A Novel Approach to Identify Inhibitors of Androgen Receptor Splice Variants
Abstract
This proposal directly addresses the overarching challenge "To develop effective treatments and address mechanisms of resistance for men with high-risk or metastatic prostate cancer" and the focus area of therapy. Androgen receptor (AR) reactivation in castrate-resistant prostate cancer (CRPC) is a critical clinical problem. Although newer therapies such as abiraterone and Enzalutamide have helped some patients subsequent to failure of first-line androgen deprivation therapy, some patients are resistant and those that respond usually develop resistance within a relatively short period of time. There are several lines of evidence that show that these failures, for the most part, are due to reactivation of AR. Among the causes for failure is the appearance of constitutively active AR variants that no longer have hormone (androgen) binding domains. Thus, therapies that target other portions of AR are needed. For AR to act as a transcription factor, it must bind to DNA and bring a variety of other proteins, termed coactivators, to the DNA. Most of these coactivators bind to a region of AR that is retained in the AR variants. We hypothesize that if we can develop a means to block this interaction, we will be able to block activation of all forms of AR. We have developed a high-throughput screen to identify compounds with the capacity to block this interaction and have identified a few candidates, but do not know whether they actually inhibit AR activity. We will perform additional screens to identify a larger number of compounds, test whether they block AR activity, and test for specificity of inhibition. One advantage of specifically targeting AR is that the side effects are not as substantial as with conventional chemotherapies, which for the most part are ineffective in treating prostate cancer. Thus, we will choose compounds that inhibit AR but not other important nuclear receptors such as the glucocorticoid receptor and mineralocorticoid receptor, which are needed for many normal physiological processes. We also will test whether the compounds preferentially inhibit growth of AR-dependent cells. At the end of the year, we hope to have a small group of compounds that can be tested for efficacy in animal models of prostate cancer. These compounds (or derivatives to improve affinity, specificity, or other aspects for efficient drug delivery) would provide important new means to treat CRPC. If side effects are minimal, subsequent uses could include combination therapies with initial classical androgen deprivation therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510077
Entities
People
- Nancy Weigel
Organizations
- Baylor College of Medicine
- United States Army