Targeting the Drivers of Androgen Receptor Pathway-Independent Prostate Cancer
Abstract
Principal Investigator: My prostate cancer (PC) research career began during graduate school, when I discovered that advanced PCs could be identified or even predicted by a specific protein modification called arginylation. My current training goals are to characterize and exploit acquired changes in PC to develop targeted therapies. For the proposed project, I will receive mentorship from Dr. Peter Nelson, a well-established researcher in the PC field. Dr. Nelson has a notable track record in successfully training graduate students and postdoctoral fellows in translational research and advancing their careers to lead independent research groups. Dr. Nelson specializes in cancer genomics and bioinformatics (using computers to analyze the genomics data) to study the acquired changes in advanced PC. Dr. Nelson holds many leadership positions that include directing the PC research groups at Fred Hutchinson Cancer Research Center (Fred Hutch) and leading a multi-institute collaboration of PC researchers across the Pacific Northwest. My training will include courses to develop bioinformatics skills, seminars in ethical research, and frequent presentations of my work within Fred Hutch and at national conferences. Thanks to the unique skills of Dr. Nelson and his laboratory, I will be provided with an excellent opportunity to execute this research plan and address a mechanism contributing to therapy resistance in men with advanced PC. Background and Research Strategy: The first stages of aggressive PC treatment aim to disrupt the androgen receptor (AR), an essential receptor for prostate tumors to survive and grow. This is first accomplished by eliminating the body’s natural androgen supply and then by using drugs that directly inhibit AR’s activity. Though targeting the AR pathway has provided significant clinical benefits, many patients eventually develop PCs that no longer depend on the AR pathway, termed Androgen Pathway Independent Prostate Cancer (APIPC). We recently identified several patients with APIPC that have cancers with significantly elevated activity in a signaling pathway termed the Fibroblast Growth Factor (FGF) pathway. FGF activity stimulates cell growth and may allow the tumor to survive, even after losing AR. However, it is not known how FGF activity becomes increased in APIPC, whether FGF activity is the direct cause of APIPC, or whether APIPC cells depend on FGF activity. Further, the FGF pathway sends growth signals across several growth pathways, such as the MAPK pathway and the PI3K pathway. APIPC tumors with higher FGF activity may depend on these pathways more than normal tumors, making MAPK or PI3K inhibitors more effective. This research proposal will use carefully designed experiments with PC cells and mice harboring live pieces of human prostate metastases to test precisely what role this FGF activity has in APIPC. I will test whether inhibiting the FGF pathway in APIPC shows potential as a future treatment for this subset of patients. Furthermore, I will test how cells may become resistant to FGF pathway inhibition and evaluate potential treatments that may prevent this therapy resistance from occurring. Significance: My proposal addresses the critical need to understand APIPC and identify treatment strategies. From 1998 to 2008, only ~10% of patients with aggressive PC had APIPC. Between 2012 and 2016, that number grew to > 30%. This research will characterize the changes that occur in APIPC cells and promote FGF signaling and establish new APIPC models that may be shared with other researchers. If my hypotheses are correct, this project will develop a new treatment in the growing population of men resistant to the standard anti-AR therapies. It will also lay the groundwork for testing the treatment at the same time as anti-AR therapies in an effort to prevent APIPC from occurring. Several FGF pathway inhibitors, including MAPK and PI3K inhibitors, are currently in clin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010084
Entities
People
- Arnab Bose
Organizations
- Fred Hutchinson Cancer Center
- United States Army