Testosterone-Related Genetic Mutation Leads to Deadlier Outcomes In Prostate Cancer

Cleveland Clinic, Mayo Clinic researchers identify biomarker that could predict response to treatment, guide personalized cancer care

A team of Cleveland Clinic-Mayo Clinic researchers has shown for the first time that patients with advanced prostate cancer are more likely to die earlier from their disease if they carry a specific testosterone-related genetic abnormality.

The findings, published in the September 2016 edition of The Lancet Oncology, suggest that a specific, inherited polymorphism, or inherited genetic change, in the HSD3B1 gene renders standard therapy for metastatic prostate cancer less effective. The researchers anticipate that the findings will lead to a simple blood test to detect the presence of the polymorphism, personalizing cancer treatment and indicating which patients may need more aggressive treatment.

The team, led by Cleveland Clinic’s Nima Sharifi, M.D., studied three groups of men at Cleveland Clinic and Mayo Clinic who were treated with androgen deprivation therapy (ADT, also known as “medical castration”), the standard of care for treatment of metastatic prostate cancer.

Because prostate cancer cells use male androgens for fuel, ADT is used to “starve” the tumor of its energy supply. While the treatment is widely successful in many patients, eventually prostate tumors are able to circumvent ADT, and patients become resistant to the treatment because the tumors make their own androgens. In 2013, Dr. Sharifi discovered that this resistance is caused by a single nucleotide polymorphism (SNP) in the HSD3B1 gene, which encodes an enzyme that is crucial to the androgen synthesis process. The altered enzyme enables prostate cancer cells to generate more of their own androgens when treated with ADT, enhancing the cancer’s ability to flourish and spread.

In the current study, Dr. Sharifi and colleagues sequenced the HSD3B1 gene in 443 men in three different cohorts who had undergone ADT and recorded their outcomes. They found a strong correlation between the presence of the SNP HSD3B1 (1245C) and poorer survival (progression-free, distant metastasis-free, and overall survival). In addition, they found that patients who had inherited two copies of the gene with the polymorphism (homozygotes) fared much worse than those who had only inherited one allele (heterozygotes), suggesting that the extra copy of the polymorphism leads to increased rogue androgen synthesis.

These results confirm the researchers’ previous mechanistic findings about HSD3B1 (1245C) and suggest that the polymorphism is a strong predictor of which patients will develop resistance to ADT.

“A simple blood test could allow us to personalize therapy by telling us which patients need to be treated more aggressively, such as with more intensive hormonal therapy,” said Dr. Sharifi. “On the contrary, patients with metastatic cancer who do not carry the polymorphism may fare better with ADT alone.” Dr. Sharifi is on the medical staff in Cleveland Clinic’s Lerner Research Institute Department of Cancer Biology, Glickman Urological & Kidney Institute, and Taussig Cancer Institute. He also holds the Kendrick Family Endowed Chair for Prostate Cancer Research.

“We are in the early stages of a clinical trial here at Cleveland Clinic that will test alternative treatments for prostate cancer patients who have inherited HSD3B1 (1245C),” said Eric Klein, M.D., co-author, chair of Cleveland Clinic’s Glickman Urological & Kidney Institute, and holder of the Andrew C. Novick, M.D., Distinguished Chair in Urology.

According to the American Cancer Society, prostate cancer is the second leading cause of death in men in the United States, killing one out of every 39 American men.

This work was supported by Cleveland Clinic, the U.S. Department of Defense Congressionally Directed Medical Research Programs, the Prostate Specialized Program of Research Excellence, the Gail and Joseph Gassner Development Funds, a Howard Hughes Medical Institute Physician-Scientist Early Career Award, the Prostate Cancer Foundation, an American Cancer Society Research Scholar Award, and additional grants from the National Cancer Institute (R01CA172382, R01CA190289, and R01CA168899).

About Cleveland Clinic

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 49,000 employees are more than 3,400 full-time salaried physicians and researchers and 14,000 nurses, representing 120 medical specialties and subspecialties. The Cleveland Clinic health system includes a 165-acre main campus near downtown Cleveland, nine community 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 2015, there were 6.6 million outpatient visits, 164,700 hospital admissions and 208,807 surgical cases throughout the Cleveland Clinic health system. Patients came for treatment from every state and 180 countries. Visit us at www.clevelandclinic.org.  Follow us at www.twitter.com/ClevelandClinic.

About the Lerner Research Institute

The Lerner Research Institute (LRI) 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. In 2015, LRI researchers published nearly 600 articles in high-impact biomedical journals (top 10% of all biomedical journals).  LRI’s total annual research expenditure was $251 million in 2015 (with $104 million in competitive federal funding). Approximately 1,200 people (including approximately 150 principal investigators, 200 research fellows, and about 100 graduate students) in 12 departments work in research programs focusing on cardiovascular, cancer, neurologic, musculoskeletal, allergic and immunologic, eye, metabolic, and infectious diseases. The LRI has more than 700,000 square feet of lab, office, and scientific core services space. LRI 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 LRI is a significant source of commercial property, generating 54 invention disclosures, 14 licenses, and 76 patents in 2015.

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