Defining Androgen Receptor Function and Disease Dependencies in BRCA1/2-Deficient Prostate Cancer
Abstract
Objective and Rationale: Mutations in the genes BRCA1 and BRCA2 are common in prostate cancer and are associated with poor response to treatment and progression to the incurable form of disease. These mutations can be inherited (germline mutations) or acquired by prostate cancer cells as the disease progresses (somatic mutations). Most prostate tumors rely on androgens and the androgen receptor (AR) for tumor growth, so blocking AR is the foundation of prostate cancer treatments; however, prostate tumors with mutations in BRCA1 and BRCA2 are often resistant to these treatments. Activated AR is a transcription factor that binds to DNA to regulate which genes are expressed within the cell. The sets of genes that AR regulates is dependent on many factors, including how the DNA is organized (chromatin structure). Both BRCA1 and BRCA2 have potential roles in regulating this DNA organization; therefore, our first objective is to determine how loss of BRCA1 and BRCA2 alters chromatin structure, and how this relates to changes in AR activity. PARP inhibitors can be used to treat tumors with BRCA1 and BRCA2 mutations, but most patients eventually develop resistance to this treatment as well. Although PARP inhibitors have been used mainly as a late-line treatment after prostate cancer progresses on anti-AR treatments, combination treatment with PARP inhibitors and anti-AR therapies is now being investigated as a first-line treatment for metastatic prostate cancer. PARP plays a role in the regulation of gene expression, and the DNA damage induced by PARP inhibition changes chromatin structure. It is not known how PARP inhibitor treatment alters AR function, and what treatments will be effective for prostate cancer patients who progress on this new combination therapy. Therefore, our second objective is to determine how PARP inhibitors alter AR function. Our third objective is to determine which genes are required for the growth of prostate cancer cells that have acquired resistance to PARP inhibitor and anti-AR combination therapy, and to validate these genes as potential therapeutic targets. Research Applicability: This proposal addresses the PCRP overarching challenges to define the biology of prostate cancer progression to lethal prostate cancer to reduce death and develop treatments that improve outcomes for men with lethal prostate cancer. This work will help define how BRCA1 and BRCA2 mutations and PARP inhibitors alter AR function in prostate cancer cells. This is important to understand since most prostate cancer treatments are based on targeting AR. It may also provide direction for the development of new treatments for BRCA1 and BRCA2 mutant prostate cancer. This study will also identify the therapeutic vulnerabilities of prostate cancer cells which have acquired resistance to PARP inhibitor and anti-AR combination treatment. Since nearly all patients treated with this combination treatment will eventually experience disease progression, this study will provide important insight into which treatments will be effective for these patients. Principal Investigator Career Goals: My career goal is to join the faculty at a cancer research center, where I plan to run a research program focused on androgen receptor function and resistance to anti-AR treatments in prostate cancer. The resources provided by this award will allow me to develop skills in generating and analyzing chromatin-based data and genome-wide screens, which will be crucial to my development as an independent prostate cancer researcher. My mentor, Dr. Myles Brown, is widely recognized as a leader in the field of AR biology and chromatin structure in prostate cancer, and he has trained >30 previous postdoctoral fellows who have gone on to successful careers as independent researchers. As part of the Brown lab, I will have the opportunity to connect with other prostate cancer researchers as part of the Dana-Farber/Harvard Cancer Cent
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310910
Entities
People
- Nicole Traphagen
Organizations
- Dana–Farber Cancer Institute
- United States Army