Customizing the Targeting of IGF-1 Receptor

Renato Baserga

Disclosures

Future Oncol. 2009;5(1):43-50. 

In This Article

IGF-IR in Cancer

The prominence of IGF-IR has increased considerably in the past few years, progressing from a redundant insulin receptor to a receptor that is important in cell and body growth, cell survival and malignant transformation. Since antibodies to the IGF-IR are in clinical trials, this review assumes the reader is familiar with the basic aspects of the IGF-IR (recent reviews in[7,8,9]). The IGF-IR can send either a mitogenic or a differentiation signal depending on substrate availability. In many cell types (fibroblasts, epithelial cells etc.), the IGF-IR sends an unambiguous mitogenic, antiapoptotic signal. In other cell types, such as myeloid cells, neuronal cells and others, activation of the IGF-IR induces differentiation. When cells do not express or express very low levels of IRS-1, a substrate of both the IGF-IR and the insulin receptor (InR), IGF-1, induces differentiation.[10] This is the case with 32D myeloid precursor cells that do not express IRS-1 and are induced to differentiate by IGF-1. Ectopic expression of IRS-1 in 32D cells abrogates differentiation; the cells become transformed and even form tumors in mice.[11] IRS-1 activates the PI3K pathway, which is the main mitogenic pathway originating from the IGF-IR. However, the Shc-Ras-ERKs pathway also plays a role in the mitogenic signal of the IGF-IR,[12] with the two pathways probably converging at GSK3-β.

The crucial finding that clearly pointed out the major role played by the IGF-IR in cellular transformation was the demonstration that knockout mouse embryo cells for this receptor were refractory to transformation by viruses, oncogenes and overexpressed growth factor receptors.[4,13] An important consideration in defining the role of the IGF-IR in cellular transformation is that overexpression of the receptor is not a requirement, although it has been sporadically reported in human cancer (see below). What is required is the presence of the receptor, even at low levels. Perhaps the presence of the receptor, even in modest amounts, is necessary for the activation of IRS-1 (see below). The strategies used to target the IGF-IR are summarized in Box 1. The original reports on the efficacy of IGF-IR targeting in cancer cells were based on antisense strategies showing that an antisense to the IGF-IR caused apoptosis of tumor cells.[14] Unfortunately, antisense strategies do not work in humans, and targeting the IGF-IR by antisense is only of historical significance. The two principal methods now in use for targeting the IGF-IR are antibodies to the receptor and small-molecule inhibitors of the receptor's tyrosine kinase. Both methods have to deal with the InR, which has a 70% homology to the IGF-IR, with homology reaching 98% in the tyrosine kinase domain. They also have to deal with the IGF-IR/InR hybrid receptors, even though these hybrid receptors are usually activated by IGFs rather than insulin.[15] Although small molecules may still be successful (for instance cyclolignans[16]), antibodies to the IGF-IR are presently preferred in clinical trials, as they discriminate between the two receptors better than available small molecules.

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