Exploiting Androgen Receptor s Allosteric Regulation to Develop Next-Gen Prostate Cancer Therapeutics
Abstract
Prostate cancer causes the death of more than 34,000 men each year in the United States alone. These deaths occur because metastatic prostate cancer stops responding to the current treatment options. The cornerstone approach for current treatment is androgen deprivation therapy. As the name suggests, androgen derivation therapy relies on depriving prostate cancer cells of androgens. Androgens are male hormones that bind a protein called the androgen receptor, which activates the androgen receptor and causes prostate cancer cells to grow. Androgen deprivation therapy blocks binding of androgens to the androgen receptor, which stops prostate cancer cell growth. However, over time, therapy fails, prostate cancer continues to grow because the androgen receptor uses alternative routes to become activated, and almost all patients die of their disease. We need new treatments that can block androgen receptor activity in prostate cancer that is no longer responsive to androgen deprivation therapy. Our laboratory is investigating how the activated androgen receptor controls prostate cancer cell growth, namely by turning on or off the expression of genes that control cancer growth. To control expression of these genes, the androgen receptor needs to partner with several other proteins that are known as coregulators. We have shown that this partnership is very gene-specific and that partnerships with different coregulators can turn on/off distinct sets of genes that are relevant for different aspects of prostate cancer progression. For instance, androgen receptor’s partnership with a coregulator known as WDR77 controls genes that are more relevant to metastatic prostate cancer that has returned after androgen deprivation; in contrast, its partnership with a coregulator known as STAT3 is less relevant. These results fit well with findings from other groups that show coregulator interactions induce distinct changes in the shape of the androgen receptor and then control distinct gene sets, a phenomenon scientifically known as allosteric regulation. This suggests that disrupting distinct interactions between androgen receptor and coregulators that contribute to aggressive prostate cancer growth (such as WDR77) may be especially worthwhile for development of new prostate cancer therapies. Unfortunately, critical information needed to succeed in these efforts is missing. For treatments that disrupt androgen receptor-coregulator partnerships to work, we need to understand the three-dimensional organization of these partnerships and how this organization impacts the expression of genes that are controlled by these partnerships. That is exactly what my proposal is designed to do. I propose to use new state-of-the-art technologies to unravel the three-dimensional interaction sites between androgen receptor and WDR77 and, as a control, STAT3, and define the impact of these two androgen receptor partnerships on the genes that the androgen receptor controls. Using information from these studies, I will design tools to disrupt these partnerships and determine whether they prevent growth of prostate cancer cells cultured in the lab and in animal models. My proposed study thus aligns well with FY22 PCRP overarching challenges to (1) define the biology behind prostate cancer progression to lethal stage and (2) develop treatment that improve outcomes for men with lethal prostate cancer. Results from my studies can ultimately slow progression of prostate cancer that kills men and may lead to an alternative and entirely novel therapy for advanced prostate cancer. If successful, my studies will lead to highly novel approaches to treat patients who (a) have locally advanced prostate cancer that cannot be treated effectively by surgery or radiation; (b) develop prostate cancer recurrence after initial surgery or radiation; or (c) develop recurrence after androgen deprivation therapy. By the end of this award, I will have obtain
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310802
Entities
People
- Ujjwal Dahiya
Organizations
- Cleveland Clinic
- United States Army