Abstract IA22: Modeling recurrent metastatic melanoma in the mouse

Recurrence and metastasis following resection and therapy are the most critical problems in progressive cancers and the main causes of cancer-related death. This problem is magnified in cutaneous malignant melanoma, which is highly metastatic in advanced stages and generally resistant to chemotherapy. Although new drugs such as Vemurafenib successfully target BRAFV600E and typically demonstrate a significant clinical response, progressive melanomas recur resulting in near uniform patient mortality. Dissection of processes underpinning recurrent and metastatic melanoma is certain to identify new therapeutic targets for more efficacious treatment. However, current preclinical studies do not model progressive recurrent disease, but rather rely on the growth response of human melanoma cell lines subcutaneously xenografted into immunocompromised mice as the efficacy endpoint; these studies have shown poor predictive power for clinical activity. Therefore we have designed new and improved genetically engineered mouse (GEM) models of progressive melanoma. These are being used to test targeted and immune-based therapies singly and in combination, and to study mechanisms associated with the resistance of recurrent/metastatic melanoma to promising clinical drugs. To identify novel targets for advanced disease we hypothesized that metastatic melanomas can exploit hard-wired pathways employed by migratory embryonic melanocytes, but not mature melanocytes, to achieve a more aggressive malignant phenotype. We had previously generated a GEM model (iDCT-GFP) that expresses Green Fluorescent Protein specifically in all melanocytic cells in a doxycycline-regulatable manner. The iDCT-GFP mouse was used in concert with FACS to isolate melanoblasts from key developmental stages, sequence their transcriptomes using RNA-Seq, and identify genes/pathways common to metastatic melanoma cells. We have thus generated a full library of the genes expressed during embryonic development of the melanocyte. A detailed comparative analysis of mouse melanoblast gene expression profiles with human metastatic melanoma cells was then performed, identifying what we believe to be a small number of critical genes common to both. We anticipate that this approach will enhance our understanding of this fatal disease at both mechanistic and prognostic levels, and facilitate the identification of novel therapeutic targets for the treatment of metastatic melanoma. Citation Format: Glenn T. Merlino, Chi-Ping Day, Pravin Mishra, Theresa Guo, Raza Zaida, Sean Davis, Paul Meltzer, Frances Noonan, Edward De Fabo, Zoe Ohler-Weaver, Terry Van Dyke. Modeling recurrent metastatic melanoma in the mouse. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA22.