Overcoming the SYNCRIP-Loss-Conferred Antiandrogen Resistance in Prostate Cancer
Abstract
Scientific Objective and Rationale: Prostate cancer has long been the most commonly diagnosed cancer among American men and has the second highest rate of cancer-related deaths after lung cancer. Localized prostate cancer is primarily treated by radical prostatectomy, radiation therapy, and androgen deprivation therapy (ADT), also known as therapeutic castration. However, most patients will unfortunately result in relapse within a few years and develop to a very deadly form of prostate cancer, the metastatic castration-resistant prostate cancer (mCRPC). Currently, this metastatic and advanced prostate cancer is incurable. Patients can be treated with a type of new, targeted therapy drug called antiandrogens, which compete with the male hormone to bind androgen receptor and inhibit androgen receptor, finally inhibiting the tumor growth. One of these drugs is enzalutamide, also called Xtandi. The clinical application of enzalutamide significantly increased the survival rate of patients with this advanced prostate cancer. Although these androgen receptor targeted therapies are highly effective, about 50% patients have no or pretty low response to these drugs. Even in patients who have good response to these treatments, resistance is inevitable in 6 months to 2 years after administration. In this proposed study, I aim to examine the enzalutamide resistance in a subtype of diseases that has lost the expression of a gene called SYNCRIP. I will explore the mechanism driving this resistance and develop novel therapeutic approaches to combat resistance. Ultimate Applicability: The overall goal of this study is to define the biology of lethal prostate cancer. About 50% of mCRPC patients showed various degree of resistance to enzalutamide. This high variability in response limits the clinical benefit of this standard-of-care treatment for patients, underscoring the importance of understanding the mechanisms of resistance. My proposed project aims to investigate the mechanism of enzalutamide resistance in a newly identified subtype of cancers that carries the gene deletion of a gene called SYNCRIP. The completion of this project will significantly expand our understanding of how tumor cells acquire therapy resistance and identify novel actionable targets that could be developed as drug targets for new therapeutic approach to combat resistance. Importantly, a comprehensive characterization of this subtype of prostate cancer with SYNCRIP-loss, occurring in around 14% of patients will significantly expand the approaches for the precision oncology practice in treating advanced prostate cancer. We will be able to develop novel combination therapy approaches to overcome the resistance in this specific group of patients, based on the results of this proposed study. Since the aims of this proposed project consist of defining the character of this subtype of cancers and identifying a novel drug target, completion of this project will immediately generate important and clinically relevant results to guide the treatment of this subtype of patients and improve their clinical outcomes. Principal Investigator’s Career Goals: My career goal is to investigate the reasons lead to drug resistance in advanced prostate cancer and develop novel therapies to combat resistance and benefit patients as an independent investigator. I am now completing my postdoctoral training under the mentorship of Dr. Ping Mu at the Molecular Biology Department of UTSW, which is one of the world’s foremost biomedical research institutions. The proposed study is based on my preliminary findings, which define a new subtype of advanced prostate cancer that has lost the expression of a gene called SYNCRIP. Through the study of this proposed project, I will greatly expand my knowledge and experimental skills in all the basic, translational, and clinical perspectives of prostate cancer research. I will learn all of the cutting-edge, basic research concep
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110418
Entities
People
- Xiaoling Li
Organizations
- United States Army
- University of Texas Southwestern Medical Center