Pharmacologic Dose Testosterone to Treat Castration-Resistant Prostate Cancer: Mechanisms of Action and Drivers of Response
Abstract
If successful, this project will directly benefit men with prostate cancer by furthering the development of high-dose (i.e., pharmacologic) testosterone as a treatment option for men with advanced prostate cancer. Past studies have documented that under certain conditions, high doses of testosterone can actually inhibit prostate cancer cell growth. Based on these observations, we launched a clinic trial testing high-dose testosterone in men with advanced prostate cancer. This study showed that approximately half of those enrolled had PSA (prostate-specific antigen) declines and half had tumor shrinkage on CT (computer tomography) scans. Given the potential for testosterone to fuel prostate cancer progression, however, it is imperative that we work to understand why some prostate cancers regress when exposed to high doses of testosterone. If successful, this project will provide critical insights into (i) which patients are most likely to benefit from pharmacologic doses of testosterone and (ii) the mechanisms driving these responses. As a result of this deeper understanding, I will design future trials to test high-dose testosterone in men I predict will have the best response to this type of treatment. In addition, through understanding what drives these responses, I will be able to develop clinical trials combining high-dose testosterone with other drugs to enhance its activity. In order to achieve the aforementioned goals, I will enroll men with prostate cancer onto an ongoing clinical trial testing intermittent, high-dose testosterone (Bipolar Androgen Therapy or BAT). These patients will be asked to donate blood and/or tissue so that we can achieve the goals laid out above. This research proposal has three aims. First, we will assess the ability of several candidate biomarkers to predict for a response to high-dose testosterone. These studies will include the use of next-generation sequencing technologies. Second, we will determine if patient-specific differences in how testosterone is transported within cells influences response to high-dose testosterone. Finally, we will perform experiments in mouse models of prostate cancer to determine if other drugs can enhance the efficacy of high-dose testosterone and to determine the optimal dosing schedule of high-dose testosterone. The completion of this research project promises to benefit men with prostate cancer by furthering the development of high-dose testosterone as a viable alternative to the plethora of drugs that act solely to inhibit the effects of testosterone. My career goal is to become a productive clinician-scientist working at the interface of translational cancer research, with the primary objective of developing new therapeutic strategies that reduce the morbidity and mortality attributable to prostate cancer. Through this mentored Physician Research Training Award, I aim to further develop and hone the skills critical for conducting rigorous, impactful, and ethically sound clinical research that is supported by strong basic science. To this end, I will (i) establish an intensive didactic training program; (ii) design and conduct early phase translational clinical trials; and (iii) exploit findings from these trials to discover new pathways, targets, and strategies capable of improving prostate cancer outcomes. This Training Award will allow me to develop a deep understanding of prostate cancer biology, learn important aspects of trial design, enhance my skills in the art and science of prostate cancer care, acquire skills in managing a research team, and develop a foundation that I will use to sustain a productive and impactful career in prostate cancer research and treatment. My mentor, Dr. Peter Nelson, is a medical oncologist and internationally recognized expert in the field of prostate cancer. His research focuses on cancer genomics, androgen receptor biology, and clinical trials of new therapeutics -- making him an ideal mento
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610484
Entities
People
- Michael T Schweizer
Organizations
- United States Army
- University of Washington