Disruption of the Interaction of the Androgen Receptor with Chromatin: A Novel Therapeutic Approach in Prostate Cancer
Abstract
Scientific Objective and Rationale: Current therapeutic strategy for advanced prostate cancer involves either the reduction of the levels of male sex hormone (androgen) called androgen deprivation therapy or the use of antagonists to androgen receptor (AR). These therapies work well, albeit temporarily, with recurrence and progression of cancer in a form that is resistant to reduced levels of androgen (called castrate-resistant). Importantly, even in this castrate-resistant prostate cancer, the AR is still functional and able to direct the expression of several thousand genes involved in cancer progression. For its functional activity, the AR interacts with essential coregulator proteins, including the so-called "pioneering factors" that facilitate the critical interaction of the AR with the regulatory regions on the genes. One such pioneering factor named FoxA1 is particularly important for AR activity and is strongly associated with metastatic prostate cancer. FoxA1 is an attractive therapeutic target, but has been considered undruggable. Simply diminishing FoxA1 levels resulted in recruiting "replacement" pioneering factors, which then interact with AR and lead to an alternative gene expression profile. We have developed a novel strategy with small molecules to precisely disrupt the interaction between AR and FoxA1. This approach maintaining FoxA1 on the chromatin may prevent the recruitment of alternative pioneering factors and may selectively and effectively disrupt AR activity in advanced prostate cancer. My preliminary results have identified the interface of AR-FoxA1 complex and validated the critical amino acids within the predicted region. Further, our rationally designed small molecules were able to block the interaction between AR-FoxA1 on chromatin. These findings provide two new opportunities that will be pursued in this proposal: (1) test whether our designed drugs will be effective in treating prostate cancer using multiple prostate cancer cell lines and xenograft models and (2) determine the molecular activity of our drugs. I believe that this proposed study will develop a novel therapeutic agent for the treatment of aggressive prostate cancer and provide an insight into this first-in-class agent targeting critical interaction between proteins. Career Goal: I have received training in prostate cancer during my PhD, and I will continue to acquire the advanced technical ability and build a wide range of prostate cancer research expertise throughout this study. I am going to dedicate my lifetime career to fighting against this disease and to finding better treatments or a cure for patients with advanced prostate cancer. I am convinced that the proposed training program and research plan will support my career goals by fostering opportunities to be mentored by Dr. Ganesh Raj, an outstanding urological surgeon and scientist, and interact with clinicians and other established prostate cancer investigators. My ultimate goal would be to obtain an independent research career at a well-recognized academic institute involved in the development of therapeutics for prostate cancer. Ultimate Applicability of Prostate Cancer Research: Information derived from this proposed preclinical study will help the development of a novel class of drugs to shut down androgen receptor signaling. This work responds to the critical unmet need for a therapeutic treatment to achieve a durable response in castrate-resistant prostate cancer patients or in men who fail with current drugs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510543
Entities
People
- Lu Miao
Organizations
- United States Army
- University of Texas Southwestern Medical Center