Home » FAQs » University of California San Francisco and Harvard University, Cambridge, MA
University of California San Francisco and Harvard University, Cambridge, MA
Targeting DNAJB1-PRKACA Driven Signaling Dependencies in Fibrolamellar Liver Cancer 2019 – 2021
Principal Investigator: John Gordan, MD, PhD, Assistant Professor, Department of Medicine, UCSF
Co-Investigator: Nabeel Bardeesy, Associate Professor, Massachusetts General Hospital, Harvard University
Even with the identification of a near universal DNAJB1-PRKACA gene fusion (encoding a chimeric protein with a domain of heat shock protein 40, HSP40, fused to most of the enzymatically active subunit of protein kinase A, PKAc) as sufficient to trigger fibrolamellar liver cancer (FLC), no treatments directed at this target are clinically available, and most patients with FLC receive cytotoxic chemotherapy. In particular, no PKA inhibitors ready for human studies are yet in hand.
Over the past two years, we have mapped the signaling cascade downstream of PRKACA in FLC and other tumors. This analysis highlights Aurora Kinase A (AURKA) as a key mediator of oncogenic growth. AURKA is best known for regulating the cell cycle, but also promotes cell survival and the expression of oncogenic genes (i.e., those that contribute to cancerous growth). Most conventional AURKA inhibitors fail to strongly inhibit the growth of human FLC cells. This finding seems consistent with limited activity observed with such a drug in clinical trials. However, colleagues at UCSF described a novel class of AURKA inhibitors designed to disrupt its interaction with members of the MYC family of oncoproteins, which are critical drivers of many cancers. We find that one of these new AURKA inhibitors does potently reduce proliferation of FLC cells. The drug also reduces expression of MYC-family oncogenic transcription factors. We hypothesize that AURKA-mediated stabilization of MYC is necessary to maintain growth of FLC cancer cells. Although these new AURKA inhibitors are not yet ready for human use, by studying them now we can understand if they are likely to be effective for FLC and whether they work well in combination with other available drugs. We plan to assess the activity and mechanism of conformation disrupting AURKA inhibitors in FLC laboratory models, including human tumors grown in mice, with the goal of identifying a drug in this class that could be advanced to clinical testing in FLC patients.
[Note that the original grant to U Washington with Ray Yeung as PI does not seem to have been listed on the web site. I suggest using the original lay Abstract, with minor edits. MEF]
Flipping the switch on PKA: synthetic lethal approaches to block PKA-driven tumor growth in fibrolamellar liver cancer 2016 – 2019
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 most cases of fibrolamellar liver cancer (FLC) creates hope that targeted therapy against PKA will have potent effects for FLC patients. However, progress is impeded by 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. We hypothesize 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.
In this project, we will apply cutting-edge proteomic methods to comprehensively map biochemical processes controlled by GPCRs and PKA across a number of cancer cell lines. We will complement these efforts with genetic approaches to identify other genes that are essential for PKA-driven cancer growth. Finally, we will use newly developed FLC models to test key targets identified with our screening techniques.
By identifying and rigorously testing the importance of the mediators of PKA signaling in FLC, we will be positioned to repurpose existing drugs to accelerate progress in the treatment of patients with FLC.