Targeting GR-ATAD2 Crosstalk in Enzalutamide-Resistant CRPC
Abstract
Despite displaying better efficacy, enzalutamide administration will eventually lose its effect and, therefore, drug resistance is the biggest challenge in the clinic for treating castration-resistant prostate cancer (CRPC). The broad objectives of our project are to provide in-depth mechanisms underlying the enzalutamide resistance in CRPC and to come up with alternative or novel therapeutic targets. Our preliminary data suggested that the crosstalk between the glucocorticoid receptor (GR) and the bromodomain (BRD)-containing protein ATAD2 could determine responses of CRPC cells to enzalutamide. In the proposed project, we will take effort to completely elucidate the mechanisms of drug resistance that is driven by the interplay between ATAD2 and GR. Findings from this study will ultimately benefit all prostate cancer patients with CRPC who no longer respond to enzalutamide treatment. By completely understanding the roles of ATAD2 and GR in CRPC, we expect to suggest more specific and efficient treatment options, identify novel drug targets, and provide prototype inhibitors of these targets. The discoveries from human cancer cell lines will be confirmed in preclinical models to facilitate its clinical translation. Our work will eventually optimize treatment regimens for CRPC in the clinic and improve the life quality of patients. I am fully dedicated to an independent career in prostate cancer research field. The research plan will offer invaluable chances for me to enhance my research ability and build a comprehensive background in molecular biology, epigenetics, bioinformatics, and translational research. I will also be able to develop new projects using the results from this study, which can potentially be my focuses for my independent research. My mentor, Dr. Kexin Xu, is a highly productive scientist with extensive experience in prostate cancer research field. I will work closely with Dr. Xu and receive valuable training from her. Meanwhile, I will strictly follow my researcher development plan to gain the essential research skills, establish collaborations, develop new projects, and earn my own reputation in the prostate cancer research field. All of these will promote my competence and get me ready for an independent position in academia. The proposed project is quite likely to bring breakthroughs in prostate cancer research. There is currently no single study focusing on the roles of the bromodomain-containing proteins in drug-resistant CRPC; therefore, our work is very innovative and highly clinically relevant. This project is well-positioned to provide critical data for justifying the development of pharmacological inhibitors of the BRD protein ATAD2. Considering the fact that CRPC represents the lethal form of the disease and causes the majority of prostate cancer deaths, this on-target epigenetic drug will potentially benefit a large group of prostate cancer patients in urgent need.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710255
Entities
People
- Mei Yang
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio