Delineating Germline, Tumor, and Extrinsic Factors Driving Mucosal Melanoma Risk and Response
Abstract
Melanoma is a cancer of the pigment-producing cells in the body. While most melanomas occur in the skin and are associated with sun exposure, there is a much less common variety called mucosal melanoma (MM) that can arise in internal mucosal tissue, like the lining of the nose, the colon, the vagina, and other sites. While we have learned a great deal about melanomas of the skin, leading to much more effective treatments, we know very little about MM – we do not currently understand how they arise, what are the risk factors, the genetics, and why they respond much less well to therapies that can cure melanomas of the skin, even when they have spread throughout the body. The work we propose here aims to bring a new, deeper level of understanding of MM with the goal of improving patient outcomes. It directly addresses the following Fiscal Year 2021 Melanoma Research Program Focus Area(s) in Section II.A.1: (1) Identify and understand risk factor determinants for melanoma, including variants (mucosal melanoma); (2) Identify how the tumor microenvironment (e.g., stromal, immune, microbiome) impact tumor initiation, response to therapy, progression, and dormancy; and (3) Delineate the molecular pathways, tumor microenvironment, and immune response that influence metastatic spread, recurrence, and/or dormancy. The work we propose focuses on two key areas that draw these focus areas together. We will determine the role of genetics in increasing the risk of MM by looking at the constitutional DNA of patients for gene mutations that are likely to have been involved in cancer development. This will include genes we already know can be involved in cancer families. We and others have already seen MM patients with these mutations, suggesting they could be important, and the work proposed will confirm this and establish how common they may be. We will also have a comprehensive look to identify the other genes that can increase risk to fully understand the genetics of MM – thus painting a complete picture of MM genetics. This work may lead to better tests and therapy choices for MM patients. The second focus area will be on developing a deep understanding of response to immune therapies. Immune therapies are the most effective treatment we have for skin melanoma, but they are much less effective for MM patients. This will involve a comprehensive study of patients’ cancers as we treat them to see what changes correlate with response or resistance. Importantly, we will focus on the whole patient, studying their microbiomes and diet in concert with the study of their tumors. This unified approach, particularly focusing on patient modifiable influences of response, will allow for new biological insights and opportunities for partnering with patients to improve response and outcomes. These tactics have changed the course of disease for skin melanomas, with our team playing an important role in these advances. The work proposed will focus this proven approach on MM patients. We expect the work our team is going to undertake to have important impacts on the outcomes for MM patients within 3-5 years. Ultimately, a deeper understanding of the many facets of MM in patients, from risk to treatment response to the role of modifiable factors, are the key to better prevention, detection, and treatment of this rare disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210973
Entities
People
- P. Andrew Futreal
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army