Targeting the Insulin-Like Growth Factor 1 Receptor in Ewing's Sarcoma: Reality and Expectations

Figure 1

The endocrine, paracrine and autocrine regulation of the IGF-1R pathway and therapeutic strategies for its disruption. (a), Systemic regulation at the endocrine level. The GH-IGF-IGFBP is directed by the hypothalamus-hypophysis axis, where GH is produced, and mediated by the hypothalamus GH releasing factors (which include GHRH and somatostatins). Disruption of the hypothalamus and hypophysis axis, and thus GH release inhibition, has been attempted with somatostatin analogues (octeotride) in a Phase III trial [18]. However, this trial failed to meet the endocrinological and clinical endpoints. Pegvisomant (Pfizer) a human recombinant GH receptor antagonist, has been tested successfully for the treatment of acromegaly [19]. This pegylated recombinant human analogue of GH can decrease the production and release of IGF-I. Other strategies in preclinical development resulting in the reduction of the proportion of free ligand include antiligand mAbs [20] or recombinant IGFBPs. (b) Free-ligand levels at tissue level are also regulated by the presence of the different IGFBPs. This figure illustrates the downstream signalling cascades that result in stimulation of the cell cycle and translation, leading to increased proliferation and growth and inhibition of apoptosis. The IGF-1R pathway can be disrupted by using anti-IGF-1R mAbs and tyrosine kinase inhibitors (TKIs). Another potential strategy is represented by the inhibition of downstream intracellular tyrosine kinase proteins, that is, multiple small molecule inhibitors against PI3K, AKT, RAF, MEK, and mTOR inhibitors [21]. (Adapted from [22]).