The role of the paralogs CBP and p300 in androgen receptor function and prostate cancer
Abstract
Objectives and Rationale: Prostate cancer is the second most common cause of death from cancer in the United States. While many cases are caught early and cured, a portion of these cases come back or have already spread to other parts of the body at the time they are caught. These more advanced cases are treated by reducing levels of the male sex hormone testosterone (a type of molecule called an androgen), which otherwise feeds the growth of most prostate cancer cells. Unfortunately, men with advanced prostate cancer are rarely cured, and eventually their disease progresses to a state where it is able to grow despite low levels of testosterone. This state is called castration-resistant prostate cancer. Newer anti-androgen therapies such as abiraterone and enzalutamide have helped men with castration-resistant prostate cancer live longer, but still no cure exists. There is growing interest in targeting two proteins in this disease state called EP300 and CBP. These proteins are closely related, are changed at the DNA level in cancer by mutation and other processes, and are known to promote androgen-induced growth in prostate cancer cells. However, a more detailed understanding of how these proteins exert their influence either together or separately is required to adequately design therapies around them. This proposal asks how EP300 and CBP impact the way DNA is organized inside these cells (chromatin structure) as a way of understanding their role in cell behavior (Aim 1). We will explore this question further by decreasing the levels of each protein in models and testing what effect this has on chromatin properties, gene levels, and cell growth (Aim 2). Finally, we will test the effect of mutations in EP300 and CBP that have been identified in patient samples. We will also create a library of mutations across whole domains of the proteins and study the ones that seem to change protein behavior. These changes may cause resistance to any future therapies that are developed against CBP and EP300 and are therefore important to understand. Applicability of Research: This study should contribute to understanding the biology of lethal prostate cancer to limit death in two ways. First, it will help define how these EP300 and CBP control the behavior of advanced prostate cancer cells and thus may identify therapeutic vulnerabilities. Second, it will create tools that can be used to test whether candidate inhibitors are actually blocking the function of CBP and EP300. This is an important question to answer when developing any new therapy. As inhibitors of these proteins are currently starting to be used on patients in clinical trials, the latter outcome from this project may impact patient care in a year or two. The first outcome from this project may take several years to result in any change in therapies, but will be an important step in that direction. In addition to addressing the care of men with this disease, this study will also generate large datasets of chromatin structure and other biological readouts using state-of-the-art molecular biology techniques that could help the research community better understand how to treat advanced prostate cancer. Principal Investigator Career Goals: I hope to eventually become a physician-scientist with a research effort that takes basic science findings and translates them into improved outcomes for the patients I take care of in the oncology clinic. The training and mentorship plan that I will pursue as part of this proposal will take place in the rich environment of the Dana-Farber/Harvard Cancer Center, where I am constantly exposed to the leading edge of cancer research and clinical care. I will be specifically mentored by Dr. Myles Brown, an expert in prostate cancer research, especially as it pertains to chromatin structure. Together, the experience from carrying out this proposal combined with my training plan will give me the expertise and foundation
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010032
Entities
People
- Alok Tewari
Organizations
- Dana–Farber Cancer Institute
- United States Army