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

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 researcherNima 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).