Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-Resistant Prostate Cancer
Abstract
Scientific Objective and Rationale of Proposed Study: The American Cancer Society has estimated that 233,000 men will be diagnosed with prostate cancer and approximately 30,000 will die from the disease annually, making it the most commonly diagnosed cancer in males, and the second leading cause of cancer deaths. Male hormones, known as androgens, activate a protein called the androgen receptor (AR) that drives prostate cancer growth and is critical for the development and progression of prostate cancer. AR is also the main therapeutic clinical target for prostate cancer. AR-targeted therapies (anti-androgens) like the drug enzalutamide provide substantial benefits in the treatment of the lethal form of prostate cancer, metastatic castration-resistant prostate cancer (mCRPC); however, a majority of patients still progress to and die from metastatic disease. Therefore, there is a critical need to develop different drugs targeting other proteins that either help AR promote cancer growth, or promote it themselves. One protein group of proteins that has been shown to do both of these things is called bromodomain and extraterminal (BET) containing proteins. These BET proteins have been previously targeted with drugs that inhibit their function; however, these drugs are not very specific and can have side effects. We are developing a new set of drugs that can cause the cancer cells to destroy BET proteins, specifically and effectively. We plan to test how well these drugs function in cell lines and in animal models and to examine how these drugs affect prostate cancer growth, particularly through AR and another cancer-promoting protein, MYC. The goal of this project is to understand how these new drugs function and to provide a rationale for clinical trial design for these drugs that have the potential to dramatically improve treatment for mCRPC. Applicability of Proposed Research: The proposed project will utilize cutting-edge technologies to test our hypotheses about how BET bromodomain-degrading drugs function and may provide a novel therapeutic strategy for advanced hormone-resistant prostate cancer. We believe the scientific discoveries made from this project will be significant and would specifically benefit advanced prostate cancer patients who become resistant to currently used drugs. This project will also increase our understanding of the basic biology of prostate cancer and specifically of BET proteins. Goals and Training Plan: For as long as I could remember, I have wanted to be a scientist. When choosing a field of study during my graduate career, I decided to focus on cancer biology. Cancer is a disease that affects a vast number of individuals and has affected me deeply on a personal level, but it is also an incredibly interesting and challenging scientific puzzle. My undergraduate and graduate education has helped me tremendously to grow into a focused and motivated scientist, and now I am incredibly fortunate to be a part of the Chinnaiyan lab. The Chinnaiyan lab has the expertise and resources to support this proposed research project, and Dr. Chinnaiyan has a long history of training successful, independent cancer researchers. I strongly believe that my postdoctoral training in translational cancer research is a critical step in achieving my career goals. Upon successful completion of my postdoctoral training, I anticipate leading a research laboratory in an academic setting with a focus on the mechanistic aspects of cancer initiation, progression, and resistance to therapies. During this training period, I will gain the necessary skills to become an independent prostate cancer researcher.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710155
Entities
People
- Steven Kregel
Organizations
- United States Army
- University of Michigan