Targeting a Novel Regulatory Mechanism of PARP1 Activation in Castrate-Resistant Prostate Cancer
Abstract
Emerging evidence suggests that inhibition of an important protein named PARP1 could be a promising therapeutic approach for cancer treatment. Recent studies demonstrate that metastatic castrate-resistant prostate cancers (CRPCs), the lethal form of prostate cancer with limited therapies, are responsive to PARP1 inhibition, which suggests that PARP1 inhibition could be a promising treatment for CRPC. However, the current class of PARP1 inhibitors has a lack of selectivity to cancer cells and could negatively impact normal cells. Therefore, there is an urgent clinical need for improving the specificity of PARP1 and lowering the off-target effects and toxicity. Our laboratory recently discovered a novel PARP1 regulatory protein, named Sam68, that is essential for the full function of PARP1 in cancer cells. We therefore hypothesized that targeting Sam68-PARP1 could be a novel strategy to develop a new category of PARP1 inhibitors for treating CRPCs. In this Idea Development Award project, we propose to utilize the high-throughput screening assays to screen an NIH library (100,000 drug-like compounds) and to examine the potential clinical relevance of the potent lead small molecule compounds for CRPC treatment using the preclinical models established in our laboratory. CRPC is the lethal form of prostate cancer with limited therapies that improve survival in this setting, and PARP inhibition could be a promising therapeutic. If successful, as a short-term outcome, our proposed research will screen and validate potent NIH library compounds that specifically inhibit PARP1. As a long-term impact, our study will establish the solid base that could lead to rational development of a new category of PARP1 inhibitors that will improve the specificity of PARP1 inhibition and lower the off-target effects and toxicity (e.g., nausea, fatigue, gastrointestinal upset, myelosuppression, anemia, neutropenia, and others) for better therapeutic value and modalities. Findings from our proposed research could significantly contribute to the goal of elimination of death from CRPC and enhance the well-being of Service members, Veterans, and all men experiencing the impact of the disease. In contrast to the conventional strategy, we proposed a new strategy to interrupt the newly identified regulatory mechanism on PARP1 activation, which is conceptually novel. Our proposed study will fulfill the urgent clinical need for improving the specificity of PARP1 inhibitors and potentially impact the following FY18 PCRP Overarching Challenges: “Develop treatments that improve outcomes for men with lethal prostate cancer,” and “Define the biology of lethal prostate cancer to reduce death.”
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910479
Entities
People
- Fengyi Wan
Organizations
- Johns Hopkins University
- United States Army