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Melanoma is the deadliest form of skin cancer. Detected in its earliest stages, melanoma is highly curable; however, the 5-year survival rate declines drastically for regional and distant metastatic disease. Recently, melanoma has emerged as the latest success story for both genomics- and immune-guided targeted therapy. Cutaneous melanoma is characterized by hotspot mutations in the mitogen-activated protein kinase (MAPK) regulators, BRAF and NRAS, found in approximately 50% and 25% of patients, respectively. The identification of these oncogenic mutations has led to the development of small molecule inhibitors targeting MAPK kinase kinases (MEK) and BRAF in melanoma. Although antitumor responses to MAPK targeted therapies have been dramatic; they are rarely durable. Furthermore, novel therapies targeting inhibitory immune checkpoint proteins have recently shown impressive clinical efficacy; nevertheless, biomarkers that predict response remain unclear.

For the past four years, I have led a number of multi-institutional collaborations (Hodis, Watson et al., 2012 Cell), which include The Cancer Genome Atlas project (TCGA, 2015 Cell), to characterize the melanoma genome and perform integrative analysis with multiple data platforms at the DNA, RNA, and protein levels. Our work has identified a number of novel significantly mutated genes in melanomas, which possess hotspot mutations in coding and non-coding regions. Based on the frequency and correlation of the most frequently significantly mutated genes, we established a framework for genomic classification into one of four subtypes: mutant BRAF, RAS, NF1, and Triple-WT (wild-type) melanomas. 

To improve on the current diagnostic and treatment modalities employed in the clinic, my lab will address the following questions:

1. What is the biological function and therapeutic relevance of novel significantly mutated genes discovered in our melanoma genome- and exome-sequencing studies?
2. How can we target melanomas lacking BRAF and RAS hotspot mutations with new approaches?
3. What are the mechanisms that mediate response and resistance to MAPK-targeted and immunotherapy?

To tackle these problems, my lab will employ computational approaches, in vivo models and biochemical techniques studying patient samples, cell lines, and melanoma mouse models.