IGF1R signalling and its inhibition

Abstract

The type 1 IGF receptor (IGF1R) is a transmembrane tyrosine kinase that is frequently overexpressed by tumours, and mediates proliferation and apoptosis protection. IGF signalling also influences hypoxia signalling, protease secretion, tumour cell motility and adhesion, and thus can affect the propensity for invasion and metastasis. Therefore, the IGF1R is now an attractive anti-cancer treatment target. This review outlines the effects of IGF1R activation in tumour cells, and will describe the strategies that are available to block IGF signalling, both as investigational tools and as novel anti-cancer therapeutics. Design of specific IGF1R inhibitors has been problematic due to close homology with the insulin receptor, but recently it has proved possible to design selective IGF1R inhibitors. These compounds and IGF1R antibodies are showing promise in preclinical models of human cancer, and several agents are now in early phase clinical trials. Both classes of agents affect insulin receptor signalling, either by direct kinase inhibition or antibody-induced insulin receptor downregulation. This effect may lead to clinical toxicity, but could be therapeutically beneficial in blocking signalling via variant insulin receptors capable of a mitogenic response to IGF-II. Specificity for IGF1R targeting can be achieved by antisense and siRNA-mediated IGF1R downregulation; these approaches have undoubted utility as research tools, and may in future generate nucleic-acid-based therapeutics. It will be important to use data from preclinical and early clinical trials to establish the molecular correlates of sensitivity to IGF1R blockade, and the optimum means of combining this new approach with standard treatment modalities.