Overcoming CRPC Treatment Resistance via Novel Dual AKR1C3 Targeting
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, which 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. As prostate cancer cells progress to the castration-resistant state, they undergo a variety of biochemical and molecular changes. Intratumoral androgen biosynthesis has been well characterized as a mechanism of CRPC, but its role in enzalutamide resistance has not been fully defined. Both abiraterone and enzalutamide are Food and Drug Administration-approved for the treatment of CRPC. Unfortunately, when prostate cancer becomes resistant to one drug, the subsequent response rate to the other drug is 20% or less. Therefore, there is clearly an unmet need to address this resistance. We have demonstrated that abiraterone does not overcome resistance in CRPC cells overexpressing AKR1C3. However, the combination of indomethacin and enzalutamide was effective. Hence, targeting abiraterone-resistant CRPC addresses a tremendous unmet medical need, and the rational design supported by our strong preclinical data will help meet this need. In this proposal, we propose to conduct a clinical trial to determine the efficacy and toxicity of an indomethacin and enzalutamide combination in the treatment of CRPC. We will recruit CRPC patients after abiraterone treatment. Patients with CRPC previously treated with abiraterone will be treated with 160 mg enzalutamide orally once daily and 50 mg indomethacin orally three times daily until disease progression or development of severe toxicity. We expect to enroll up to 26 patients in 16 months (1.5 per month) in order to obtain a sample of 21 evaluable patients (20% attrition rate). This sample size provides 90% power to detect, at the 0.05 level (1-sided), the difference between a prostate-specific antigen (PSA) response rate of 50% (expected with the study treatment) and a PSA response rate of 20% (the null hypothesis, historical control) based on recent clinical trials of enzalutamide alone. With the follow-up to 20 months, the entire duration of the study is expected to be completed in 3 years. This application will have a significant impact on (1) understanding novel mechanisms of treatment resistance and (2) targeting resistance mechanisms to overcome resistance and improve current AR-targeted therapies in CRPC. Indomethacin has been on the market and safely taken by patients for decades. Therefore, this application with the newly discovered role of indomethacin synergizing with enzalutamide therapy directly translates into clinical application: a direct Phase II clinical trial with a lead-in safety phase to determine the toxicity and efficacy of combination therapy with indomethacin and enzalutamide.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610625
Entities
People
- Chong-Xian Pan
Organizations
- United States Army
- University of California, Davis