TAS::75 0849::TAS SBIR TOPIC 292 PHASE I DEVELOPMENT OF MOLECULAR PHARMACODYNAMIC ASSAYS FOR TARGETED THERAPIES

The RON and c-MET signal pathways are critical regulators of cell growth, survival, migration, differentiation, and drug resistance. High levels of activated RON or c-MET have been observed in a number of human cancers. Activation of RON and c-MET by phosphorylation initiates a signal transduction cascade that promotes cancer cell proliferation, invasiveness, apoptotic and drug resistance, and metastasis. A number of anticancer drugs currently in clinical trials are targeting both of of these pathways. Further, the activation state and protein levels of RON and c-MET are good indicators of drug treatment efficacy and cancer cell survival outcome. In Phase I, we will develop a quantitative immunoassay to monitor the phosphorylation state of either RON or GAB1(the target of c-MET) in various activated and unactivated cancer cell lines. The ELISA kit will be manufactured and written SOPs created. In Phase II, we will use the RON or GAB1 kit to measure activation and protein levels in clinical samples from a wide range of cancers and additional PD assays, including studies using drugs that upregulate or downregulate these targets. The availability of RON and GAB1 detection kits will aid clinicians and researchers to monitor these proteins in a number of diseasesand predict the efficacy of cancer treatment.