Targeting ARv7 by Niclosamide Overcomes Treatment Resistance CRPC
Abstract
In the mid-1940s, Dr. Charles Huggins demonstrated that castration (also known as androgen deprivation therapy) or removal of testosterone from a dog with widespread (metastatic) prostate cancer improved the dog s outcome. This then became standard practice in humans. However, eventually prostate cancer escapes its response to castration, progresses, and results in death. Through androgen deprivation therapy, patients live longer but ultimately die from "castration-resistant prostate cancer" (CRPC). Despite researchers best efforts, improvements to androgen-deprivation therapy have not been achieved, and almost all research efforts in the past 20 years have shifted to treating CRPC. There has been a major focus on the androgen receptor (AR) pathway as the principal therapeutic target for CRPC, including recently approved therapies such as next-generation antiandrogen enzalutamide. Despite these advances that provide temporary respite, almost all patients will go on to die from progressive and resistant prostate cancer. Therefore, there is an urgent need to identify resistant pathways that perpetuate disease progression during an effective AR blockade. We believe that a better understanding of the mechanisms leading to the development of treatment-resistant CRPC will be vital for providing better treatment strategies for this currently incurable stage of disease. Considerable evidence from both clinical and experimental studies demonstrate that androgen receptor variant 7 (AR-V7) plays vital roles in the induction of resistance to enzalutamide and abiraterone therapy. AR-V7 is not targeted by either enzalutamide or abiraterone. Therefore, there is an urgent need to develop novel agents that target AR-V7 to overcome resistance. We discovered niclosamide as a novel inhibitor of AR-V7. This project will determine whether niclosamide can be used for the treatment of CRPC. Niclosamide is already approved by the Food and Drug Administration (FDA), and the pharmacology and toxicology properties are fully known. Therefore, if niclosamide is proven to be effective in prostate cancer, it will circumvent the need for the money and time needed for preclinical studies required for new drug development. Our preliminary data showed that niclosamide enhances enzalutamide therapy and overcomes enzalutamide resistance in CRPC. In addition, niclosamide can also overcome resistance to abiraterone, another drug recently approved by the FDA for CRPC. Therefore, most CRPC patients will benefit if niclosamide is effective. This proposal will fill the gap of overcoming enzalutamide resistance and improving current AR-targeted therapies in CRPC patients by targeting AR-V7 using niclosamide. As such, our proposed studies have the potential to make a paradigm shift in how we understand and treat therapy-resistant metastatic CRPC. It will also point the way to future research and ultimately benefit patients by improving current AR-targeted therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610353
Entities
People
- Allen Gao
Organizations
- United States Army
- University of California, Davis