Leveraging Conditional DNA Repair Deficiency for Synthetic Lethality in Lung Cancer
Abstract
Scientific Objective and Rationale: The goal of this project is to develop a mechanism-driven therapeutic combination that could lead to first-in-human clinical trials in patients with lethal non-small cell lung cancer (NSCLC). Our overall objective here is to determine the utility of combining Food and Drug Administration (FDA)-approved inhibitors of Poly (ADP-ribose) polymerase (PARP) and Cyclin-dependent kinase 4/6 (CDK4/6) for the treatment of a subset of patients with lethal NSCLC. A majority of patients with lethal NSCLC are unlikely to benefit from single-agent treatment with PARP inhibitor because they rarely display mutations in canonical DNA damage repair genes. We endeavor to exploit using CDK4/6 inhibitor as a means to partially turn off the DNA repair response that can be selectively potentiated by PARP inhibitor. Our plan is to test this combination strategy in different lung cancer models. The overarching hypothesis is that CDK4/6 inhibitor combined with PARP inhibitor blocks DNA damage repair in lung cancer and produces a combined effect greater than the sum of their separate anti-tumor effects. LCRP Area(s) of Emphasis: This application addressed one of eight Areas of Emphasis: Identify innovative strategies for prevention and treatment of lung cancer. Ultimate Applicability of the Research: This project is to develop combinational treatment strategies to improve the efficacy of PARP inhibitor and identify biomarkers to stratify responsive patients in the context of lung cancer. What types of patients will it help and how will it help them? This project aims to enlarging the number of candidates for PARP inhibitor therapy to those that are proficient for DNA damage response. What are the potential clinical applications, benefits, and risks? By focusing on FDA-approved drugs, this approach could dramatically simplify the path to clinical trials and reduce the failure of potential therapeutics at later stages of testing. This approach could also reduce the timeline and costs of bringing a therapeutic combination to benefit military Service members and their families in need. What is the projected time it may take to achieve a clinically relevant outcome? If successful, our studies will provide a solid basis for translating this combination strategy into the clinical setting in the near future. We would expect that we could immediately translate this knowledge into clinical trials to develop a more effective therapeutic combination for patients with lethal lung cancer. What are the likely contributions of this study to advancing the field of lung cancer research? The proposed study will advance the lung cancer field by helping us elucidate the impact of cell cycle manipulation on vulnerability to PARP inhibitors in lung cancer. The primary contribution of our proposal relates to the clinical implementation of FDA-approved PARP and CDK4/6 inhibitors, personalized for a subset of lung cancer patients. How is the project relevant to military Service members, Veterans, and their families? The proposed research will help patients with the most common type of lung cancer. In addition, military Service members and Veterans develop lung cancer at a much higher rate than the general population, making it highly relevant to many people.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910645
Entities
People
- Yi Yin
Organizations
- United States Army
- University of Texas Southwestern Medical Center