Targeting Fibroblast Growth Factor Receptors in Preclinical Patient-Derived Xenograft Models of CRPC
Abstract
Prostate cancer cells require androgen receptor (AR), a protein that uses testosterone and other similar hormones to turn on cell growth and survival functions. Prostate cancer treatment strategies focus on using drugs that block the AR protein, thereby preventing cancer cell growth and survival. Unfortunately, resistance to AR blocking therapies occurs over time causing tumors to reappear or begin growing again. The factors controlling growth and survival in cells with blocked AR protein are poorly understood. Our previous experiments showed that a subset of tumor cells turn off AR protein production and instead use fibroblast growth factor receptor (FGFR) protein to sustain themselves. However, whether or not FGFR protein is important for survival in tumor cells that still produce AR protein remains to be determined. The objective of this proposal is to support the use of FGFR blockers in combination with AR blocking therapy in men with treatment-resistant prostate cancer. We hypothesize that prostate cancer cells with AR protein become resistant to AR blocking therapy by using the FGFR protein for survival. Thus, blocking both AR and FGFR proteins at the same time will stop tumor cell growth and survival. In this proposal, AR and FGFR blocking therapies will be used alone or in combination in cell-based assays and preclinical animal models to examine the efficacy of treatments and the mechanisms of treatment resistance. The vast majority of treatment-resistant prostate tumors still produce AR protein, and current therapeutic options are limited and ineffective. If correct, completion of the proposed project could impact a significant proportion of all men with late-stage prostate cancer by providing compelling evidence for human clinical trials using combination FGFR and AR blockers. Importantly, FGFR blockers are readily available, and several have already been approved for treatment of other diseases. Consequently, a clinical trial designed to evaluate the efficacy of combination FGFR and AR blockers in prostate cancer could be achieved rapidly. My training will occur in the research groups of Dr. Colm Morrissey, PhD, at the University of Washington and Dr. Peter Nelson, MD, at the Fred Hutchinson Cancer Research Center. Dr. Morrissey is a research scientist who is adept at investigating the molecular mechanisms of treatment resistance in advanced prostate cancer. Dr. Nelson is a renowned medical oncologist with extensive experience in translational and clinical prostate cancer research. Together, we have developed a comprehensive development plan that includes weekly meetings with each mentor to guide experimental approaches, interpret data, and advise on career development, as well as yearly conferences to present data and foster multidisciplinary relationships. Importantly, access to (1) biospecimens and preclinical animal models through Dr. Morrissey; (2) advanced molecular biology platforms through Dr. Nelson; and (3) a multidisciplinary and collaborative training environment through the Seattle prostate cancer research program will be critical for completion of the proposed project and will engender a diversity of “cell to society” experiences that will prepare me for a career at the forefront of translational prostate cancer research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910729
Entities
People
- Mark P Labrecque
Organizations
- United States Army
- University of Washington