Cleveland: Cleveland Clinic researchers have shown for the first time how a class of advanced prostate cancer drugs are processed in the body and how their anti-tumor activity might change depending on how they are metabolized. Their pre-clinical findings, just published in Cell Chemical Biology, may lay the foundation for improving therapies for treatment-resistant, aggressive prostate cancer.
Next-generation anti-androgens are potent drugs that work by cutting off the prostate tumor's supply of androgens (male hormones), which fuel prostate cancer. The drugs, used in patients whose cancer has become resistant to hormone deprivation therapy, have been shown to improve survival in men with metastatic disease. Unfortunately, prostate tumors eventually become resistant to these drugs, highlighting the need for new therapies.
"Despite an array of improved treatment options that have become available over the past decade, prostate cancer remains the second leading cause of cancer mortality in men in the United States. There are few therapeutic options for men whose cancer has become resistant to all therapies," said Nima Sharifi, M.D., lead author on the study. "Our goal is to improve the use and role of these existing drugs and hopefully design new therapies that work better and longer."
Galeterone is a steroidal anti-androgen that was recently studied in a clinical trial. Dr. Sharifi's team in the Cleveland Clinic Lerner Research Institute's Department of Cancer Biology has shown that when galeterone is metabolized, it is converted to the intermediate molecule D4G, which blocks androgen synthesis and reduces the amount of androgens available to cancer cells. A pitfall is that galeterone is also converted to another molecule that may stimulate the tumor.
Dr. Sharifi previously found that another steroidal anti-androgen drug, abiraterone, is metabolized in a similar manner. He went on to show in landmark studies that abiraterone's metabolite D4A has greater anti-tumor activity than abiraterone alone and that other molecules stimulate tumor growth, suggesting that the drug should be fine-tuned to improve efficacy.
Dr. Sharifi's new findings suggest that effective steroidal anti-androgens share common metabolic activities and that their metabolites should be closely examined for their effects on tumor survival. The findings may also guide medical decision making in the use of steroidal vs. nonsteroidal drugs for advanced prostate cancer.
"New agents and a clearer understanding of drug mechanisms are both urgently required to improve outcomes for treatment-resistant advanced prostate cancer," said Dr. Sharifi. "This work provides an important foundation that hopefully will lead to better treatment strategies for this disease."
Mohammad Alyamani, Ph.D., and Zhenfei Li, Ph.D., of Lerner Research Institute are first authors on the paper. Dr. Sharifi is also a member of the Glickman Urological & Kidney Institute and Taussig Cancer Institute of Cleveland Clinic. He holds the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic.
This work has been supported in part by funding from a Howard Hughes Medical Institute Physician-Scientist Early Career Award, a Prostate Cancer Foundation Challenge Award, an American Cancer Society Research Scholar Award, grants from the National Cancer Institute (R01CA168899, R01CA172382, and R01CA190289), and a grant from the US Army Medical Research and Materiel Command, a Prostate Cancer Foundation Young Investigator Award.
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 51,000 employees are more than 3,500 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, 10 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 2016, there were 7.1 million outpatient visits, 161,674 hospital admissions and 207,610 surgical cases throughout Cleveland Clinic's health system. Patients came for treatment from every state and 180 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/ClevelandClinic.
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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.
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