Imaging endpoints to predict response to IGF1R/IR inhibition in CRC models

Abstract

Abstract Colorectal cancer (CRC) represents a major health burden and accounts for nearly 10% of all cancer-related deaths in the U.S. Among the many new pathways being exploited for cancer treatment is the insulin-like growth factor receptor (IGF1R) signaling pathway, which appears to be a robust target in CRC (e.g., hyperactivated in more than 50% of CRC patients). OSI-906 is a novel selective dual inhibitor IGF-1R and IR kinase activities. Despite advances in molecular predictive markers, a substantial proportion of patients selected for targeted therapy has nonresponsive tumors and require additional combination-based regimens. Unlike cytotoxic chemotherapeutic agents, most novel signal transduction modulators (STMs) induce only modest tumor regression, thus there is significant need for establishing functional pharmacodynamic (e.g., therapy response) endpoints for inhibition of signaling via particular pathways. In the present study we established noninvasive imaging-based endpoints for response to OSI-906 in CRC mouse models. Female nude mice were implanted with either of two human CRC cell lines (one sensitive and one resistant) or individual human surgical CRC explants (with unknown sensitivity). Metabolic changes (decreased glucose uptake and lactate production by FDG-PET and proton MRS, respectively) were apparent in OSI-906-sensitive xenografts as early as 2 days post-treatment when no changes in tumor size were yet detected. A significant decrease in tumor size and membrane choline-containing phospholipids by MRI and MRS, respectively, were seen after 27 days of treatment in OSI-906-sensitive xenografts. No changes in FDG-PET, MRS, or tumor progression were observed in OSI-906 resistant xenografts. Our data indicate that noninvasive functional imaging endpoints can provide early and sensitive markers for cytostatic action of IGF1R/IR inhibitors. This talk is also presented as Poster A14.