Overview
Biliary tract cancer (BTC) is a rare, aggressive malignancy with limited treatment options and poor prognosis. It is the first disease-area expansion of the GRIT initiative beyond pancreatic cancer, chosen because RAS-pathway alterations are recurrent and clinically meaningful in BTC.
Our work spans two fronts: understanding what molecular features determine benefit from current chemotherapy, and preparing RAS-directed trials for the roughly one in six BTCs that carry KRAS alterations.
Molecular determinants of chemotherapy benefit
Our first BTC study analyzed clinical and genomic data from patients with advanced disease treated with gemcitabine, cisplatin, and nab-paclitaxel (GAP) versus gemcitabine and cisplatin (GC).
Single-gene mutations did not predict benefit, but pathway-level analysis showed that PI3K-pathway activation was associated with inferior outcomes on GAP — with clinical benefit from GAP confined to patients without PI3K activation, replicated in an independent validation cohort. This establishes molecular stratification as a way to match BTC patients to the right chemotherapy backbone.
RAS-directed BTC (next)
KRAS alterations occur in roughly 16% of biliary tract cancers, making BTC a natural extension of our KRAS-driven vulnerabilities program. Dr. Vincenzo Nasca is leading the translational work, with KRAS-directed BTC trials planned under the GRIT initiative.
The goal is to bring the same degrader and RAS(ON) strategies developed in pancreatic cancer to RAS-mutated BTC, guided by genomic and ctDNA biomarkers.