Research Projects

Common skin melanomas (also called “cutaneous” melanomas) are typically caused by ultra-violet (UV) exposure from the sun. Mucosal melanomas arise from melanocytes in soft “mucosa” tissues, which have a much different architecture and composition. Since mucosa tissues are not sun-exposed, researchers do not know what causes these melanomas to form. We are studying multiple conditions which may contribute to the development of mucosal melanomas including:

• Fundamental differences between skin and mucosa melanocytes: Melanomas develop from normal cells called melanocytes, and understanding how the melanocytes in mucosa tissues are different from skin tissue could give us clues into mucosal melanoma development
• Possible viral, fungal, or bacterial cause: Mucosa tissue environments, such as the nose, rectum, and vagina, have a different composition of normal and pathogenic viruses, funguses, and bacteria. We are studying which species of these are present in mucosal melanomas, and whether they make be associated with causing it in the first place.

Immunotherapy is a new type of cancer treatment that is highly effective in cutaneous melanomas. It is also very effective in patients with acral melanomas. However, immunotherapy response rates in mucosal melanoma is overall less than cutaneous and acral melanoma, and mucosal melanomas are considered “cold” tumors with few immune cells surrounding them. We are taking multiple approaches to understand why they do not respond as well, and how we can improve responses:

• Signaling pathways underlying lack of immunotherapy response: Our preliminary data has highlighted one specific signaling pathway that is lost in mucosal melanomas, which may be an underlying reason for why they do not respond as well to immunotherapy. We are using small molecule inhibitors to re-activate this pathway in hopes of improving responses. Interestingly, this pathway is also lost in cutaneous melanomas that don’t respond, so this treatment could benefit patients with all subtypes of melanoma.
• Screening for drugs to improve immunotherapy response: Since we have developed a few cell lines from mucosal melanoma patients, we can use these cell lines to screen a large number of drugs and determine which drugs may have the potential to improve immunotherapy responses.

The majority of cutaneous melanomas have a mutation in the BRAF gene that can be targeted using drugs in the clinic. However, rare melanomas (including acral, mucosal, and ocular) rarely have these mutations and there are few “targeted” therapies in the clinic that can benefit patients with rare melanomas. We are working on identifying new targeted drugs that will be effective for rare melanomas:

• Drugs targeting the cell death pathway: Melanomas, including the rare subtypes, develop complicated ways of avoiding death. We are studying drugs that block the “anti-death” pathways as a strategy for killing tumor cells.
• Drugs targeting RNA splicing: We recently reported a high frequency of mutations in the SF3B1 gene in mucosal melanomas. The SF3B1 protein is a splicing factor that processes RNA, and we are currently working to determine if inhibitors of SF3B1 or its downstream targets could be effective in treating rare melanomas.
• Screening for novel targeted treatments: Since we have developed a few cell lines from mucosal melanoma patients, we used these cell cells and screened over 3500 compounds to determine which ones could effective kill rare melanoma cells. We have identified over 100 compounds and are investigating several new classes of drugs that may be effective in rare melanomas.