Identification of Novel Biomarkers in African American Prostate Cancer for PARP Inhibitor Sensitivity Beyond the Canonical Homologous Recombination Genes
Abstract
African American men are more likely to be diagnosed with prostate cancer, tend to be diagnosed at younger age and with more advanced disease, and are more than twice more likely to die of prostate cancer than white men. While the precise reasons for these disparities are unknown, socioeconomic factors affecting access to and utilization of health care as well as genetic and environmental factors are implicated. Successful completion of this project will provide insights into the biology underlying these prostate cancer disparities, will improve our ability to specifically target highly aggressive prostate cancer, and will identify novel diagnostic and therapeutic approaches across prostate cancer subgroups. An accumulating body of recent studies suggest that the distribution of molecular subtypes in prostate cancer varies by race and ethnicity. In this study, we aim to characterize alterations that are differentially present between African American and Caucasian American prostate cancer and cause cellular instability and vulnerability, resulting in opportunities for new treatments. In Preliminary unpublished studies, we have discovered that the loss of a gene called CHD1 and the presence of mutations in another gene called SPOP are two alterations that are more frequent in African American prostate cancer compared to Caucasian American prostate cancer. In our proposed study, we aim to validate these preliminary observations in larger groups of prostate cancer specimens. Next, we aim to understand the consequences of these alterations for the prostate cancer cell. Specifically, we propose to investigate how SPOP mutation and/or loss of CHD1 disrupt the function of the androgen receptor (AR) in the prostate cancer cell. Moreover, we will also investigate whether African American prostate cancers that have lost the CHD1 gene or harbor mutations in the SPOP gene experience higher levels of DNA damage and whether they are less effective in repairing damage to their DNA. We provide preliminary data in support of deficiency in DNA damage repair in prostate cancer cells that have alterations in SPOP and CHD1. Last, we propose to investigate whether African American prostate cancers with SPOP mutation and/or CHD1 loss are more sensitive to a class of drugs called PARP inhibitors. In 2020, the FDA approved two PARP inhibitors for the treatment of advanced prostate cancer: Olaparib and Rucaparib. These inhibitors were approved for men with metastatic castration-resistant prostate cancer who have certain genetic mutations (in genes such as BRCA1, BRCA2, or ATM) that impair their capacity to repair DNA damage. We propose that the utility of PARP inhibitors can be expanded to additional men with prostate cancer who do not have a genetic mutation in the DNA damage repair pathway but harbor a mutation in SPOP or loss of CHD1. We hypothesize that SPOP mutation and/or CHD1 loss create a state of cellular malfunction that is similar to the one caused by genetic mutation in the DNA damage repair pathway such as the BRCA1, BRCA2, or ATM mutations. Because SPOP and CHD1 are important for protein modifications of DNA damage repair proteins, prostate cancer-specific alterations of SPOP and CHD1, which are significantly upregulated in African American prostate cancer, result in defects in the protein modifications necessary for repair of DNA damage and, hence, create a state of therapeutic vulnerability. We propose that African American prostate cancer, including hormone-sensitive prostate cancer, with SPOP mutation and loss of the CHD1 gene will be highly sensitive to PARP inhibitors. We propose to test these hypotheses in novel preclinical models. Successful completion of this project will pave the way for an individualized approach for early detection, disease stratification (indolent vs. aggressive), and prediction of treatment response to PARP inhibitors in African American men. Ultimate Applicability of the Research
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110253
Entities
People
- Salma Kaochar
Organizations
- Baylor College of Medicine
- United States Army