Customizing the Targeting of IGF-1 Receptor

Renato Baserga

Disclosures

Future Oncol. 2009;5(1):43-50. 

In This Article

Abstract and Introduction

Abstract

The type 1 IGF receptor (IGF-IR) is activated by two ligands, IGF-1 and IGF-2, and by insulin at supraphysiological concentrations. It plays a significant role in the growth of normal and abnormal cells, and antibodies against the IGF-IR are now in clinical trials. Targeting of the IGF-IR in cancer cells (by antibodies or other means) can be improved by the appropriate selection of responsive tumors. This review focuses on the optimization of IGF-IR targeting in human cancer.

Introduction

It is generally accepted that the type 1 IGF receptor (IGF-IR) plays an important role in cancer, and antibodies to the IGF-IR are now in clinical trials. This review focuses on the IGF-IR and its docking protein, the insulin receptor substrate (IRS)-1, and offers suggestions on how to identify and exploit certain aspects of the IGF-IR signaling pathway that could maximize the therapeutic effects of IGF-IR antibodies. This review also offers the hypothesis that tumor cells can switch allegiance from one growth factor to another, depending on extra- or intra-cellular conditions. This is especially true in the relationship between the IGF-IR and the EGF receptor (EGFR), a relationship established experimentally and clinically (see below). Interestingly, although extrapolation from cell culture experiments would have predicted otherwise, deletion of the EGFR in mouse embryos does not yield a growth phenotype. The modest decrease at birth is due to a smaller placenta and is only observed in certain strains of mice.[1] However, there is no question that the EGFR is a valid target in cancer therapy, as evidenced by well-controlled clinical trials. The unexpected role of the EGFR in cancer supports a hypothesis that the requirement for specific growth factors by tumor cells is not hard-wired, but is instead an acquired taste. Indeed, the relationship between the IGF-IR and the EGFR is a good illustration of how cancer cells can develop resistance to therapy by switching from one growth factor to another.[2,3,4,5,6]

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