Research Abstract
Dr. Bardeesy's lab studies the basic mechanisms of malignant growth of hepatobiliary and pancreatic cancer controlled by key oncogenic mutations and investigates targeting these pathways. This work is facilitated by the development and use of a series of genetically engineered mouse (GEM) models and patient-derived models. He has extensive leadership experience in programmatic initiatives in this area, serving as co-PI of the Dana-Farber Harvard Cancer Center SPORE in Gastrointestinal Cancer, PI of two DOD Translational Team Science Awards on cholangiocarcinoma, Project Leader in a long- standing Program Project Grant (NCI/P01) on the pancreatic cancer biology, and formerly, co-Director of the Scientific Advisory Board of the Cholangiocarcinoma Foundation.
Dr. Bardeesy and colleagues across the Harvard system have created a comprehensive translational discovery pipeline for cholangiocarcinoma. They have made a concerted effort to expand the studies of this cancer, by increasing the number of clinical trials for this disease and establishing a strong basic science and translational infrastructure, supported by robust model development effort. His lab has made important discoveries regarding two major oncogenic drivers in the disease, FGFR2 and IDH. The team uncovered the mechanisms of clinical acquired resistance in patients with treated with FGFR inhibitors, elucidated downstream signaling programs, and identified combination therapies utilizing novel model systems (Cancer Discovery [Goyal, 2017; Goyal, 2019; Cleary, 2021; Wu Q, 2022; and Nature Comm. [Zhen, 2024]). Work on mutant IDH1, the most frequently mutated metabolic enzyme across cancers, elucidated the functions of this oncogene and the mechanism of therapeutic response to its inhibition. The team demonstrated that mutant IDH1 drives immune-evasion and subverts differentiation programs to support tumor growth and defined the molecular circuits underlying response and resistance to mutant IDH1 inhibition including regulation of immune interplay (Saha, Nature, 2014; Cleary, NPJ Precision Onco 2022, Wu MJ, Cancer Discovery, 2022, Wu, Science 2024).
Other pioneering work has established the Salt-Inducible Kinases as major tumor suppressors downstream of oncogenic PKA signaling and revealed their functional inactivation as the central pathogenic mechanism for pancreatic tumors driven by mutant GNAS (Patra, Nature Cell Biol. 2018), and fibrolamellar liver cancers driven by the DNAJB1-PRKACA fusion (Gritti, Cancer Discovery, 2024).