Cleveland Clinic Researcher Discovers Altering Metabolite of Prostate Cancer Drug More Effective at Treating Aggressive Tumors

Discovery could lead to improved treatments for metastatic prostate cancer

For the first time, Cleveland Clinic researchers have fine-tuned an FDA-approved antisteroidal prostate cancer drug to alter its drug metabolism and achieve better anti-tumor activity, according to research published May 26 in Nature.

 Cleveland Clinic researcher Nima Sharifi, M.D., discovered a new strategy for fine-tuning how the body processes abiraterone to optimize therapy for men with metastatic, treatment-resistant prostate cancer (mCRPC).

“These findings hold enormous potential for changing the way abiraterone is prescribed to patients. While more work is needed to determine the ultimate clinical effect of biochemically altering abiraterone metabolism in this way, our team has identified a promising new combination therapy that stands to improve the care of men with mCRPC,” said Nima Sharifi, MD, Kendrick Family Endowed Chair for Prostate Cancer Research at the Cleveland Clinic and the study’s senior author.

In 2015, Sharifi and his team 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. It is a next-generation androgen inhibitor that was approved by the FDA in 2011 for the treatment of mCRPC. The medication works by blocking the production of androgens and is effective even in patients who have previously received chemotherapy. While abiraterone is effective in prolonging the lives of men with mCRPC, patients ultimately develop resistance and experience disease progression.

In the current study, the team showed that D4A is further broken down into a compound called 5α-Abi, a metabolite that promotes prostate cancer progression. Based on this observation, they hypothesized that the efficacy of abiraterone could be improved by adjusting its metabolism to block conversion to the “bad” 5α-Abi and promote the accumulation of “good” D4A.

The team then tested this idea in a clinical trial that combined abiraterone with another medication called dutasteride, which is an inhibitor of the enzyme that converts D4A into 5α-Abi. They discovered that adding dutasteride to abiraterone allowed for the accumulation of D4A to higher therapeutic levels by preventing its transformation into 5α-Abi.

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).

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. More than 3,000 full-time salaried physicians and researchers and 11,000 nurses represent 120 medical specialties and subspecialties. The Cleveland Clinic health system includes a main campus near downtown Cleveland, eight community hospitals, more than 75 Northern Ohio outpatient locations, including 16 full-service Family Health Centers, Cleveland Clinic Florida, the Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, and, scheduled to begin seeing patients in 2015, Cleveland Clinic Abu Dhabi. In 2012, there were 5.1 million outpatient visits throughout the Cleveland Clinic health system and 157,000 hospital admissions. Patients came for treatment from every state and from more than 130 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 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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