Project Background: Metastatic melanoma is resistant to almost all of the conventional therapies and results in dismal prognosis. About 60% of melanoma cases exhibit BrafV600E mutation, and the targeted drug, vemurafenib, was approved for treatment of Braf-mutated melanoma by FDA via fast track in 2011. In clinical studies, the drug induced tumor shrinkage in 70% of patients. However, the disease recurred in almost all the treated patient within 12-15 months, and the overall survival was prolonged for only a few months. On the other hand, there is no efficacious treatment for non-BrafV600E metastatic melanoma so far. Studies have shown both types of melanoma may take advantage of constitutively activated receptor tyrosin kinases (e.g. c-Met) and their downstream pathways (e.g. MEK pathways) for their growth and resistance to primary treatment. Therefore, development of more efficacious and durable treatment to a). prevent recurrence of Braf-mutated melanoma, and b). provide therapies for non-BrafV600E melanoma, is urgently needed. Key Goal: The metastatic melanoma GEM model development project collaborators will work together to employ their best practices, knowledge and expertise to build clinically relevant preclinical models of metastatic melanoma for identification of resistance and recurrence mechanisms and development/testing of effective treatments and diagnostic strategies. Rationale: We set quality criteria for the preclinical model as following: (1) to represent human melanoma subtypes, a Braf-mutated and a non-Braf-mutated mouse melanoma with genetics or signaling relevant to human counterparts should be chosen;(2) the tumors should be expanded, passed, and tested only on syngeneic immunocompetent mice to maintain them in an appropriate microenvironment and prevent their alteration by in vitro cell culture condition or lack of immune response;(3) the tumors should be labeled/tagged to allow in vivo tracking of disease progression and response to therapies;(4) to test therapies, the model should be able to recapitulate the melanoma progression and treatment procedures in patients.
|Day, Chi-Ping; Carter, John; Weaver Ohler, Zoe et al. (2014) ""Glowing head"" mice: a genetic tool enabling reliable preclinical image-based evaluation of cancers in immunocompetent allografts. PLoS One 9:e109956|
|Van Dyke, Terry; Merlino, Glenn (2012) ?-catenin in metastatic melanoma--the smoking gun reloaded. Pigment Cell Melanoma Res 25:125-6|