Targeting Notch Signaling to Augment Immunotherapy in Small Cell Lung Cancer
Abstract
Immunotherapy has revolutionized the treatment of cancer, particularly cancers of the lung. Today, because of immunotherapy, many patients with metastatic lung cancer have a chance for long-term remission. However, the greatest benefit with immunotherapy is among patients with non-small cell lung cancer (NSCLC). For patients with small cell lung cancer (SCLC), the benefit of immunotherapy has been modest and long-term remissions are rare. In the United States, 34,000 people are diagnosed yearly with SCLC with a mortality rate of 95%. Moreover, SCLC is a significant cause of morbidity and mortality within the Veteran and military Service populations. Until recently, very little has been known about why response to immunotherapy in SCLC is modest. Last year we discovered that activation of a particular pathway known to be suppressed in SCLC, the Notch pathway, is enriched in SCLC patients with clinical benefit to immunotherapy. This work is among the first to show a specific mechanism that may be altering immune response in SCLC. In our proposal, we seek to further understand why patients with SCLC with activation of the Notch pathway have the greatest benefit to immunotherapy. The project will focus on the following LCRP Areas of Emphasis: (1) identify innovative strategies for the treatment of lung cancer and (2) develop or optimize prognostic or predictive markers to assist with therapeutic decision making. Through experiments with SCLC preclinical models, we will decipher whether the Notch pathway boosts activity of a key immunomodulatory protein, known to be important for anti-tumor immune response. Moreover, we will use animal models to assess whether clinical stage pharmacologic drugs that activate the Notch pathway can boost the anti-tumor immune response. We will also assess whether high expression of a critical Notch pathway gene in SCLC patient tumors is associated with better survival with the addition of immunotherapy to chemotherapy. The studies in this proposal are anticipated to lead to new clinical trials designed to augment immunotherapy in SCLC within 2-3 years. Such clinical trials will be of great importance to improving outcomes of SCLC patients, including those within the Veteran and military Service populations. The goal of these studies and future clinical trials is to develop immune based therapies that will lead to long-term remissions for all patients with SCLC. My career goal is to become a physician-scientist studying and developing new therapies for patients with SCLC. This award will provide the means to study clinically relevant questions and provide a strong basis for me to continue studying SCLC in my own independent laboratory.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310093
Entities
People
- Nitin Roper
Organizations
- National Cancer Institute
- United States Army