A Combination Approach for Treatment of Castration-Resistant Prostate Cancer
Abstract
Rationale and Objective: The majority of prostate cancer deaths and suffering are caused by metastatic, castration-resistant prostate cancer (CRPC), an advanced and progressive stage of the disease that remains incurable despite recent advances in prostate cancer research and treatment. Docetaxel (Taxotere) chemotherapy is a first-line treatment and standard of care for patients with metastatic CRPC. However, about half of patients do not respond to the treatment, and those that do respond become refractory within 1 year. Several new therapies, including abiraterone (Zytiga), enzalutamide (Xtandi), and the new taxane cabazitaxel (Jevtana), have been approved by the Food and Drug Administration as post-docetaxel treatments for metastatic CRPC. However, the survival benefits are moderate (<5 months), and essentially all patients will become refractory to these treatments. Thus, understanding the mechanisms of resistance and developing effective strategy to overcome the resistance is an urgent task. Disease progression after abiraterone, enzalutamide, or taxanes is all associated with persistent androgen receptor (AR) signaling. Recently, a new class of AR, AR variants (AR-Vs), has been discovered. Unlike the canonical AR, AR-Vs do not depend on the presence of androgen to become activated and cannot be targeted by any of the anti-androgens that are currently accepted in the clinic. Strikingly, a recent study showed that metastatic CRPC patients with detectable AR-V in circulating tumor cells do not respond to either abiraterone or enzalutamide and have poor survival. The data provided compelling evidence for the importance of AR-Vs in limiting the efficacy of abiraterone and enzalutamide. Significantly, preliminary studies conducted in our laboratory suggest that these AR-Vs also play an important role in the resistance of CRPC to taxane chemotherapy (docetaxel and cabazitaxel). In this application, we have designed a series of animal and cell-line-based studies to validate this idea and to understand the underlying mechanism. In addition, studies conducted in our laboratory have shown that 20(S)-protopanaxadiol-aglycone (PPD), a major intestinal metabolite of ginseng, can effectively decrease the levels and activities of AR-Vs in prostate cancer cells. This unique property provides a strong rationale of using PPD to overcome resistance of metastatic CRPC to abiraterone, enzalutamide, and cabazitaxel. In this application, we have designed a comprehensive preclinical trial to test the potential of using PPD to improve the therapeutic outcome of these therapies and to determine how PPD exerts its actions. Ultimate Applicability: This study is based on novel and untested ideas and it is designed with patient-related outcomes in mind. We aim to develop a new and improved therapeutic regimen for patients with metastatic CRPC. If successful, this study will equip clinicians with an agent to prevent progression of metastatic CRPC on treatment with abiraterone, enzalutamide, or cabazitaxel, three Food and Drug Administration-approved new therapies for metastatic CRPC, and to treat patients who have progressed on these therapies. Moreover, developing therapeutic strategies using an affordable natural product such as PPD will significantly reduce the economic burden associated with prostate cancer treatment. Furthermore, PPD has a low toxicity profile. Using it in conjunction with the other drugs is expected to lower the effective dose of the other drugs, thereby reducing drug toxicity and improving the quality of life for patients. Thus, the research will have a significant impact on improving survival of patients with metastatic CRPC while reducing suffering and improving quality of life. We project that we will have sufficient data to initiate a clinical trial by the time the proposed study is completed. A patient-related outcome could be expected in 5-10 years. Likely Contributions: Emerging clinica
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510439
Entities
People
- Yan Dong
Organizations
- Tulane University of Louisiana
- United States Army