AR Alternative Polyadenylation as a Therapeutic Vulnerability in Prostate Cancer
Abstract
Scientific Objective: Prostate cancer is the second leading cause of male cancer death in the United States. While many patients can be cured by radiation or surgery, a subset will form prostate cancer that spreads throughout the body, called metastatic prostate cancer. Treatment for metastatic prostate cancer can initially be controlled by androgen-deprivation therapy, a process that stops the androgen receptor that is responsible for detecting male hormones in the body. While effective initially, patients on androgen-deprivation therapy typically develop a more aggressive form of the cancer termed castration-resistant prostate cancer. This form of the cancer is responsible for practically all prostate cancer-specific deaths. One major cause of resistance in castration-resistant prostate cancer is thought to be the emergence of androgen receptor-variants. Androgen receptor-variants are altered forms of the androgen receptor that are resistant to typical androgen receptor targeted therapies. This proposal aims to determine novel ways to stop emergence of androgen receptor-variants so that patients can be treated more effectively by androgen-deprivation therapy. Current therapies for castration-resistant prostate cancer prolong survival, but they are not curative, highlighting the importance of identifying new treatment options. Discovering new methods to target androgen receptor-variants in patients will provide more therapeutic options to serve as alternatives or complements to current therapies in castration resistant prostate cancer patients to prolong survival. Research Applicability: This research will help men with metastatic prostate cancer who develop resistance to androgen-deprivation therapy. Androgen receptor-variants are resistant to current treatments, and this proposal studies a process that is critical for the emergence of androgen receptor-variants in castration-resistant prostate cancer. I have demonstrated that I can manipulate this process to inhibit androgen receptor-variants in castration-resistant prostate cancer cells, and this proposal will test the ability of this manipulation to inhibit growth of castration-resistant prostate cancer cell lines and mouse models of castration-resistant prostate cancer. I will examine growth of these treated models in androgen-deprivation conditions and with treatment of androgen receptor targeted therapies to mimic therapies that patients undergo routinely in the clinic. The methods I propose to manipulate this process are already used in the clinic to treat other disorders, and I expect this work to provide a strategy that can transition quickly to clinical testing. This research will also study factors that drive androgen receptor-variants in castration-resistant prostate cancer, and this information can be used for the development of novel drug targets and serve to screen for patients at high-risk for development of castration-resistant prostate cancer. Overall, this work aims to provide new treatment options that can be provided alone or in combination with current therapies in patients to prolong survival, as well as learn the factors that drive castration-resistant prostate cancer so that we can manage this disease more effectively. Career Goals: My overall career plan is to be an independent researcher that pioneers novel treatment options for castration-resistant prostate cancer to increase the likelihood of survival for patients. One of the main reasons we conduct science is to improve the quality of life for society and the work in this proposal will help improve the lives of prostate cancer patients. The proposed research I will conduct during my postdoctoral training will allow me to apply my established skills and understanding of basic regulation in biology to discover new therapeutic options for patients suffering from castration-resistant prostate cancer. The mentorship from Dr. Dehm and Dr. Ryan, the enriching environment fro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210098
Entities
People
- Kiel Tietz
Organizations
- United States Army
- University of Minnesota