Back-to-back discoveries from Cleveland Clinic have important implications for patients with an inherited form of aggressive prostate cancer. The studies, published in JAMA Oncology, shed light on how a genetic variant related to testosterone production alters patient response to different types of prostate cancer therapies. Presence and identification of this variant can help predict how individual patients will respond to different therapies and in turn, help clinicians deliver personalized treatment plans. Nima Sharifi, MD, staff, Department of Cancer Biology, Lerner Research Institute, is senior author on both publications.
One of the cornerstone therapies for recurrent prostate cancer is androgen deprivation therapy (ADT). ADT works by blocking prostate cancer's supply of male hormones (androgens) in the testes. It often stops working, however, allowing cancer to progress and spread.
In the first study, Dr. Sharifi and colleagues from Memorial Sloan Kettering Cancer Center and Dana-Farber/Harvard Cancer Center identified that the genetic variant HSD3B1 (1245C), which enables prostate tumors to generate their own androgens for fuel, serves as a useful predictor of outcomes in patients with recurrent prostate cancer.
The researchers retrospectively analyzed 213 men whose prostate cancer recurred after radiation therapy and subsequently underwent ADT. They found for the first time that tumors metastasized much more quickly in men who had the HSD3B1 (1245C) variant.
The second study, performed in collaboration with researchers at University of California, San Francisco, examined a group of 90 men with metastatic cancer that had become resistant to ADT and were later treated with the drug ketoconazole. Ketoconazole blocks the production of androgens outside of the testes, including those developed by prostate cancer cells that are evading ADT treatment.
Surprisingly, men with the genetic anomaly fared better on ketoconazole than men without the variant. This discovery suggests that targeting variant tumors' backup androgen supply, which is external to the testes, may be a successful treatment strategy when ADT fails.
"We hypothesized that HSD3B1 (1245C) variant tumors become resistant to ADT because they have a backup supply of androgens," said Dr. Sharifi. "But it appears relying on these extra-gonadal androgens is what makes them more sensitive to ketoconazole."
While the outlook for patients with the HSD3B1 (1245C) variant is poor, this discovery suggests that blocking back-up androgen supplies outside of the testes is a more effective approach for extending the lives of men with this treatment-resistant metastatic prostate cancer than current therapies.
"We are hopeful that these findings will lead to more personalized and effective treatments for prostate cancer," said Dr. Sharifi. "If men carry a specific testosterone-related genetic abnormality, we may be able to personalize their therapy and treat specific patients more aggressively."
Dr. Sharifi holds the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic and co-directs Cleveland Clinic's Center for Excellence in Prostate Cancer Research, which brings together top researchers and clinicians to speed the translation of lab discoveries into patient care. He is also a member of the Glickman Urological and Kidney Institute and Taussig Cancer Institute.