Deciphering the Role of PRAC1 in Castration-Resistant Prostate Cancer
Abstract
Prostate cancer is highly dependent on the growth promoting action of male hormones, called androgens. Hormone therapy, the treatment with agents that block the effect of the male hormone androgen, is a highly effective way to suppress prostate cancer growth. Although most men initially respond to such medicines, resistance to this treatment emerges in almost all patients as tumors progress to an androgen deprivation- insensitive or castrate-resistant prostate cancer (CRPC) stage. The lack of response to these therapies poses a major challenge and is often associated with rapid progression of the tumor and poor outcomes. We therefore reasoned that, in order to effectively intercept this process, we need to understand how tumor cells can develop resistance to these hormone therapies. We have taken on this task in the laboratory and, through a series of experiments, we were able to unmask that a very small protein named PRAC1 appears to be at the center of orchestrating resistance to hormone therapy. When PRAC1 is lost, tumors can grow even in the presence of hormone therapy. Notably, we have found that ~30% of advanced prostate cancers no longer express PRAC1. We therefore hypothesize that by losing PRAC1, tumor cells gain the ability to grow, despite hormone therapy. We are now determined to find out how exactly PRAC1 permits treatment resistance and use these insights to identify new ways to treat advanced prostate cancer. In this proposal, we will take a closer look at PRAC1 and its role in prostate cancer. We will first investigate the relationship between PRAC1 in the tumor and the clinical presentation of a large number of men with advanced prostate cancer. We will then work to understand how PRAC1 loss changes the molecular makeup of prostate cancer cells using cutting-edge technologies. The ultimate goal of this research is to develop new and innovative therapies that allow us to uniquely target tumors in which PRAC1 is corrupted. To achieve this, we will perform genetic screens and we will develop a new set of therapies that will allow us to restore the normal function of PRAC1 and therefore make tumors sensitive to hormone therapy again. Prostate cancer is a devastating disease and we urgently need better therapies. The work proposed here will provide important new information on how prostate cancer can become resistant to hormone therapy. These insights will allow us to identify vulnerabilities and to develop novel ways to overcome resistance by delivering effective new treatments to patients suffering from advanced prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210199
Entities
People
- Michael C. Haffner
Organizations
- Fred Hutchinson Cancer Center
- United States Army