Despite recent therapeutic advances, melanoma remains a major burden that is expected to rise faster than any other cancer in the coming decades. Surgery is frequently curative when tumors are confined to the skin, however long-lasting and/or curative treatments are currently lacking for patients diagnosed with metastatic disease, that is, those whose tumors have spread to other organs. Novel-approved targeted agents have impressive initial efficacy in a subset of melanoma patients; however, therapeutic resistance has been almost universal. In contrast, immunomodulatory therapies can produce durable responses, but these occur rather infrequently and are often associated with significant toxicity, generate resistance to immunotherapy eventually, and are ineffective against melanoma with low immune-infiltrates. Collectively, these treatments have been unable to substantively reduce the mortality of metastatic melanoma patients, Thus, there is a clear need for new therapeutic targets and approaches. Proteins in the cell membrane often acquire sugar modifications, which shape the interactions between a tumor cell and its environment. For instance, these sugar branches modify the recognition of tumor cells by the immune system and their ability to invade and colonize other organs. We have found that certain enzymes that modify those sugar branches (called glycosyltransferases) are altered in melanoma patient tissues during melanoma dissemination in various organs. We plan to elucidate how those sugar structures and the enzymes in particular a specific type of glycosyltransferases known (FUT8) is responsible for interaction with immune cells in the tumor microenvironment and plays a role in immune escape. Elucidating the novel mechanisms of action by a-1,6 fucosyltransferase in melanoma will be of prime importance not only for our understanding of cancer biology but also to developing novel therapies for personalized medicine.

Applicability of the research. Inhibitors designed against specific glycosylation enzymes and glycosidases are already being used in the treatment of metabolic disorders (Zavesca for Gaucher’s disease) and infectious diseases (i.e. Relenza) and Tamiflu)). However, they remain relatively unexploited as anti-cancer agents, in part due to our partial understanding of the mechanism of action in various cancer. Our proposal will address this issue by identifying the mechanism of action of FUT8 against resistance to immunotherapy in melanoma. In addition, because sugar branches can be highly specific to tumor cells and trigger an immune response, they are ideal candidates for the development of small-molecule inhibitors. Therefore, our studies have the potential to open an unexplored avenue for melanoma therapy, alternative or complementary to current immunomodulatory strategies.