Moffitt researchers identify inhibitor that overcomes drug resistance in prostate cancer
TAMPA, Fla. (June 12, 2017) – Prostate cancer is the third most common cause of cancer-related death in men in the United States. It is estimated that 161,360 men will be diagnosed and more than 26,700 men will die from the disease in this year. The majority of these deaths are caused by prostate cancer that becomes resistant to initial therapy and spreads to other sites, called metastatic castration-resistant prostate cancer. In a study published today in Cancer Cell, Moffitt Cancer Center researchers report that a newly discovered epigenetic mechanism can lead to the development of castration-resistant prostate cancer. They identified a novel drug that targets this epigenetic mechanism and may be able to combat the deadly form of the disease.
Uncontrolled activity of male hormones, called androgens, contributes to the development of prostate cancer. One of the primary ways doctors treat prostate cancer is by inhibiting the activity of androgens by either surgically removing the testicles or with drugs that decrease androgen levels or activity. Unfortunately, even though most patients have early success with anti-androgen treatments, many patients eventually develop metastatic castration-resistant prostate cancer within two to three years. Castration-resistant prostate cancer is more difficult to treat and cure because scientists are unsure how it develops resistance to anti-androgen therapies.
"Undoubtedly, the foremost reason for transient effectiveness of the androgen deprivation therapy is a poor understanding of the molecular mechanisms driving progression to castration-resistant prostate cancer, which in turn has hampered development of new therapeutics," explained Nupam P. Mahajan, PhD, associate member of the Chemical Biology and Molecular Medicine Program at Moffitt.
The Moffitt team performed an extensive set of experiments in prostate tumor cells and mice. They discovered a protein, called ACK1, also known as TNK2 that activates a pathway that causes the DNA-bound proteins called histones to undergo a type of modification called epigenetic modification. This modification was specifically accomplished by androgen receptor protein with the help of ACK1 around the region of the androgen receptor gene! This results in high levels and activity of the androgen receptor even when prostate cancer cells have been treated with anti-androgen therapy.
Following this discovery, the researchers developed a novel drug called (R)-9bMS that targets ACK1 and performed experiments to determine if it could block prostate cancer growth. They discovered that the ACK1 inhibitor blocked epigenetic modification of the androgen receptor gene and decreased its levels and activity. Importantly, the ACK1 inhibitor blocked the growth of prostate cancer cells that were resistant to the anti-androgen drug enzalutamide (also known as XTANDI) and decreased the growth of castration-resistant prostate tumors in mice.
"This discovery is highly relevant because almost two thirds of castration-resistant prostate cancer patients do not respond to enzalutamide. Overall, (R)-9bMS opens up as a new, and desperately needed, therapeutic option for those castration-resistant prostate cancer patients who either do not respond to enzalutamide or have acquired resistance, post-treatment," said Dr. Kiran Mahajan, the first author of this paper.
This study was supported by grant funding from the National Cancer Institute (1R01CA135328), Department of Defense (W81XWH-14-1-0002, W81XWH-14-1-0003, W81WXH-15-1-0312, W81XWH-12-1-0248, W81XWH-14-1-0251, and W81XWH-15-1-0059), State of Florida's Bankhead-Coley Program (6BC08), and a Miles for Moffitt award (09-33661-15-13).
About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 47 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt's excellence in research, clinical trials, prevention and cancer control. Moffitt is the No. 6 cancer hospital in the nation and has been listed in U.S. News & World Report as one of the "Best Hospitals" for cancer care since 1999. Moffitt devotes more than 2.5 million square feet to research and patient care. Moffitt's expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 5,200 team members, Moffitt has an economic impact in the state of $2.1 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter and YouTube.