Insulin-like growth factor receptor inhibitors: baby or the bathwater?

Abstract

The success of targeted therapies for cancer is undisputed; strong preclinical evidence has resulted in the approval of several new agents for cancer treatment. The type I insulin-like growth factor receptor (IGF1R) appeared to be one of these promising new targets. Substantial population and preclinical data have all pointed toward this pathway as an important regulator of tumor cell biology. Although early results from clinical trials that targeted the IGF1R showed some evidence of response, larger randomized phase III trials have not shown clear clinical benefit of targeting this pathway in combination with conventional strategies. These disappointing results have resulted in the discontinuation of several anti-IGF1R programs. However, the conduct of these trials has brought to the forefront several important factors that need to be considered in the conduct of future clinical trials. The need to develop biomarkers, a clearer understanding of insulin receptor function, and defining rational combination regimens all require further consideration. In this commentary, the current state of IGF1R inhibitors in cancer therapy is reviewed.

Figure 2.

Homodimers and heterodimers of insulin receptor (InsR) and insulin-like growth factor-1 receptor (IGF1R) hemireceptors exist in various conformations. The IGF and insulin receptors can homo- and heterodimerize into eight different receptor subtypes that are assumed to take on different conformations and that may appear on the cell in varying proportions. Monoclonal antibodies (moAb) to IGF1R will inactivate and/or decrease the cell surface expression of IGF1R homodimers and InsR-IGF1R heterodimers. However, InsRs are not affected by existing anti-IGF1R monoclonal antibodies. Response to IGF1R monoclonal antibodies might be dependent on receptor subtype distribution and conformation.

Figure 1.

Insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (InsR) family members. The IGF1 and insulin receptors are synthesized by similar mechanism. In each case, transcripts from a single gene are translated into a long polypeptide that is cleaved to release the extracellular ligand binding domain (α subunit) and transmembrane tyrosine kinase domain (β subunit). The receptor subunits are covalently linked to form αβ hemireceptors that are further linked to form an α2β2 tetrameric structure. Splicing variants exist for both receptors (InsR-B, InsR-A, IGF1R, and IGF1R splice [shown as IGF1Rs]). The four InsR and IGF1R hemireceptors can homo- and heterodimerize to form multiple receptor subtypes.