Desai Sethi Research Team Identifies How to Reverse the Genetics of Poor Prostate Cancer Outcomes
Article Summary
- Desai Sethi Urology Institute researchers contributed to a study that helps resolve a therapy path for prostate cancer patients with a gene mutation that shortens survival.
- The study showed that participants with the adrenal-permissive HSD3B1 allele had more favorable survival outcomes when treated with androgen deprivation therapy (ADT) plus enzalutamide or ADT plus nonsteroidal antiandrogen.
- Desai Sethi Scientific Director Dr. Nima Sharifi helped discover the HSD3B1 genotype more than 10 years ago.
A University of Miami Miller School of Medicine research team led by Desai Sethi Urology Institute (DSUI) Scientific Director Nima Sharifi, M.D., contributed significantly to a study that helps resolve a therapy path for prostate cancer patients who have inherited a specific gene mutation that otherwise shortens survival.
A genetic analysis of the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial showed that prostate cancer patients with the adrenal-permissive HSD3B1 allele had more favorable survival outcomes when treated with androgen deprivation therapy (ADT) plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with study participants who did not have the gene.
The results of the study were published in The Journal of Clinical Investigation today.
“We have been studying how this gene drives prostate cancer for over a decade,” said Dr. Sharifi, a professor of urology at the Miller School and Sylvester Comprehensive Cancer Center member. “When we look at the statistics, 50 percent of men who have this inherited, androgen-driving gene are faced with a poorer prognosis. Our findings show that these poor outcomes can be successfully reversed with specific, intensified treatment.”
HSD3B1 Produces Active Androgens in Prostate Cancer
Dr. Sharifi helped discover the HSD3B1 genotype more than 10 years ago. In a paper he authored for Cell in 2013, Dr. Sharifi and team showed HSD3B1 stimulates local production of active androgens in prostate cancer. His team’s additional studies found about half of men with prostate cancer have the adrenal-permissive HSD3B1 genotype and are more likely to rapidly develop castrate-resistant disease and have worse outcomes.
Dr. Sharifi’s work spurred a genetic analysis in the ENZAMET trial to look for therapeutic solutions to the HSD3B1 conundrum. Prostate cancer progression depends on androgen receptor signaling. ADT, a type of hormone therapy, exploits this dependency. But ADT alone proved less effective for prostate cancer patients with the hyperactive HSD3B1 allele.
A Better Course of Prostate Cancer Treatment
The ENAZMET study found a better way, as participants who usually have worse outcomes attributable to HSD3B1 inheritance actually have better outcomes with upfront treatment intensification that blocks adrenal androgens.
“This is a very positive step forward in the understanding the genetics of advanced prostate cancer at a clinical level,” Dr. Sharifi said. “We need to continue to pursue these findings to better focus clinical trials in the future so we can develop more targeted and effective therapies that best treat advanced prostate cancer to reduce mortality and improve survival.”
According to the American Cancer Society (ACS), prostate cancer is the second-leading cause of death of American men. ACS estimates that nearly 300,000 men in the U.S. will be diagnosed with prostate cancer in 2024 alone, with more than 35,000 dying due to the disease.
“Treating prostate cancer is complex, with many variables that influence a course of action for patients,” said study co-author Ian Davis, Ph.D., a medical oncologist and professor of medicine at Monash University. “Our research findings enable us to better assess specific genetic factors for men living with advanced prostate cancer that ultimately gives us more power to predict a patient’s response to treatment to help improve their survival outcomes.”
The ENZAMET trial is led by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group and sponsored by the University of Sydney, in collaboration with the Canadian Cancer Trials Group, Dana-Farber Cancer Institute, and Cancer Trials. The University of Sydney NHMRC Clinical Trials Centre provided central study coordination. Astellas Pharma provided drug and financial support but was not involved in study design, conduct or data analysis.
Tags: cancer research, Department of Urology, Desai Sethi Urology Institute, Dr. Nima Sharifi, genetic variants, prostate cancer