Defining the Genetic Determinants of Head and Neck Cancer Progression and Immune Evasion Through Computational and Functional Investigation
Abstract
Our research proposal, Defining the Genetic Determinants of Head and Neck Cancer Progression and Immune Evasion Through Computational and Functional Investigation, seeks to improve our understanding and treatment of head and neck squamous cell carcinoma (HNSCC). Head and neck cancer is one of the fiscal year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas, and has particular impact on U.S. military Service Members and Veterans, due to its markedly higher incidence in these communities, and because its high symptom burden has led to elevated risks of suicidal self-directed violence in Veterans diagnosed with HNSCC. HNSCC arises from the lining of the mouth and throat. It is the seventh leading cause of cancer death around the world. The most aggressive types of HNSCCs are non-virus associated tumors, for which tobacco and alcohol exposure are major risk factors. These tumors, and the intense surgical, radiation, and chemotherapy treatment that we use to treat them, profoundly debilitate our patients speech, swallowing, breathing, and physical appearance. Unfortunately, there have been few new therapies for HNSCC over the past 3 decades; as a result, rates of recurrence have remained high and survival rates have not improved during this time. Because of the disproportionate impact of HNSCC on Service Members and Veterans, improvements in how we treat this cancer, and reduce risk of relapse, will have substantial impact on these patients and overall mission readiness - a PRCRP Military Health Focus Area. The major unmet clinical need we face in the field of head and neck oncology is that we have identified many genetic alterations in these tumors, but we do not yet have the necessary biological knowledge to understand what many of these genetic alterations mean for tumor behavior or how to target them with effective therapies. There is currently a daunting list of potential new targets and new drugs, and we need better data to prioritize the most promising clinical trials for this cancer type. To tackle this significant challenge, we have formed a collaborative multi-institutional team. Our team brings together scientific experts in HNSCC tumor genetics and animal modeling as well as immunology and immunotherapy, developers of new techniques to study the functions of genes in cancer models at scale, developers of new artificial intelligence-based analyses of large cancer genetics datasets, and clinical oncology experts in HNSCC in special populations such as Veterans. In Aim 1, we will use a novel artificial intelligence-based learning approach to glean new insights from a large set of clinical and tumor genomic profiling data for over 2,200 patients with head and neck cancer. This analysis will allow us to find new genetic alterations that predict aggressive tumors and poor survival in HNSCC patients, and to provide clinicians with an accurate prediction tool to help guide treatment decisions. In Aim 2, we will study the functions of these genes, and a set of genes suggested by prior research, by modeling what happens when they are altered in models of HNSCC that we have developed. These new models represent the human disease better than many existing models. We will determine how these genes affect tumor growth and metastasis, and whether these alterations we see in tumors confer resistance to chemotherapy or radiation therapy. Such treatment resistance poses major limitations in our current ability to treat patients. In Aim 3, we will examine a new dataset of over 300 HNSCC patients treated with immunotherapy, to identify genetic alterations that allow tumors to be resistant to these treatments. We will then perform experiments in mouse models of cancer to examine how these genes, and a list of genes we have selected from prior research studies, affect the ability of tumors to evade the immune system or to develop resistance to immunotherapies. Because most HNSCC tumors
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310557
Entities
People
- Robert Samstein
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army