Research Track

Despite advances in molecular predictive markers, a substantial proportion of patients selected for targeted therapy are non responsive and require additional treatment partners. Unlike cytotoxic chemotherapeutic agents, most novel signal transduction modulators (STMs) exhibit modest tumor regression, therefore, there is significant need for establishing functional pharmacodynamic (e.g. therapy response) endpoints for inhibition of a particular oncopathway, even in patients preselected for therapy. IGF1R is an oncoreceptor which is overexpressed in 50% of colorectal cancer (CRC) patients. The overall goal of this project is to establish translational metabolic end-points of IGF1R pathway inhibition that will allow for rational selection of combination partners in non-responding CRC tumors. The working hypothesis is that metabolic response to upstream target inhibition of IGF1R consists of changes in two distinct metabolic pathways which are mediated by two distinct downstream pathways: (i) glucose uptake and metabolism by PI3K/AKT/mTOR and (ii) choline metabolism by Ras/Raf/MEK pathway. If no response in CRC mouse xenografts will be seen by FDG-PET, an additional mTOR inhibitor will be added to the treatment plan; if no 18F-choline-PET response is detected, a novel MEK inhibitor will be introduced in addition to IGF1R inhibitors.