Exploiting Androgen Receptor-Mediated DNA Damage for Radiosensitization
Abstract
Scientific Objectives and Rationale: Prostate cancer is the most common non-skin cancer in men in the United States. The androgen receptor, which binds testosterone and other male hormones, is central to the growth and survival of cancerous cells of the prostate. Therefore, management of locally advanced prostate cancer often includes medications to lower the levels of androgens produced in the body and radiation therapy directed to the pelvic region. We have previously shown that when the androgen receptor is experimentally stimulated by testosterone to bind DNA, an enzyme that prevents DNA from becoming entangled, topoisomerase-2-beta (TOP2B), is recruited to the target sites throughout DNA as well, and makes transient breaks in DNA. Our preliminary evidence suggests that elevated levels of toxic reactive oxygen compounds in cancer cells act to trap TOP2B onto DNA, producing these transient breaks. Radiation therapy potently produces DNA breaks as well; though normal tissues, such as the urinary tract and rectum, are often damaged along with cancer tissues because it does not distinguish between normal and cancer cells. It is known that some Food and Drug Administration (FDA)-approved, clinically used compounds that inhibit the ability of androgen receptor to support cancer cell growth maintain the ability to direct the receptor to sites throughout DNA. We will test the ability of these compounds to cause DNA damage selectively in prostate cancer cells to sensitize these cells to radiation therapy. If this approach is successful, radiation therapy doses may perhaps be lowered to avoid toxicity to normal tissues while prostate cancer cells would be targeted, because most non-cancer cells do not contain the androgen receptor. The specific locations of DNA breaks throughout the DNA will also be mapped to identify sensitive breakpoints, which may help us understand how androgen receptor inhibitors sensitize cells to radiation therapy. Career Goals: My long-term career goal is to become an independent investigator involved in basic and translational research yielding rapid and long-lasting impacts to the field of prostate cancer research and, most importantly, for prostate cancer patients. The Prostate Cancer Research Program Postdoctoral Fellowship Award will represent a critical step in achieving this goal by allowing me to pursue the proposed research in a collaborative research group with a history of mentoring postdoctoral fellows who transition to independent investigators, becoming leaders in their fields. Toward the completion of the fellowship award, I plan to have published our findings and to have generated multiple hypotheses from these findings, which will serve as preliminary data for grant applications. The fellowship award and its associated meetings will also allow me to develop close, collaborative relationships both within my institution and within the greater prostate and cancer research fields. Having demonstrated an ability to acquire financial support and publish our findings, my goal at this time will be to compete for National Institutes of Health K-awards and Prostate Cancer Foundation awards in order to transition into a more independent junior faculty position. The individualized training plan of this application will include three major components: didactic training and seminars, mentoring and teaching, and laboratory and analytical training. Srinivasan Yegnasubramanian, M.D., Ph.D., the primary mentor of the application, has an extensive background in cancer biology, genetics/epigenetics, and genomics technologies. Dr. DeWeese, the co-mentor of the application, is Professor and Chair of the Department of Radiation Oncology and Molecular Radiation and Professor of Urology and Oncology at Johns Hopkins. He sees and treats men with prostate cancer and actively conducts therapeutic and non-therapeutic clinical trials for these patients. Working with mentors who have expertise in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610453
Entities
People
- Jonathan Coulter
Organizations
- Johns Hopkins University
- United States Army