A Cleveland Clinic research team has uncovered a biological pathway that renders a common prostate cancer drug useless and, for the first time, restored the drug’s cancer-killing power in human prostate cancer tumor cells grown in mice.

Results from the study were published online today in the medical journal, eLife.

Resistance to prostate cancer drugs is a common clinical problem that many patients and their oncologists face. While standard therapies like androgen deprivation (or “medical castration”) can be effective for advanced prostate cancer, they typically stop working at some point, and the disease continues to progress. When medical castration fails, patients are often then treated with a potent drug called enzalutamide to block the tumor’s male hormones. Unfortunately, enzalutamide does not work indefinitely, and tumors eventually become resistant to it as well.

Nima Sharifi, M.D.

Nima Sharifi, M.D.

Within prostate tumor cells, male hormones (androgens) bind to and activate an androgen receptor protein. This hormone-receptor complex then instructs the cell to flourish and proliferate. Enzalutamide – an androgen receptor blocker – blocks this interaction so that tumors androgens are no longer active.

The team, led by Cleveland Clinic’s Nima Sharifi, M.D., uncovered a complex cascade of events – a “metabolic switch”– that occurs when androgen receptors are blocked with enzalutamide. Results showed that enzalutamide treatment causes levels of an enzyme called 11βHSD2 to plummet, which creates a surplus of the stress hormone cortisol in the tumor cells. This extra cortisol activates its own receptor protein complex, which then takes on the role of the disabled androgen receptor, instructing the cancer cells to make more androgens.

Since simply blocking cortisol from its receptor is not compatible with life, Dr. Sharifi’s team searched for alternative means of turning off this metabolic switch. Remarkably, they found that restoring levels of 11βHSD2 reversed enzalutamide resistance.

“This major discovery demonstrates that tweaking the metabolism induced by cancer drugs can have major benefits to patients in prostate and possibly other cancers,” Dr. Sharifi said. “We need more studies to determine how to safely increase 11βHSD2 in patients, but we are a step closer to finding answers and hopefully prolonging the lives of men who are in the unfortunate situation of being resistant to all current therapies.”

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 and was recently named a 2016 Harrington Fellow by University Hospitals’ Harrington Discovery Institute.

The research was supported by the National Cancer Institute (R01CA168899, R01CA172382, and R01CA190289), the Prostate Cancer Foundation, and the American Cancer Society. The funders had no role in the study’s design, data collection and interpretation, or the decision to submit the work for publication.

 

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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 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 ~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 2015. Visit us at www.lerner.ccf.org. Follow us on Twitter at www.twitter.com/CCLRI.