Targeting the insulin-like growth factor receptor: developing biomarkers from gene expression profiling

Abstract

Overwhelming evidence implicates insulin-like growth factor (IGF) signaling in the growth and survival of many types of human cancer cells. Numerous inhibitors of the IGF1 receptor (IGF1R) have been developed, and they displayed remarkable antineoplastic activity in preclinical models and promising success in early phase clinical trials. However, while responses have been observed in numerous cancer types, they have occurred in a minority of patients, and serious toxicities have been observed. Identifying patients likely to benefit from anti-IGF1R therapy requires further characterizing the role of IGF1 signaling in various stages of tumorigenesis in order to identify critical downstream factors that may be used as predictors of response, or to serve as novel therapeutic targets. Recent microarray analyses have begun to unravel expression "signatures" specific for IGF1 that correlate with poor breast cancer prognosis and with response to anti-IGFIR inhibitors. In this review we briefly discuss the history of the IGF1 family in neoplasia, how it is targeted, results from clinical trials, and the quest for biomarkers that will predict response to IGF1R-targeted therapy.

FIGURE 1

IGFR and InsR complexes. IGF1R and InsR exist as heterotetramers consisting of an external ligand-binding alpha subunit and an internal signaling beta subunit. In addition, InsR has a fetal (InsR-A) and an adult isoform (InsR-B) resulting from alternative splicing. IGF1R and InsR can form hybrid heterotetramers. IGF2R is homologous to the mannose-6-phosphate receptor. The ligands insulin (Ins), IGF1, and IGF2 exhibit selectivity in their receptor binding profiles, as indicated in the figure. IGF binding proteins (IGFBPs) and IGFBP-related proteins (IGFBPrPs) bind IGFs to regulate their bioavailability and activity.