October 12, 2017, Cleveland: Back-to-back discoveries from Cleveland Clinic demonstrate for the first time how a testosterone-related genetic abnormality can help predict individual patient responses to specific prostate cancer therapies.
The studies, published in the October 12 issue of JAMA Oncology, suggest that men who inherit this variant would benefit from a personalized treatment plan that targets specific hormonal pathways.
The research teams, led by Nima Sharifi, M.D., of the Cleveland Clinic Lerner Research Institute, studied the role of the HSD3B1(1245C) genetic variant in two different prostate cancer patient populations, following androgen deprivation therapy (ADT). ADT works by blocking prostate cancer's supply of male hormones in the testes. It is a cornerstone treatment for recurrent prostate cancer, but it often stops working, allowing cancer to progress and spread. In 2013, Dr. Sharifi discovered that prostate cancer cells with the genetic abnormality survive ADT by producing their own androgens.
In the first new study, Dr. Sharifi and colleagues from Memorial Sloan Kettering Cancer Center, Harvard/Dana-Farber Cancer Institute and University of Michigan Comprehensive Cancer Center analyzed 213 men whose prostate cancer recurred after radiation therapy and underwent ADT. They found for the first time that following radiation and ADT, prostate cancer was much more likely to spread–and spread rapidly–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. These patients were subsequently treated with the drug ketoconazole, which blocks the production of androgens outside of the testes (e.g., 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 finding raises the possibility that targeting variant tumors' backup androgen supply (outside of the testes) could be a successful 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. "However, relying on these extra-gonadal androgens makes them more sensitive to ketoconazole."
These discoveries complement earlier studies and support the use of HSD3B1(1245C) as a predictive biomarker to help guide critical treatment decisions. While the outlook of patients with this gene variant is poor, these studies offer hope for a new treatment strategy for these men, and more studies are needed using next-generation androgen inhibitors, such as abiraterone and enzalutamide.
"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 is also a member of the Glickman Urological and Kidney Institute and Taussig Cancer Institute of Cleveland Clinic. He holds the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic and co-directs Cleveland Clinic's Center of Excellence for Prostate Cancer Research. In 2017 he received a Top Ten Clinical Research Achievement award from the Clinical Research Forum for his landmark discovery that men who carry the HSD3B1(1245C) variant are more likely to die from their disease.
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This work was supported by the U.S. Department of Defense, Howard Hughes Medical Institute, Prostate Cancer Foundation, American Cancer Society, the U.S. Army Medical Research and Materiel Command and grants from the National Cancer Institute.
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Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S. News & World Report consistently names Cleveland Clinic as one of the nation's best hospitals in its annual "America's Best Hospitals" survey. Among Cleveland Clinic's 51,000 employees are more than 3,500 full-time salaried physicians and researchers and 14,000 nurses, representing 140 medical specialties and subspecialties. Cleveland Clinic's health system includes a 165-acre main campus near downtown Cleveland, 10 regional hospitals, more than 150 northern Ohio outpatient locations – including 18 full-service family health centers and three health and wellness centers – and locations in Weston, Fla.; Las Vegas, Nev.; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2016, there were 7.1 million outpatient visits, 161,674 hospital admissions and 207,610 surgical cases throughout Cleveland Clinic's health system. Patients came for treatment from every state and 180 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/ClevelandClinic.
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About the Lerner Research Institute
The Lerner Research Institute is home to Cleveland Clinic's laboratory, translational and clinical research. Its mission is to promote human health by investigating in the laboratory and the clinic the causes of disease and discovering novel approaches to prevention and treatments; to train the next generation of biomedical researchers; and to foster productive collaborations with those providing clinical care. Lerner researchers publish more than 1,500 articles in peer-reviewed biomedical journals each year. Lerner's total annual research expenditure was $260 million in 2016 (with $140 million in competitive federal funding, placing Lerner in the top five research institutes in the nation in federal grant funding). Approximately 1,500 people (including approximately 200 principal investigators, 240 research fellows, and about 150 graduate students) in 12 departments work in research programs focusing on heart and vascular, cancer, brain, eye, metabolic, musculoskeletal, inflammatory and fibrotic diseases. The Lerner has more than 700,000 square feet of lab, office and scientific core services space. Lerner faculty oversee the curriculum and teach students enrolled in the Cleveland Clinic Lerner College of Medicine (CCLCM) of Case Western Reserve University – training the next generation of physician-scientists. Institute faculty also participate in multiple doctoral programs, including the Molecular Medicine PhD Program, which integrates traditional graduate training with an emphasis on human diseases. The Lerner is a significant source of commercial property, generating 64 invention disclosures, 15 licenses, 121 patents, and one new spinoff company in 2016. Visit us at http://www.lerner.ccf.org. Follow us on Twitter at http://www.twitter.com/CCLRI.
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