Grant: Project Grant

Unlike the majority of cancers where the rate of newly diagnosed cases and deaths are declining, melanoma rates have been increasing significantly in both men and women. Skin cancer is the most common cancer in Canada, and in 2015, melanoma was responsible for 70% of skin cancer-related deaths. Much progress has been made in the development of treatment options for melanoma patients based on basic science discoveries. For example, from focused gene sequencing studies, we know melanoma is caused by mutations in two genes, BRAF and NRAS, that lead to uncontrolled growth of melanocytes in about 70% of patients. These findings led to the development of targeted therapies, so-called "smart drugs", designed against BRAF and targeting NRAS in an indirect way. Unfortunately, many patients that are given these "smart drugs" eventually develop resistance. Furthermore, targeted therapy options for patients that lack BRAF and NRAS mutations are limited. In contrast, other immune-based therapy that harness the power of a patient's immune system have shown incredible clinical utility for melanoma patients. However, over 50% of melanoma patients do not have durable long-term responses to immune therapy. It is still unclear why some patients respond to immune therapy and why others do not. With the advent of next generation sequencing technology, we recently gained the ability to sequence all genes in many melanoma patient samples. Our studies revealed half of patients that lack mutations in BRAF and NRAS possess mutations in a gene called NF1. However, it is still unclear how we can use this information in the clinic to treat patients. Our preliminary work suggests that NF1 regulates components of the immune system that may have implications for immune therapy response. The goal of this project is to understand how NF1 promotes melanoma and modulates the response to immune therapy, as well as to develop novel therapeutic strategies to treat this melanoma subtype.