Preclinical Model of Human Melanoma for Evaluation of Targeted Drug Treatment and for Immunotherapy Validation

Abstract Malignant melanoma accounts for less than 5% of skin cancer cases, yet it represents 75% of deaths from skin cancer. The high mortality rate is due to the malignant, metastatic nature of the disease and resistance to chemotherapeutic treatments. Most mouse melanoma models have not fully recapitulated the histopathology of the disease and its metastatic nature. At NCI's Center for Advanced Preclinical Research (CAPR), we have adapted the HGF/SF; CDK4R24C transgenic mouse model to an optimized allograft transplant model for preclinical therapeutic studies in primary and metastatic melanoma. This genetically engineered mouse-derived Allograft (GDA) model recapitulates the features of the original GEM, including the epithelioid histopathology and key marker expression of human melanoma. It is an efficient and tractable tool for monitoring of both tumor growth and therapeutic responses in primary and metastatic melanoma in the context of a normal immune system. Additionally, aberrant expression of c-Met and upregulation of the downstream signaling pathway in HGF-GDA tumors is relevant for targeted therapeutics in melanoma. Thus, the model is a useful platform for evaluating therapies that target tumor cells and/or immunomodulatory pathways in intervention or adjuvant settings. Although drugs such as the c-Met inhibitor crizotinib and the MEK inhibitor trametinib were potent in cell culture, PD analyses of short-term (4-6 hour) treatment with small molecule therapies indicated that treatment incompletely suppresses the pathway in vivo compared to the corresponding primary cell line, and does not inhibit tumor growth. Therefore the HGF-GDA can be exploited to examine combination treatments that either prevent feedback activation of downstream pathway nodes in vivo, or modify alternate pathways, such as immunomodulatory targets. Hence, we are currently exploring rational combinations of oncogene-targeted therapy with immune-targeted therapy, for example, combined trametinib and anti-CTLA4 antibody treatment. In the HGF-GDA, complete response was observed in a subgroup of mice treated with anti-CTLA-4, i.e. established tumors fully regressed, yet the durable response and increased survival time (based on tumor volume) was not enhanced by concurrent treatment with trametinib. Future treatment studies will involve alternative regimens. Additionally, since metastasis, not the primary tumor, leads to progression of melanoma in patients, we have characterized a primary tumor resection model in which only metastatic disease is treated. Lung metastases develop after resection of the HGF-GDA primary tumor, which may be treated in an intervention or adjuvant setting. Therefore we evaluated the effect on survival of the same combination therapy (trametinib and anti-CTLA-4) we previously used to treat the primary tumor, but as adjuvant treatment for the metastatic melanoma model. Citation Format: Rajaa El Meskini, Michelle Gumprecht, Alan Kulaga, Anthony Iacovelli, Terry Van Dyke, Chi-Ping Day, Glenn Merlino, Zoe Weaver Ohler. Preclinical model of human melanoma for evaluation of targeted drug treatment and for immunotherapy validation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1479.