Cleveland: Cleveland Clinic researchers have discovered for the first time that a metabolite of an FDA-approved drug for metastatic prostate cancer, abiraterone (Abi), has more anti-cancer properties than its precursor. The research will be published online June 1st in Nature.
Cleveland Clinic researcher Nima Sharifi, M.D., found that abiraterone, a steroid inhibitor, is converted into the more physiologically active D4A (Δ4-abiraterone) in both patients and animal models with prostate cancer who take the drug. Furthermore, they found that D4A is more effective than abiraterone at killing aggressive prostate cancer cells, suggesting that some patients may benefit from direct treatment with D4A.
Prostate cancer cells are fueled by androgens (male hormones). When prostate cancer spreads, androgen deprivation therapy ("medical castration") is used to cut off the tumor's energy supply. However, aggressive, metastatic tumors can become resistant to this type of therapy. In a landmark 2013 publication in Cell, Dr. Sharifi described a genetic mutation that enables prostate cancer cells to produce their own hormones for fuel, making them resistant to traditional hormone deprivation therapies.
Abiraterone works by blocking CYP17A1, an enzyme that is crucial for the production of androgens. Dr. Sharifi's team found that the more active D4A inhibits two additional enzymes responsible for producing androgens, as well as blocks the androgen receptor, which renders existing androgens inactive. They found that 12 patients on active abiraterone therapy had detectable serum levels of D4A. D4A levels varied among patients, however, suggesting that individuals may differ in their metabolism of abiraterone to D4A.
"More studies are needed to uncover the exact mechanisms involved, but we predict that direct treatment with D4A could prolong survival in some patients with metastatic prostate cancer," said Dr. Sharifi, "Further studies will also help us develop a potential biomarker profile to predict which patients will respond to D4 - abiraterone."
Dr. Sharifi holds positions in Cleveland Clinic's Lerner Research Institute, Glickman Urological & Kidney Institute, and Taussig Cancer Institute, and is the Kendrick Family Endowed Chair for Prostate Cancer Research.
Prostate cancer is the most common cancer in men, with nearly 240,000 new cases diagnosed each year in the United State. According to the American Cancer Society, there will be an estimated 30,000 deaths due to prostate cancer in 2013. Almost every man who dies of prostate cancer dies with castration-resistant prostate cancer.
This research was funded by the Prostate Cancer Foundation, the American Cancer Society, the Department of Defense (U.S. Army Medical Research and Material Command), the Howard Hughes Medical Institute and the National Cancer Institute (R01CA168899, RO1CA172382 and RO1CA190289).
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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 2014, LRI researchers published nearly 600 articles in high-impact biomedical journals (top 10% of all biomedical journals). LRI's total annual research expenditure was $255 million in 2014 (with $98 million in competitive federal funding). More than 2,000 people (including approximately 175 principal investigators, 200 postdoctoral fellows, and about 170 graduate students) in 13 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 66 invention disclosures, 4 licenses, and 50 patents in 2014.
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