Genetically Directed HSD3B1 Therapeutics for Metastatic Prostate Cancer
Abstract
Prostate cancer is an androgen-driven tumor. Two major sources of androgens (male hormones such as testosterone) are known to drive prostate cancer, and this knowledge has led to the current clinical strategies for the treatment of metastatic prostate cancer. The first source is the gonadal or testicular source that makes testosterone. The long-standing treatment for metastatic prostate cancer had been androgen deprivation therapy (ADT) by medical or surgical castration, which blocks the generation of testicular androgens. The second source is the adrenal gland, which makes DHEA, an androgen that in prostate cancer can be converted to the more potent testosterone and dihydrotestosterone. An enzyme, 3ß-HSD1, which is encoded by the gene HSD3B1, is required for prostate cancer cells to convert DHEA to dihydrotestosterone. The HSD3B1 gene is inherited in two forms: a slow “restrictive” form and a fast “permissive” form. The permissive form allows prostate cancer to make higher levels of testosterone and dihydrotestosterone, promoting tumor progression in patients treated with ADT. In contrast, the restrictive form blocks testosterone and dihydrotestosterone synthesis, and patients have prolonged responses to ADT. This proposal has two overarching goals that address the overarching challenges of developing treatments that improve outcomes for men with lethal prostate cancer and defining the biology of lethal prostate cancer to reduce death. The first goal is to determine whether the permissive and restrictive forms of the HSD3B1 gene can help determine which patient requires what therapy. Currently, there are several treatment options that may be given along with ADT for patients who have a new diagnosis of metastatic prostate cancer, but we have no good method to determine which treatment is best for each patient. We will determine whether genetic analysis of HSD3B1 helps determine which patients benefit most from upfront treatment with enzalutamide, which blocks the downstream effects of the permissive form of HSD3B1. This will allow us to give the individual patient treatments that match his own genetics and biology. This goal is achievable within 2 years. The second goal is to identify a drug that effectively blocks HSD3B1. This genetic factor is a clear driver of prostate cancer in about half of all patients. Therefore, development of a drug that directly blocks this genetic cancer driver is expected to lead to an entirely new and effective treatment option for patients with metastatic prostate cancer. We anticipate this goal is achievable within 3-5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010137
Entities
People
- Nima Sharifi
Organizations
- Cleveland Clinic
- United States Army