Thursday, January 20, 2011

Why IGF-1R Receptor Blockers May Not Work

The Importance of IGF-1 ligand expression in a setting of selective IGF-1R blockade

Though clinical trials are still accruing, the selective blockade of IGF-1R may not be as efficacious as intended.  As suggested by a growing body of basic science literature, IGF-1 ligand can potentially circumvent selective blockade through a number of different mechanisms.

Hybrid Receptors
Many tissues contain hybrid receptors assembled with one chain of the IGF-1R and one of the IR.  IGF-1R/IR-B hybrids have higher affinity for IGF-1, whereas IGF-1R/IR-A hybrids have an equal affinity for IGF-2 and insulin.

In vitro work at MDACC has shown that both IGF and Endothelial Growth Factor (EGF) can induce heterodimerization of the IGF-IR and the EGF Receptor (EGFR). 1 With heterodimerization, IGF can phosphorylate both the IGF-IR as well as EGFR (the converse was not true, in that EGF treatment did not phosphorylate IGF-IR). 1

Stimulation of Alternative Pathways

IGF-1 can also stimulate other pathways important in cancer biology. Stimulation of HNSCC SCC-9 cell lines with IGF-1 Ligand has been shown to upregulate vascular endothelial growth factor (VEGF) promotor activity and subsequent VEGF secretion2.

IRS-1 Deficiency
Some HNSCC cell lines, like those of other cancers, may potentially be IRS-1 deficient.  Without IRS-1, IGF-R sends a signal of differentiation, not mitogenesis.  Thus, IGF-IR blockers will not induce mitogenic downregulation in cells deficient in IRS-1, and in fact, may inhibit the differentiation and growth arrest signaling associated with IGF-1 in these situations. 3,4

Insulin Receptor
Insulin receptor shares 70% homology with IGF-1R.  The functions of the two, though physiologically distinct, are still partially overlapping, with IR capable of stimulating growth and IGF-1R able to regulate a metabolic response.  Activated by multiple IGF’s, IR can can also activate IRS-1, bypassing IGF-1R blockade4.

As demonstrated in vitro, and given the theoretical propensity of the IGF-1 ligand to circumvent selective blockade in vivo, it becomes important to study potential determinants of elevated IGF-1 expression.

1.            Barnes CJ, Ohshiro K, Rayala SK, El-Naggar AK, Kumar R. Insulin-like growth factor receptor as a therapeutic target in head and neck cancer. Clin Cancer Res. 2007 Jul 15;13(14):4291-9.
2.            Slomiany MG, Black LA, Kibbey MM, Day TA, Rosenzweig SA. IGF-1 induced vascular endothelial growth factor secretion in head and neck squamous cell carcinoma. Biochem Biophys Res Commun. 2006 Apr 14;342(3):851-8.
3.            Sun XJ, Pons S, Wang LM, et al. The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action. Mol Endocrinol. 1997 Feb;11(2):251-62.
4.            Baserga R. Customizing the targeting of IGF-1 receptor. Future Oncol. 2009 Feb;5(1):43-50.

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