RT Journal Article
SR Electronic
T1 Molecular predictors of response to a humanized anti–insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 2110
OP 2121
DO 10.1158/1535-7163.MCT-09-0381
VO 8
IS 8
A1 Zha, Jiping
A1 O'Brien, Carol
A1 Savage, Heidi
A1 Huw, Ling-Yuh
A1 Zhong, Fiona
A1 Berry, Leanne
A1 Lewis Phillips, Gail D.
A1 Luis, Elizabeth
A1 Cavet, Guy
A1 Hu, Xiaolan
A1 Amler, Lukas C.
A1 Lackner, Mark R.
YR 2009
UL http://mct.aacrjournals.org/content/8/8/2110.abstract
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]