Mechanism of Hormone Independence and Drug Resistance in Prostate Cancer
Abstract
Following surgical or hormonal castration, men with metastatic prostate cancer commonly progress to so-called "castration-resistant prostate cancer" (CRPC), the lethal form of the disease. Unfortunately, the majority men with CRPC survive for less than 2 years. Despite the recent Food and Drug Administration approval of drugs such as abiraterone that block the production by the tumor of male hormones, androgens, and enzalutamide, a drug that more effectively blocks the protein in cells that responds to androgens, the androgen receptor (AR), most men with CRPC will die from their disease. Work from many groups including our own has shown that the growth of CRPC tumors relies on persistent AR signaling even in an environment lacking androgens. The ability of AR to continue to function is the result of changes in the program of the cell, its epigenetic state. A protein that plays an important role in epigenetic regulation, EZH2, has been proposed as a potentially promising new drug target for the treatment of CRPC. EZH2 is overexpressed in CRPC and has been shown to work with AR to regulate the development and growth of CRPC in model systems. Recently, several pharmaceutical companies have been developing EZH2 inhibitors for the treatment of other cancers including lymphoma and melanoma. Our work suggests that these drugs may be effective in the treatment of CRPC as well. Despite these exciting advances, the mechanisms that govern the progression of prostate cancer to CRPC are unknown, and even with optimal AR blockade, men with advanced CRPC invariably relapse. This proposal will employ a revolutionary gene-editing approach termed genome-wide CRISRP/CAS9 screens to systematically identify the key genes underlying hormone independence and drug resistance in CRPC. Identification of these genes will provide both new therapeutic targets and predictive biomarkers of response to therapies targeting AR and EZH2. This Synergistic Idea Development Award builds on the prostate cancer biology expertise of the Brown lab and the sophisticated computational know-how of the Liu group. A track record of more than a decade of very productive collaboration between these two groups that has produced a number of important innovations predicts for the success of this project.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510593
Entities
People
- Myles A. Brown
Organizations
- Dana–Farber Cancer Institute
- United States Army