Translational application of mouse models of melanoma brain metastases

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Much has been learned about the molecular pathology of melanoma in recent years and significant progress has been made towards its treatment, yet late-stage melanoma still remains one of the least curable cancers with high metastatic propensity. The brain is a common site of metastasis for patients with various neoplasia including melanoma, breast cancer, lung cancer, and colorectal cancer. The mainstay for treatment of brain metastasis has been radiation therapy; sometimes surgery and chemotherapeutic agents have been included. Most clinical trials usually excluded patients with brain metastases because of the unlikelihood these patients will benefit from such regiment, however, recently a few trials have included melanoma patients with or without brain metastases. Preliminary results from these trials are suggestive that similar responsiveness was observed for patients with or without brain metastases, and further trials are needed to confirm these results. Despite these improvements, patients with multiple brain metastases from solid tumors often show progression in the brain contributing to neurological deterioration, decreased quality of life, and poor survival. Mouse models reflecting human cancers are important tools towards the translation of basic science discoveries to clinical therapies. However, rapidly evolving technologies within the last few years require further refining current approaches that enable models to be more suitable in robust translational applications to provide consistent information to meet patients’ needs. In our studies of melanoma, we discovered that >65% of human melanoma cell lines and melanoma biopsies express metabotropic glutamate receptor 1 (GRM1), independent of N-RAS/B-RAF genotypes, while normal human melanocytes do not. Based on this discovery, our group was the first to propose the link between GRM1-mediated glutamatergic signaling and melanoma. In recent clinical trials, we observed that >90% of all enrolled patients expressed GRM1 within their late-stage melanomas. However, the conventional mouse models of melanoma do not mimic this genetic alteration common to melanoma patients. Therefore, we developed mouse models (MASS and TGS) where the ectopic expression of GRM1 in previously normal melanocytes leads to consistent, wide-spread development of melanocytic lesions and metastasis to various organs including the lung and brain, two common metastatic sites for human melanoma. In this application, we propose to characterize the ability of these two different but complementary innovative models that mimic human melanoma with brain metastases and fill the gap, to expand, improve, and transform the utility of mammalian tumor models for translational research. Completion of this proposed work is an essential step towards establishing fundamentally important and relevant animal models of human cancer that will improve and save cancer patient lives.