Modeling UV-induced Initiation and Progression of Human Melanoma in the Mouse

Authors

• HT Michael
• C Day
• A Michalowski
• M Lee
• G Merlino

Abstract

The main causes of cancer-related deaths, including from melanoma, are recurrence and metastasis following therapy. Although pathway-targeted drugs elicit significant clinical responses, melanomas invariably recur. Immune checkpoint inhibitors elicit durable clinical responses, but only in a subset of patients. Dissection of processes underpinning recurrent/metastatic melanoma should identify new targets for more efficacious treatment. We hypothesized that metastatic melanomas exploit hardwired pathways employed by embryonic melanocytes to achieve an aggressive phenotype. We tested this in GEM models that allowed us to isolate melanoblasts and identify genes/pathways common to metastatic melanoma. Novel candidate therapeutic targets were identified, and can be tested in preclinical mouse models we have designed. Currently available preclinical studies don’t address progressive recurrent disease, and show poor predictive power for clinical activity. Our immunocompetent mouse models of progressive melanoma are being used to study mechanisms of drug resistance, identify more reliable response markers, and evaluate targeted small molecules and immunotherapy.

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