The development of castration-resistant prostate cancer (CRPC) occurs in large part by tumors acquiring the capability of synthesizing their own supply of 5α-dihydrotestosterone (DHT) from nongonadal sources, particularly from adrenal precursors. The role and requirement for intratumoral DHT synthesis in the development of CRPC is evident from the efficacy of next-generation hormone therapies that have entered into clinical practice. This includes abiraterone acetate, which blocks androgen synthesis, and enzalutamide, which is a potent androgen receptor antagonist.
Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy
Despite the long-recognized phenomenon of elevated androgens in CRPC, no mutation has yet been described that is responsible for increasing DHT synthesis.
At Cleveland Clinic, oncologist Nima Sharifi, MD, has identified the first such example of a genetic alteration that increases the conversion of precursor steroids to DHT, permitting tumors to grow in the absence of gonadal testosterone. Dr. Sharifi is an associate staff member of the Taussig Cancer Institute’s Department of Solid Tumor Oncology, and of the Glickman Urological & Kidney Institute’s Department of Urology,
Mutation opens DHT synthesis floodgates
The enzyme 3β-hydroxysteroid dehydrogenaseisoenzyme-1 (3βHSD1) is required for the first and rate-limiting step in the conversion of adrenal dehydroepiandrosterone (DHEA) en route to DHT. A mutation occurs in 3βHSD1 in a subset of human CRPC tumors that blocks degradation of this enzyme, increasing the amount of enzyme available in the cell and resulting in an increase in the flow of precursor steroids to DHT.
The essential consequence is that this mutation opens the floodgates to DHT synthesis, permitting tumors to grow in the absence of gonadal testosterone.
Dr. Sharifi found not only that this mutant 3βHSD1 occurs in human CRPC tumors, but also that it occurs in a mouse model of resistance to abiraterone acetate. Current studies are aimed at determining whether clinical resistance to abiraterone acetate and enzalutamide is attributable in part to 3βHSD1 mutations.
Future research directions
In addition to the 3βHSD1 mutation that occurs in tumors with the development of CRPC, the same genetic alteration exists as an inherited germline variant. In this form, it is possible that this germline variant plays a part in upfront resistance to hormonal therapy.
Other ongoing studies will identify how germline variant inheritance regulates androgen metabolism in localized prostate cancer. It is conceivable that upfront genetic information on hormone therapy response/resistance may help determine the best treatment modality for a specific patient.
First-of-its-kind research investigates the viability of standard screening to reduce the burden of late-stage cancer diagnoses
Study demonstrates ability to reduce patients’ reliance on phlebotomies to stabilize hematocrit levels
Findings highlight an association between obesity and an increased incidence of moderate-severe disease
Cleveland Clinic Cancer Institute takes multi-faceted approach to increasing clinical trial access
Key learnings from DESTINY trials
Gene editing technology offers promise for treating multiple myeloma and other hematologic malignancies, as well as solid tumors
Study of 401,576 patients reveals differences in cancer burdens as well as overall survival
Enfortumab plus pembrolizumab reduced risk of death by 53% compared with platinum-based chemotherapy
