Preclinical discovery and clinical validation of predictive markers of response to cetuximab (Erbitux™) in metastatic colorectal cancer

摘要: 4032 Cetuximab (Erbitux™) is a chimeric monoclonal antibody that binds to the extracellular ligand-binding domain of epidermal growth factor receptor (EGFR) and inhibits EGFR-dependent signaling. Clinical data has shown whereas EGFR levels mutations do not appear correlate with response in colorectal cancer (CRC), an increased number gene copies for may be predictive. Our goal identify predictive markers will ultimately developed into molecular diagnostics enhance effectiveness therapy CRC. Preclinical approaches using transcriptional profiles 164 primary CRC tumors 21 sensitive resistant cell lines have identified list genes response. A Phase II study monotherapy patients metastatic was conducted examine whether preclinically could validated clinical setting. Patients were enrolled monotherapy. RNA isolated from pre-treatment core biopsies all profiled on Affymetrix chips. DNA being used copy analysis as well mutation analysis. An interim statistical profiling performed are differentially expressed between who derive benefit (Partial Responders PR Stable Disease SD) those (Progressive PD). Pathway tools biological relationships this study. Several candidates able distinguish PR/SD PD high accuracy. The top candidate sensitivity key players signaling pathway. Their strikingly higher expression responders suggest addicted pathway respond Cetuximab. Approximately twenty prediction found associated network. potential either singly or combination patient selection therapy. This currently extended include larger set