Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor.
IGF2 is a strongly mitogenic peptide and imprinted gene primarily involved in foetal development. In the foetus, IGF2 is highly expressed and is involved with foetal growth and tissue differentiation. However, postnatally IGF2 expression decreases although its expression level is still higher in blood than of IGF1. In adults, the physiological function of IGF2 is poorly understood, but may have a metabolic function. Although expression of IGF2 normally decreases in adults, IGF2 is overexpressed in a variety of cancers causing an increase in insulin-like growth factor 1 (IGF1R) receptor and insulin receptor (IR) activity. This subsequently causes increases in downstream AKT, FOXO and MAPK activity and leads to increased proliferation, survival and overall worse prognosis in patients which overexpress IGF2. As IGF1R activation has been found in several types of cancers, many different IGF1R targeted therapies have been tested in clinical setting, although elicited only limited anti-cancer efficacy. In this review, the physiological function of IGF2 will be outlined in relation to gene expression regulation, imprinting and signalling. Additionally, the differences in physiological and aberrant cancer IGF2 signalling will be summarized.
