Defining and Exploiting the Molecular and Cellular Responses to Supraphysiological Androgens for Prostate Cancer Treatment
Abstract
Scientific Objective and Rationale: Prostate cancer (PC) is a major health issue in the U.S. Metastatic PC (mPC) that has spread beyond the prostate is essentially incurable. A notable feature of mPC is the activity of a signaling program comprising the hormone testosterone and the androgen receptor (AR) which is activated in tumor cells by testosterone. The AR drives PCs to survive and grow. Therapies designed to eliminate testosterone in the blood – androgen deprivation therapy (ADT) – or block the activity of the AR – AR signaling inhibitors, are first-line therapies for most men with mPC and these approaches produce excellent initial responses. However, ADT and ARSIs do not cure patients with mPC; these tumors essentially always recur to a clinical state termed castration resistant PC (CRPC). Though cancer control is initially achieved, ADT and ARSIs have substantial effects on quality of life and other aspects of health. Surprisingly, a strategy for treating patients resisting ADT and ARSI therapy is to give back high doses of testosterone – termed supraphysiological androgen therapy (SPA). SPA can enigmatically inhibit the abnormal functions of AR, but not its critical normal activities. However, SPA is not effective in all patients (~50%), and the mechanisms responsible for SPA anti-tumor effects remain poorly understood. My doctoral work revealed that SPA can activate an innate anti-viral response in PC cells that is normally designed to attack viral pathogens within a cell. Notably, the anti-viral reaction in cells can cause tumor cell death; however, the full-extent of the anti-cancer effects of this process remain unanswered. With this background, the objectives of this research project are to: (1), rigorously evaluate anti-cancer effects of SPA-mediated anti-viral responses in clinically relevant models of PC (patient-derived tumors on dish and in mice) and determine whether potential abnormalities in other cellular material such as DNA (the cell’s instruction manual) and proteins (the cell’s action molecules) can affect this response; (2) fully characterize the SPA-mediated anti-viral response in PC cells, aiming to precisely understand the process involved in the activation of this reaction by cancer cells; and (3) investigate other drugs that can maximize anti-cancer activities of SPA. Applicability of Research: The overall concept and strategy comprising this study is original, and it is based on research that I conducted. If successful, the results may enhance the depth and duration of responses to SPA in PC patients who are no longer responding to conventional therapies. The goal of this research is to further our understanding of SPA-mediated anti-cancer effects, with a focus on anti-viral responses, to develop novel therapeutic strategies such as new drug combinations that can avert the development of resistance to SPA in therapy responder patients and overcome resistance to SPA in patients who have failed SPA. Results of these studies will contribute vital information towards personalized therapeutic strategies for patients. Success in these aims could profoundly influence how SPA is administered to patients with advanced PC in the clinic. Principal Investigator’s Goals in Prostate Cancer Research: My overall career ambition is to become an independent scientist leading a world-class team to deliver impactful research for clinically relevant issues in the field of PC research, particularly in the area of molecular endocrinology. My ultimate research goal is to maximize the quantifiable aspects of this disease (e.g., overall survival and therapy response) and minimize the qualitative side effects of current therapies (e.g., stress, fatigue), which significantly influence the quality of life. Clinical trials (e.g., NCT02090114, NCT02286921) have revealed that SPA-based therapy can produce substantial and durable responses in patients who are not responding to conventional therapie
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310102
Entities
People
- Reza Alizadeh Ghodsi
Organizations
- Fred Hutchinson Cancer Center
- United States Army