Frequent Loss of CHD1 in the Prostate Cancer of African Americans and Its Potential Role in Increased Sensitivity to Platinum or PARP Inhibitor-Based Therapy
Abstract
African American individuals with prostate cancer have significantly worse clinical outcomes than European Americans with the same disease. In our preliminary analysis, we identified a specific molecular aberration that is present in up to 40% of African American prostate cancer cases, two to three times more frequently than in European Americans with the same disease. This aberration, the loss of the CHD1 gene, leads to impaired homologous recombination (HR) and increased genomic instability. HR deficiency, however, can be therapeutically exploited by either platinum- or PARP inhibitor-based therapy. In this proposal, we will seek evidence that clinical samples of African American prostate cancer cases indeed show robust signs of homologous recombination deficiency, and therefore are likely respond to platinum agents or PARP inhibitors. Our results are expected to change significantly the course of disease in African American prostate cancer cases, since the molecular mechanism rendering those cases more aggressive will also make them particularly sensitive to the above-described therapeutic approaches. Consequently, if our hypothesis is correct, the outcome of aggressive prostate cancer in African American individuals will significantly improve, and thus the differences in outcome between African American and European American individuals will be significantly reduced. Since platinum is a widely used cancer therapeutic agent and our clinician collaborators have used this agent for the treatment of aggressive prostate cancer in clinical trials, platinum-based therapy could soon enter everyday treatment practice. Similarly, clinical trials with PARP inhibitors for the treatment of HR-deficient aggressive prostate cancer are in advanced stages; therefore, PARP inhibitors may also enter clinical practice in the very near future. Our results may well change the treatment of aggressive prostate cancer in African Americans in the foreseeable future (2-4 years). Our aim with this proposal is to provide a strong biological rationale and validated diagnostic biomarkers to prioritize patients most likely to respond to these forms of therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1820056
Entities
People
- Zoltán Szállási
Organizations
- United States Army