Contribution of the Androgen Receptor mRNA per se to Castration Resistance
Abstract
Rationale and Objective: Hormone therapy (androgen deprivation therapy) is the primary treatment for advanced prostate cancer. However, nearly all prostate cancers become resistant to hormone therapy over time, and the cancers turn into an incurable form called metastatic castration-resistant prostate cancer, the major cause of prostate cancer deaths and suffering. Several new, more potent hormone therapy drugs, including abiraterone (Zytiga) and enzalutamide (Xtandi), were recently approved by the Food and Drug Administration as treatments for metastatic castration-resistant prostate cancer. However, the survival benefits are moderate (<5 months). Many patients treated with these drugs presented with therapy-resistant disease, and essentially all initial responders became refractory to these treatments within months of therapy initiation. Thus, understanding the mechanisms of resistance and developing effective strategies to overcome resistance is an urgent task. Disease progression after hormone therapy, including the new drugs abiraterone and enzalutamide, is associated with increased mRNA levels of the receptor for androgens, androgen receptor (AR). However, this increased AR mRNA is often not associated with elevated AR protein. Strikingly, our preliminary studies showed for the first time that the increased AR mRNA per se (not through its protein product) can drive disease progression after hormone therapy. We propose that the way that the increased AR mRNA promotes prostate cancer progression is not limited to its protein coding capacity but also through the signaling influences of its RNA. This novel and untested concept, conceived through close interactions between the two PIs with ideally complementary expertise, represents a paradigm shift from the major focus of the AR research and hormone therapy, viz., the AR protein. In this application, we have designed a series of animal and tissue culture studies as well as analyses of clinical databases to validate this idea. The knowledge gained from this study could revolutionize our view of the mechanisms driving prostate cancer progression after hormone therapy and change radically the way we think about how best to approach the development of effective therapeutics. Ultimate Applicability: This study is designed with patient-related outcomes in mind. We aim to unveil a new mechanism of resistance that is inherent to all current hormone therapies and likely more severe for the more potent drugs. If successful, this study could substantially alter our view of how to best target AR for more effective treatment of prostate cancer. The current paradigm of hormone therapy is to magnify androgen depletion using more potent drugs. However, this would lead to further increase of AR mRNA. The data from the proposed study will support a shift in therapy away from further androgen depletion. For example, since AR mRNA is induced by hormone therapy, alternating hormone therapy with androgen replacement may avert AR mRNA induction, enhance the efficacy of hormone therapy, and, at the same time, improve the quality of life for patients. This should be achievable with physiological (low) androgen concentrations, not necessarily the pharmacological (high) doses tested in the bipolar androgen therapy protocol that was nevertheless shown recently to have the potential to reverse resistance to hormone therapy. Moreover, the increased AR mRNA is not targeted by the current approach of hormone therapy, which inhibits the activity of the AR protein via lowering androgen levels (by surgical castration, Lupron, or Zytiga etc.) or using anti-androgens (Casodex, Nilandron, or Xtandi etc.). Our data will suggest that directly targeting the AR mRNA may offer a better treatment outcome than merely targeting the AR protein. Thus, the research will have a significant impact on developing rational strategies to more effectively treat prostate cancer. We project that we wil
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610317
Entities
People
- Yan Dong
Organizations
- Tulane University of Louisiana
- United States Army