Researchers find prostate cancer drug byproduct can fuel cancer cells
June 25, 2018, Cleveland: A genetic anomaly in certain men with prostate cancer may impact their response to common drugs used to treat the disease, according to new research at Cleveland Clinic. The findings may provide important information for identifying which patients potentially fare better when treated with an alternate therapy.
In a newly published study in Journal of Clinical Investigation, researchers found that abiraterone, a common prostate cancer drug, yields high-levels of a testosterone-like byproduct in men with advanced disease who have a specific genetic variant.
The study's lead researcher, Nima Sharifi, M.D., Cleveland Clinic Lerner Research Institute Department of Cancer Biology, previously discovered that men with aggressive prostate cancer who have a specific variant in the HSD3B1 gene have poorer outcomes than patients without the variant. HSD3B1 encodes an enzyme that allows cancer cells to use adrenal androgens for fuel. This enzyme is overactive in patients with the variant HSD3B1(1245C).
In the new study, Dr. Sharifi and his team, including first author Mohammad Alyamani, Ph.D., found that men with the genetic anomaly metabolize abiraterone differently than men without the variant.
"We are hopeful these finding will lead to us being able to better tailor prostate cancer treatments based on a patient's specific genetic make-up," said Dr. Sharifi. "More studies are needed, but we have strong evidence that HSD3B1 status affects abiraterone metabolism and probably its effectiveness. If confirmed, we hope to identify an effective alternative drug that might be more effective in men with this genetic anomaly."
Traditional therapy for advanced prostate cancer – called androgen deprivation therapy (ADT) – blocks cells' supply of androgens (male hormones), which they use to grow and spread. While ADT is successful early on, cancer cells grow resistant, allowing the disease to progress to a lethal phase called castration-resistant prostate cancer (CRPC). In CRPC, cancer cells utilize an alternative source of androgens produced in the adrenal glands. Abiraterone blocks these adrenal androgens.
In the study, the researchers examined small molecule byproducts of abiraterone in several groups of men with CRPC and found that patients with the gene variant had high levels of a metabolite called 5α-abiraterone. The metabolite tricks androgen receptors into turning on dangerous pro-cancer pathways. Remarkably, this byproduct of abiraterone – which is designed to block androgens – may behave like an androgen and cause prostate cancer cells to grow. Investigating abiraterone's impact on clinical outcomes in CRPC patients will be an important next step.
"This study adds to our understanding of the deleterious effect of inherited variants of the HSD3B1 gene and holds promise for precision medicine approaches in the management of men with advanced prostate cancer," said Eric Klein, M.D., chair of Cleveland Clinic Glickman Urological and Kidney Institute.
"This study helps to define a novel resistance pathway for abiraterone, a commonly used medication for patients with advanced prostate cancer. Dr. Sharifi's results could enable selection of different systemic therapies for patients who are carriers of certain genetic alterations in the HSD3B1 gene in order to prolong clinical response," said Howard Soule, Ph.D., executive vice president and chief science officer of the Prostate Cancer Foundation. "The Prostate Cancer Foundation is thankful to Dr. Sharifi for his continued investigations to improve therapy for advanced prostate cancer patients, and is proud to have funded this study."
The study was supported in part by grants from the National Cancer Institute and Prostate Cancer Foundation.
Dr. Sharifi holds the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic and co-directs the Cleveland Clinic Center for Excellence in Prostate Cancer Research. He has joint appointments in the Glickman Urological and Kidney Institute and Taussig Cancer Institute. In 2017, he received the national Top Ten Clinical Achievement Award from the Clinical Research Forum for his earlier discoveries related to HSD3B1.
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 52,000 employees are more than 3,600 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, 11 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 2017, there were 7.6 million outpatient visits, 229,000 hospital admissions and 207,000 surgical cases throughout Cleveland Clinic's health system. Patients came for treatment from every state and 185 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/ClevelandClinic. News and resources available at newsroom.clevelandclinic.org.
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.