PT - JOURNAL ARTICLE AU - Zha, Jiping AU - O'Brien, Carol AU - Savage, Heidi AU - Huw, Ling-Yuh AU - Zhong, Fiona AU - Berry, Leanne AU - Lewis Phillips, Gail D. AU - Luis, Elizabeth AU - Cavet, Guy AU - Hu, Xiaolan AU - Amler, Lukas C. AU - Lackner, Mark R. TI - Molecular predictors of response to a humanized anti–insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer AID - 10.1158/1535-7163.MCT-09-0381 DP - 2009 Aug 01 TA - Molecular Cancer Therapeutics PG - 2110--2121 VI - 8 IP - 8 4099 - http://mct.aacrjournals.org/content/8/8/2110.short 4100 - http://mct.aacrjournals.org/content/8/8/2110.full SO - Mol Cancer Ther2009 Aug 01; 8 AB - The insulin-like growth factor-I receptor (IGF-IR) pathway is required for the maintenance of the transformed phenotype in neoplastic cells and hence has been the subject of intensive drug discovery efforts. A key aspect of successful clinical development of targeted therapies directed against IGF-IR will be identification of responsive patient populations. Toward that end, we have endeavored to identify predictive biomarkers of response to an anti-IGF-IR-targeting monoclonal antibody in preclinical models of breast and colorectal cancer. We find that levels of the IGF-IR itself may have predictive value in these tumor types and identify other gene expression predictors of in vitro response. Studies in breast cancer models suggest that IGF-IR expression is both correlated and functionally linked with estrogen receptor signaling and provide a basis for both patient stratification and rational combination therapy with antiestrogen-targeting agents. In addition, we find that levels of other components of the signaling pathway such as the adaptor proteins IRS1 and IRS2, as well as the ligand IGF-II, have predictive value and report on the development of a pathway-focused panel of diagnostic biomarkers that could be used to test these hypotheses during clinical development of IGF-IR-targeting therapies. [Mol Cancer Ther 2009;8(8):2110–21]