Targeting the CPSF Complex to Prevent Expression of AR Variants in Prostate Cancer
Abstract
Androgen Receptor in Prostate Cancer: Prostate cancer continues to be a leading cause of death for men in North America. The main factor required for all stages of prostate cancer development and progression is the androgen receptor (AR), a molecular signaling protein resident within prostate cancer cells that is switched on by male sex steroid hormones, such testosterone. When the AR protein is switched on by testosterone, it interacts with DNA to orchestrate a genetic program that promotes the growth of prostate cancer cells. The Problem - Prostate Cancer Therapeutic Resistance: Conventional therapies for prostate cancer that can’t be cured with surgery or radiation exploits this hormone requirement of prostate cancer cells by targeting the specific site on the AR protein that physically binds testosterone. The major problem for prostate cancer patients is that these AR-targeted therapeutic approaches are not curative because they invariably fail. This stage of the disease is lethal and termed castration-resistant prostate cancer. The importance of lethal castration-resistant prostate cancer is evident from three of the four fiscal year 2019 Department of Defense Prostate Cancer Research Program Overarching Challenges being focused on this disease stage: (1) develop treatments that improve outcomes for men with lethal prostate cancer, (2) reduce lethal prostate cancer in African Americans, Veterans, and other high-risk populations, and (3) define the biology of lethal prostate cancer to reduce death. How Our Research Addresses This Problem: We have found that the testosterone binding site on the AR protein becomes altered or lost in lethal prostate cancers. These alterations often switch the AR protein on permanently without the normal signal from testosterone, allowing it to continue interacting with DNA and orchestrating the genetic program that promotes the growth of prostate cancer cells. Because many prostate cancer therapies also target the testosterone binding site on the AR protein to turn the AR protein off, these therapies are ineffective for inhibiting growth of prostate cancer cells that have accumulated these alterations. Our preliminary data have shown for the first time that a cellular process termed alternative polyadenylation is responsible for the alterations to the testosterone binding site on the AR protein. Alternative polyadenylation has not been studied in the prostate cancer field, so our work is ideal for a funding mechanism that emphasizes “Idea Development.” One goal of our work is to understand the clinical relevance of alternative polyadenylation in tumors from patients with lethal prostate cancer. This will allow us to know whether the studies we are performing in prostate cancer models are accurate and properly reflect clinical prostate cancer. An additional goal of our work is to use these prostate cancer models to test the applicability of a new therapeutic we have developed to inhibit alternative polyadenylation. Our preliminary data show that inhibiting alternative polyadenylation therapeutically can reverse the alterations on the testosterone binding site on the AR protein, inhibit the testosterone-independent growth of prostate cancer cells, and restore therapeutic responsiveness to drugs that are designed to turn the AR protein off. Although our work is at an early stage, we are hopeful these new therapeutics we are developing to block alternative polyadenylation of AR will ultimately advance to clinical testing within 3-5 years of completing the studies proposed in this application. In this regard, our research will define the biology of lethal prostate cancer to reduce death, as well as develop treatments that improve outcomes for men with lethal prostate cancer. Since this alternative polyadenylation process appears to be active in a significant fraction of lethal prostate cancers, there is every reason to expect that a long-term outcome of our work could be a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010402
Entities
People
- Scott M Dehm
Organizations
- United States Army
- University of Minnesota