Deciphering Altered Metabolism and Immune Evasion in FAT1-Mutated Head and Neck Cancer
Abstract
Our research proposal, Deciphering altered metabolism and immune evasion in FAT1-mutated head and neck cancer, seeks to advance our understanding and treatment of head and neck squamous cell carcinoma (HNSCC). Head and neck cancer is one of the Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas, and is a cancer type with markedly higher incidence in U.S. military Service Members and Veterans. HNSCC arises from the lining of the mouth and throat. It is the sixth leading cause of cancer death around the world. The most aggressive type 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 treatments that we use to treat them, have devastating effects on our patients’ speech, swallowing, breathing, and physical appearance. Unfortunately, there have been few new therapies for HNSCC over the past three decades; as a result, rates of recurrence have remained high, and survival rates have not improved during this time period. Since HNSCC has a disproportionate impact on Service Members and Veterans, improvements in the treatment of this cancer and a reduction in the risk of relapse will have a substantial effect on these patients and their overall mission readiness – a PRCRP Military Health Focus Area. In the field of head and neck oncology, we have already identified many genetic alterations in these tumors, but we face a major unmet clinical need when it comes to understanding the biological underpinnings of what many of these genetic alterations mean for tumor behavior, or how to target them with effective therapies. This study focuses on the second most commonly mutated gene in HNSCC, FAT1, which has a largely unknown function. FAT1 is genetically inactivated in close to 30% of HNSCCs, but it is unclear whether, or how, this inactivation promotes cancer cell growth and aggressiveness. However, we have recently discovered that this gene is associated with changes in the metabolic functions of tumor cells, which may allow HNSCC cells to grow more aggressively and create a microcellular environment that counteracts the immune system’s ability to recognize and eliminate cancer cells. To tackle this significant challenge, we have formed a collaborative team. Our team brings together scientific experts in HNSCC tumor genetics and animal modeling as well as experts in studying cancer cell metabolism in living tumor cells and in sequencing data from tumor cell DNA and RNA. Our study leverages the unique resource of a novel model of HNSCC that we have developed, which initiates tumors that closely resemble the human disease in the mouth of mice. In Aim 1, we will use specialized scientific equipment that can measure the changes in how tumors consume nutrients and oxygen, to identify how mutation of the FAT1 gene affects tumor cell behavior, and to go a level deeper by examining how the FAT1 protein interacts with mitochondria inside cells. In Aim 2, we will examine the immune cells that infiltrate tumors and study mechanisms by which FAT1 can affect the function of anti-tumor immune cells. Over 3 years, by completing these two Aims, we will learn important information about what mutations in FAT1 mean for patients with HNSCC tumors. Our patients need new therapies, but the current number of possible treatments being investigated in clinical trials is daunting. This study’s analyses will allow us to find new genetic markers of tumor behavior, which will help clinicians choose better therapies, and to identify previously unknown cellular processes that we should investigate targeting in HNSCC tumors with FAT1 alterations. Ultimately, this improved knowledge of HNSCC will help us to focus our field’s collective effort on the most promising new treatment strategies, and to improve outcomes and reduce toxicity for patients suffering with this cancer. Focus
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210672
Entities
People
- Luc Morris
Organizations
- Sloan-Kettering Institute
- United States Army