Targeting DNA Repair Pathways in Prostate Cancer
Abstract
Radiation therapy and chemotherapy both kill prostate cancer cells by damaging their DNA. However, cancer cells use cellular genes known as DNA damage repair genes to repair the DNA damage and survive these therapies: survival of cancer cell leads to therapeutic resistance and leads to poor outcomes and death from prostate cancer. Our recent findings that many lethal prostate cancers have DNA repair defects that can impact cancer vulnerability to different treatments has led to this grant application. We have now shown that a specific protein known as BRD4 is absolutely critical for DNA repair in prostate cancer. Importantly, this finding can be used in the clinic since drugs targeting BRD4 are in clinical trials. In this grant proposal, we plan to establish the molecular rationale for using drugs targeting BRD4 in three distinct contexts of prostate cancer: (1) Patients with advanced metastatic prostate cancer resistant to multiple therapies, in whom DNA damage repair genes are altered. Nearly a fourth of these patients may benefit from these drugs. Drugs targeting BRD4 may help to improve the survival of these patients. (2) Patients with intermediate-risk and high-risk localized prostate cancer: currently more than half of these patients will fail the conventional treatment with hormonal therapy and radiation and will progress to metastatic disease and death. Drugs targeting BRD proteins are likely to improve radiotherapy sensitivity and decrease risk of recurrence after radiation treatment by inhibiting DNA repair, improving overall survival. (3) Patients with inherited abnormal mutations in their DNA damage repair genes are at high-risk of developing lethal prostate cancer. Drugs targeting BRD4 may be useful as an early therapeutic intervention in these patients to prevent the development of lethal prostate cancer. We envision that our data will lead to clinical trials in patients with lethal prostate cancer and as an adjunct to radiation therapy in patients at high risk for developing metastatic disease. We also anticipate that within the 3-year time frame of this grant that we will establish a rationale for clinically testing drugs targeting BRD4 in prostate cancer. We also hope that we will develop a deeper understanding of the early events involved in the development of prostate cancer and identify therapeutic strategies to improve patient outcome with these agents.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710675
Entities
People
- Ram S Mani
Organizations
- United States Army
- University of Texas Southwestern Medical Center