FCF Funded Projects

Flipping the switch on PKA: synthetic lethal approaches to block PKA-driven tumor growth in fibrolamellar liver cancer

Status: Completed

Timeframe: 2016 – 2019

Goal: Understand growth mechanisms and identify potential therapeutic targets

Principal Investigators: John Gordan. M.D., Ph.D, Clinical Instructor, University of California San Francisco; Nabeel Bardeesy, Ph.D, Associate Professor, Harvard University

The discovery of a genetic change in the protein kinase A (PKA) gene in nearly all cases of fibrolamellar liver cancer (FLC) creates hope that targeted therapy against PKA will have potent effects for FLC patients. However, progress has been limited due to the relative scarcity of established model systems and the current lack of an effective anti-PKA drug. PKA is a component of the G protein-coupled receptor (GPCR) pathway, which is thought to play a role in many other cancer types. However, little is known about how this pathway makes tumors grow, and if it creates any specific liabilities in tumor cells that can be effectively targeted even when PKA is still active. The study team hypothesized that common mechanisms support the growth of different cancers where PKA is abnormally activated and that deciphering these mechanisms will lead to new treatment strategies for FLC.

This study applied cutting-edge proteomic methods to comprehensively map biochemical processes controlled by GPCRs and PKA across a number of cancer cell lines. These efforts were complemented with genetic approaches to identify other genes essential for PKA-driven cancer growth. Finally, newly developed FLC models were used to test key targets identified with our screening techniques. By identifying and rigorously testing the importance of the mediators of PKA signaling in FLC, the study hoped to lay groundwork for the repurposing of existing drugs to accelerate progress in the treatment of patients with FLC.