Genotoxic Stress and Androgen Receptor Signaling: Integration of Dynamic Noninvasive Biomarkers Postradiotherapy in Prostate Cancer
Abstract
Scientific Objective and Rationale: Radiation therapy is one of the primary therapies used to treat men with prostate cancer. Randomized clinical trials over the past 20 years have consistently demonstrated that the addition of androgen deprivation therapy (ADT), a treatment that lowers testosterone levels or blocks testosterone, increases survival when combined with radiotherapy. However, the use of ADT is based on conventional parameters to calculate risk of treatment failure (tumor histology, extent of tumor on physical exam, and blood tests [prostate specific antigen or PSA]), rather than the specific biology of each man s tumor. For this reason, some men are unnecessarily treated and others need more aggressive therapy. This is evident in that >40% of men treated with ADT and radiotherapy fail treatment and require additional "salvage" therapies. The scientific objective of the current proposal is to gain insights into why these two therapies work in synergy by looking at pathways the tumor uses to repair the damage induced by radiotherapy to identify new drug targets to overcome radiation resistance. Additionally, we aim to optimize currently available treatments by understanding the optimal sequencing of radiotherapy and the optimal type of ADT to maximize this synergy. Furthermore, our goal is to develop a non-invasive way of monitoring how the tumor is responding to ADT and radiotherapy in order to customize treatment for each patient. Career Goals in Prostate Cancer Research and Patient Care: Dr. Spratt is a radiation oncologist who treats men with prostate cancer, and also performs research in the laboratory with the hopes of bringing his discoveries back into to the clinic to help men battling prostate cancer. His career goals are to provide unparalleled care for his patients. Furthermore, he hopes to be a successful independent physician-scientist and investigate ways to individualize therapy for each patient s tumor. In order to reach these goals he has designed a training plan with his three world-class mentors, Dr. Chinnaiyan, Dr. Sawyers, and Dr. Feng, to maximize his hands-on experience and educational exposure to basic, translational, and clinical research. Dr. Spratt will attend journal clubs, national and international meetings, and attend biomarker and clinical trial development courses. Additionally, Dr. Spratt and his mentors have developed a research plan that is designed to not only provide invaluable laboratory experience, but also to work on a vitally important area of research that has a high likelihood of improving the treatment of prostate cancer. Dr. Spratt s three scientific aims have been carefully selected to investigate mechanisms of radiation resistance, methods to improve therapeutic efficacy, and translational biomarker development. These tools will greatly assist Dr. Spratt in achieving his career goals in prostate cancer research and patient care. Applicability of the Research: The current research proposal aims at helping the 600,000 men with intermediate and high-risk localized prostate cancer diagnosed annually worldwide. Of these men, those that choose to under radiation therapy will benefit from the present research proposal by allowing individualization of therapy via greater insights into mechanisms that drive the synergy of ADT and radiotherapy to nominate new therapeutic targets, knowledge of the optimum sequence and intensity of combination therapy, and biomarkers to predict response to treatment. The potential clinical applications include (1) selection of novel drugs that could further increase the therapeutic benefit of combination therapy by targeted pathways identified through our mechanistic and biomarker discovery aims, (2) increased survival for men by optimizing the current standard of care, and (3) individualizing treatment to avoid overtreatment and decrease toxicity, and escalate treatment to improve cure rates. The clinical risks asso
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610571
Entities
People
- Daniel E. Spratt
Organizations
- United States Army
- University of Michigan