Targeting Replication Stress Vulnerabilities in Small Cell Lung Cancer
Abstract
Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, with approximately 20,000 cases diagnosed annually in the U.S. Most of these cases are related to smoking or other environmental exposures such as diesel exhaust or radiation, making SCLC a particularly devastating and relevant health concern for active duty Service members and Veterans in the U.S. SCLC is the most aggressive form of lung cancer; the overall 5-year survival rate is 7%. For decades, the only systemic treatment option for this disease has been chemotherapy, which is effective for most patients when it is first administered, but nearly all SCLC tumors come back, at which point chemotherapy no longer works. Therapies designed to act on SCLC’s molecular drivers have been developed, but have not significantly improved outcomes for patients. Immunotherapy is similarly only beneficial for a small fraction of patients. We propose research that addresses this urgent need for more effective drugs to treat SCLC, building on our work so far showing that this cancer is likely to be especially vulnerable to specific classes of drugs. Because SCLC cells proliferate at such a high rate and can survive even when their DNA is damaged, DNA replication often stalls, inducing a state called replication stress. This kind of stress can be exploited therapeutically using drugs that increase it by blocking the mechanisms that resolve it, such as the DNA damage response. We also have evidence that these drugs will work even better when combined with immunotherapy, because prolonged replication stress increases immune responses to affected cancer cells. Our studies will provide evidence to support clinical trials of this combination treatment strategy. Specifically, we will test whether a variety of drugs and genetic alterations that exacerbate replication stress prevent SCLC cells and tumors from growing and investigate the effects of these drugs on the immune-modulating properties of SCLC cells and immune responses to SCLC tumors. The latter studies will use both preclinical models and samples from patients on a trial of chemotherapy in combination with a drug that blocks repair of damaged DNA, which prevents escape from replication stress, and immunotherapy. This project is especially likely to advance the treatment of SCLC given the strengths of our team and the resources available at Memorial Sloan Kettering Cancer Center (MSK). Investigators on these studies, all experts in SCLC, include a renowned translational researcher who has pioneered several broadly innovative treatment strategies, an experienced leader of clinical trials, and a developer of key genetic models. At MSK, they have access to many patients with SCLC at various stages of disease and therapy; established infrastructure supporting the conduct of clinical studies, collection and banking of biological samples, and advanced sequencing technologies; and many resources supporting the development of new immunotherapies that are led by innovators in that field. Our research evaluating the potential of exacerbating replication stress as a means of treating SCLC directly addresses the following LCRP Areas of Emphasis: (1) identify innovative strategies for the treatment of lung cancer and (2) develop or optimize predictive markers to assist with therapeutic decision-making. If the expected clinical trials demonstrate clinical benefit of combining replication stress-targeted therapies with immunotherapy, such a combination could be included in current therapy guidelines. A new and efficacious treatment option would extend life expectancy for patients with SCLC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010602
Entities
People
- Triparna Sen
Organizations
- Sloan-Kettering Institute
- United States Army