The Role of DHEAS in Abiraterone-Resistant Prostate Cancer
Abstract
Scientific Objective: Prostate cancer (PCa) is a leading cause of cancer deaths in American men and is responsible for 27,000 deaths annually. PCa is driven by androgens (male hormones like testosterone and dihydrotestosterone), which cause androgen receptor signaling that results in cellular activity that fuels cancer cell growth. The first line of treatment for advanced PCa is androgen deprivation therapy. Androgen deprivation therapy lowers the levels of androgens in the bloodstream to an extent that mimics the levels observed with castration. Despite initial success with androgen deprivation therapy, resistant PCa develops within 24 months of treatment; this state is termed castration-resistant PCa (CRPC) and remains primarily driven by androgens. Abiraterone acetate is a second-line therapy used to treat patients who have developed CRPC. Abiraterone acetate works by reducing the amount of androgens produced by the adrenal system during CRPC, namely dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS). Although tumors respond well to abiraterone acetate, patient survival is prolonged by only about 4-5 months before secondary resistance develops. Recently, new studies highlighted the benefits of using abiraterone acetate as a first-line treatment for advanced PCa in combination with androgen deprivation therapy, showing the importance of continued efforts to understand why abiraterone resistance occurs. Despite abiraterone acetate’s ability to reduce the amount of adrenal androgens in the bloodstream, a significant amount of DHEAS remains. Although DHEA can easily enter PCa cells and be metabolized for androgen receptor signaling, it is unknown whether DHEAS can enter the cell for this purpose. Our preliminary data indicate that (1) abiraterone-resistant prostate cells have the machinery to transport and utilize DHEAS and (2) loss of HSD3B1, a gene that encodes 3ßHSD1 (an essential enzyme for DHEA metabolism to dihydrotestosterone), affects DHEAS uptake. I hypothesize that residual DHEAS serves as the major remaining androgen pool in abiraterone-resistant PCa. To answer this question, I will (1) determine the role that DHEAS uptake and HDSD3B1 expression play in AR signaling in long-term abiraterone-treated cells, (2) define DHEAS metabolism to dihydrotestosterone in abiraterone-resistant cells, and (3) identify genetic modifiers of abiraterone-resistant PCa. In probing the role of DHEAS as a source of androgens, this research will illuminate a poorly understood mechanism of CRPC tumors that are resistant to second-line therapy. Applicability and Contribution to PCa Research: This project can contribute to saving the lives of thousands of CRPC patients every year. Nearly all of the PCa deaths occur because resistance develops to currently available therapies. This project will investigate a poorly understood potential mechanism of abiraterone resistance in PCa by investigating PCa cell utilization of residual serum DHEAS as a source of androgens. Further elucidation of the role of abundant DHEAS is an important step in determining how to address the development of treatment resistance, the principal obstacle to effective CRPC treatment. Currently, CRPC and abiraterone-resistant PCa are incurable. Understanding key drivers of resistance will move the field forward toward more effective treatments. Career Goals: My goal is to become an independent PCa researcher who can make a substantive impact in the study of CRPC. This project will provide me with the skills in studying androgen uptake and metabolism in the context of CRPC that I need to become independent. While developing my technical skills, I will improve my written and oral communication, leadership, mentorship, and teamwork skills by attending meetings and workshops and participating in professional development organizations. My prior experience in drug development and characterization, combined with the experience gained fro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810163
Entities
People
- Kelsey Bohn
Organizations
- Cleveland Clinic
- United States Army