Metastatic cutaneous melanoma is resistant to conventional therapies, resulting in poor prognoses. About 60% of these melanomas harbor the BrafV600E mutation, and most are responsive to the recently approved therapies that target the mutant Braf protein. However, disease generally recurs within 12-15 months. Additional promising results that demonstrate the possibility of durable responses in a subset of patients have recently been achieved with immune checkpoint modulation therapy that targets PD1/PDL1 or CTLA4 or the combination, and further immunomodulation therapies are being developed. However, it is not clear why some patients respond so well, while others don't respond at all. In addition, it will be critical to determine dosing regimens, effective combinations of multiple immunotherapies and their combination with cancer cells or other components of the cancer stroma. The metastatic melanoma GDA models developed in this project will be highly valuable in determining potential mechanisms of drug resistance and the development of effective combination treatments, dosing regimens and diagnostic strategies for evaluation in patients. We have established and validated several GDA models thus far. These include HGF/MET-driven primary and metastatic melanoma, including models in which tumors express luciferase. In addition, primary Braf driven and primary and metastatic HGF/MET/Braf driven models have been established. All models have been validated for responses totargeted therapies (vemarafinib in Braf and crizotinib in HGF/MET models). Recently CAPR entered into an NCI-CRADA supported funded collaboration with a biotech company to apply HGF/SF-tg;CDK4r24C GDA model for assessment of biodistribution and therapeutic efficacy of an experimental theranostic formulation delivering radioactive isotope via melanoma-specific melanocortin-1 receptor (MC-1R) mediated targeting. We have successfully completed the first milestone of the project aimed at determining the PK profiles of the test compound in tumor-bearing animals.
