We hypothesize that there is a convergence of prosurvival, angiogenesis and motility signals at common pathways in the local tumor microenvironment for therapeutic targeting and monitoring. Our findings suggest that molecular therapeutics targeted against the tumor microenvironment may to be more active when administered to inhibit pathways in series rather than in parallel and also when they affect both the tumor and the local interactive cells. The novel statistically based predictive drug modeling project was successful in identification of unanticipated targets affected by clinical agents. Further studies are ongoing by Dr. Hays with initial support via cell lines and drugs from the MSS. Confirmation of success of this pilot project will lead to a more comprehensive examination of agents and shRNA against their primary and potential key targets such that the biochemical cause of activity is identified and will be done by Dr. Hays as part of his translational laboratory objectives at OSU. 2) Our findings of the interactive role of PARP inhibition with angiogenesis inhibition was initiated based upon findings that gH2AX was required for overcoming endothelial cell hypoxic drive. We observed an interaction of a pan-VEGFR inhibitor, cediranib, with a PARP inhibitor and demonstrated a sequence specificity to administration. Further examination of the mechanisms underlying this are on hold due to resource limitations, although the clinical trial is in progress with our group responsible for translational endpoints.
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