title: Molecular predictors of response to a humanized anti-insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer.
abstract: 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.
authors: Department of Research Pathology, Genentech, Inc, South San Francisco, California 94080, USA.
authors: Jiping
authors: J
authors: Zha
authors: Carol
authors: C
authors: O'Brien
authors: Heidi
authors: H
authors: Savage
authors: Ling-Yuh
authors: LY
authors: Huw
authors: Fiona
authors: F
authors: Zhong
authors: Leanne
authors: L
authors: Berry
authors: Gail D
authors: GD
authors: Lewis Phillips
authors: Elizabeth
authors: E
authors: Luis
authors: Guy
authors: G
authors: Cavet
authors: Xiaolan
authors: X
authors: Hu
authors: Lukas C
authors: LC
authors: Amler
authors: Mark R
authors: MR
authors: Lackner
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1