRa libraries are screened across patient-derived organoids and cell lines to map context-specific dependencies.
Arrayed and pooled small-molecule libraries — including epigenetic, DDR, and RAS-pathway probes — are combined in synergy matrices to nominate rational pairings.
Hits are triaged through orthogonal validation, isogenic models, and dose-response confirmation before advancing to in-vivo and translational testing.
Why it matters
PDAC is notoriously resistant to monotherapy. Screening lets us pre-empt resistance and assemble combinations before they reach patients, feeding directly into our KRAS and DNA-damage-repair programs.
Open questions
Which dependencies are conserved across the molecular subtypes of PDAC, and which are private to a genetic context such as KRAS dosage or HRD status?
How do screen-nominated vulnerabilities shift under therapeutic pressure, and can we anticipate the adaptive escape routes that drive clinical relapse?