Elucidating Tumor Intrinsic and Extrinsic Drivers of Mucosal Melanoma
Abstract
This project is focused on understanding the biology of mucosal melanoma (MM), a rare and understudied form of melanoma that is distinct from the more common skin melanoma, cutaneous melanoma (CM). It is clear that MM is rare, aggressive, and less likely to respond to the existing therapies that show benefit in skin melanoma (CM). This disease has been challenging to study because the patients present to many different medical specialties based upon the site of their disease (head and neck, female reproductive tract, male reproductive tract) making large-scale studies challenging. The team for project 1 has built a large scale collaborative effort across multiple academic hospitals and bridging across many specialties to create a very unique resources of MM patient tumors across the spectrum of disease allowing them to ask multiple different questions of value to MM patients and the MM community: 1. How does the biology of initial, localized MM differ from MM that has metastasized to other organ sites? 2. Why do some patients with MM respond to current therapies while others do not? 3. How does MM biology change over time or after treatment within an individual? The combination of these complementary studies in different phases of care for MM patients allows the team to identify MM biology that will allow more successful therapies for MM. In addition, these different clinical contexts allow the team to understand in which setting (prevention of metastasis, treatment of metastasis) a given therapy may be most relevant. Therefore, the projects will add short-term value in the form of knowledge, therapeutic options, and how to most effectively deploy them in the clinic. The Principal Investigator s team will accomplish these goals by using multiple different approaches to examine the genetics of the tumor, changes in the immune cells within the tumor environment, and how these variables correlate with clinical outcomes (good or bad). The data generated from this project will be freely shared and available to the melanoma community as resources for other research projects. In addition, throughout this project the team will create resources for the melanoma community including cell lines and tools for high throughput studies of patient samples, called a tissue microarray. The in-depth studies using the latest available technology to study bulk tumor and single-cell resolution analysis of tumor-immune interactions will be applied to highly specific MM patient populations to answer key questions of relevant to MM patients. This will have a direct impact on Service Members, their Families, Veterans, and patients with MM. The long-term goal is to identify targets for prevention of metastasis (Aim 1), improve therapy response (Aim 2), and understand the biological evolution over time and during treatment (Aim 3). MM, a melanoma that arises on surfaces that line internal organs, is a rare and deadly disease. Patients with MM have an increased chance of life-threatening metastasis and a decreased chance of responding to existing therapies. Instead of DNA damage from the sun that occurs for skin melanomas, MM have rearrangements of their DNA with extra copies of some genes and loss of other genes. It is unknown how these genetic changes contribute to mucosal melanoma. It is also unknown why patients do not have many lasting responses to existing immunotherapies, although it is likely that the lack of sun-associated mutations may contribute. Our objective is to build animal models to: (1) discover what causes mucosal melanoma to be deadly and (2) to test new immune system activating strategies that may help patients respond strongly to immune therapies. We anticipate that animal models for MM will allow us and other groups to discover successful therapies for MM patients. Our team has recently made the first animal model of MM by copying genetic changes that occur in MM patients. Our zebrafish mode
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310948
Entities
People
- Genevieve Boland
Organizations
- Massachusetts General Hospital
- United States Army