Development of an Integrated Genomic Classifier for a Novel Agent in Colorectal Cancer: Approach to Individualized Therapy in Early Development

摘要: Background: A plethora of agents is in early stages development for colorectal cancer (CRC), including those that target the insulin-like growth factor I receptor (IGFIR) pathway. In current environment numerous targets, it imperative patient selection strategies be developed with intent preliminary testing latter phase trials. The goal this study was to develop and characterize predictive biomarkers an IGFIR tyrosine kinase inhibitor, OSI-906, could applied CRC-specific studies agent. Methods: Twenty-seven CRC cell lines were exposed OSI-906 classified according IC 50 value as sensitive (≤1.5 μmol/L) or resistant (>5 μmol/L). Cell subjected immunoblotting immunohistochemistry effector proteins, copy number by fluorescence situ hybridization, KRAS/BRAF/phosphoinositide 3-kinase mutation status, baseline gene array analysis. most used pathway analyses, along shRNA knockdown highly ranked genes. resulting integrated genomic classifier then tested against eight human explants vivo . Results: Baseline data from xenografts a k -top scoring pair ( -TSP) classifier, which, combination hybridization KRAS mutational able predict 100% accuracy test set patient-derived xenografts. Conclusions: These results indicate approach individualized therapy feasible should novel agents, ideally conjunction late-stage Clin Cancer Res; 16(12); 3193–204. ©2010 AACR.