Targeting 3beta-HSD1 phosphorylation to reverse prostate cancer hormone therapy resistance
Abstract
Scientific Objective: Prostate cancer is the most common malignancy in men and the second leading cause of cancer-related death in men in the United States. Prostate cancer is driven by androgens, and androgen deprivation therapy (ADT) by medical or surgical castration is the front-line treatment. However, ADT eventually fails, and disease almost always progresses as castration-resistant prostate cancer (CRPC). Nearly all prostate cancer deaths are due to CRPC. Intratumoral androgen synthesis is required to drive CRPC progression. The enzyme 3betahydroxysteroid dehydrogenase type 1 (3B-HSD1) is likely a critical gatekeeper that provides tumors with the ability to harness androgens. 3B-HSD1 has been mechanistically linked to CRPC and is associated with prostate cancer resistance to ADT. Recently, we reported that an inherited variant of the gene HSD3B1 regulates abiraterone treatment effects of another treatment (abiraterone) and affects prognosis. Therefore, targeting 3BHSD1 activity might be a new strategy for CRPC treatment that improves CRPC prognosis. Adding a phosphate molecule to protein (phosphorylation) modifies the protein function and is mediated by kinase enzymes. My preliminary work shows that 3B-HSD1 is most likely phosphorylated. 3B-HSD1 is critical to androgen synthesis and prostate cancer growth, but how phosphorylation might enable this is unknown. My preliminary studies also show that, in prostate cancer cell lines, Compound C, an inhibitor of AMP-activated protein kinase (AMPK), inhibits 3B-HSD1 activity without affecting its expression, but decreases its phosphorylation. Furthermore, deletion of AMPK in prostate cancer cells inhibits 3B-HSD1 activity and androgen synthesis. Taken together, these findings suggest that phosphorylation of 3B-HSD1 is important to its activity and that the regulatory kinase may be a potential treatment target. Hypothesis: I hypothesize that phosphorylation of 3B-HSD1 modifies its function and the phosphorylation or regulatory kinase promotes CRPC. If so, targeting the phosphorylation or kinase could be a new strategy for CRPC treatment. Applicability: If my hypothesis is correct, this investigation will provide entirely novel insights to regulation of 3B-HSD1 in prostate cancer and aid in development of biomarkers for response and resistance to standard therapies and discovery of new treatment strategies. Career Goals: My professional goal is to lead an academic research laboratory that focuses on the role of androgen synthesis in prostate cancer and the discovery of new therapeutic targets. During my PhD research, I focused on identifying new treatment targets for colon cancer. This experience enabled me to gain expertise in biochemistry, which is essential for the research I propose here. After receiving my Ph.D., I joined Dr. Nima Sharifi’s research team at the Cleveland Clinic, which includes both PhD scientists and graduate students as well as clinical urology and oncology trainees. Dr. Sharifi is a medical oncologist who leads a translational prostate cancer research program and identified the first gain-of-function mutation of HSD3B1 in the androgen synthesizing machinery that is responsible for CRPC. He identified a novel abiraterone metabolite, delta-4-abiraterone, which is present in patients with CRPC treated with abiraterone acetate and has more potent anti-tumor activity than abiraterone itself. He also showed that fine-tuning abiraterone metabolism benefits patients. He identified a possible mechanism that explains the finding that the glucocorticoid receptor pathway confers resistance to enzalutamide. This combination of clinical insight and extensive scientific knowledge of steroid metabolism will be of enormous benefit in the proposed research and is especially suited for moving this project toward clinical translation, as well as preparing me to make valuable contributions to the field and to transition to a successful inde
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010093
Entities
People
- Xiuxiu Li
Organizations
- Cleveland Clinic
- United States Army