Targeting BRD9 in Treatment-Resistant Prostate Cancer
Abstract
In the United States, prostate cancer is the most common cancer diagnosed in men. Every year, 191,930 men will be diagnosed with prostate cancer and 33,330 men will die. Surgery can cure local cancers, but about half of these develop into metastatic cancer that require drug treatment. These drugs target androgen-dependent cancer growth by inhibiting testosterone production or inhibiting testosterone from binding to the androgen receptor (AR). In castration-resistant prostate cancer (CRPC), the androgen receptor can function in regulating genes even in the presence of these therapies. The majority of prostate cancer deaths are from castration--resistant prostate cancer because there are no effective treatments. One approach to treat castration-resistant prostate cancer is to block proteins that allow the androgen receptor to function in the presence of these therapies. Many of these proteins are epigenetic regulators, which means they make it easier for androgen receptor to turn genes on. We recently identified an epigenetic regulator called BRD9, which is increased in patients whose cancers have come back after therapy. BRD9 is not required for most cells to survive, but is required for castration-resistant prostate cancers to survive. In part of this grant, we aim to understand how BRD9 allows prostate cancer cells to become resistant to therapy. This addresses the FY21 Overarching Challenge to define the biology of lethal prostate cancer to reduce death. Understanding how cells become resistant to therapy by changing their genome will provide new avenues for battling and preventing lethal prostate cancer. In the rest of this grant, we will determine whether targeting BRD9 with drugs can treat castration-resistant prostate cancer. There are several drugs available that inhibit BRD9, and we have found that these drugs kill castration-resistant prostate cancer cell lines. We want to determine whether these drugs can be used in mice to kill castration-resistant prostate cancer or prevent castration-resistant prostate cancer from happening in the first place. This addresses the FY21 Overarching Challenge to develop treatments that improve outcomes for men with lethal prostate cancer. Drugs that target BRD9 are being developed in the pharmaceutical industry for rare childhood cancers. If we successfully define BRD9 as a minimally toxic target for castration-resistant prostate cancer, we will provide support for pursuing Food and Drug Administration approval for BRD9 therapies. Importantly for prostate cancer patients with no other treatment options, we will provide support for designing clinical trials to treat castration-resistant prostate cancer with BRD9 drugs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210222
Entities
People
- Emily C Dykhuizen
Organizations
- Purdue University
- United States Army