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.

Insulin-like growth factor 2 (IGF2) is a strong mitogenic peptide with an imprinted gene that is primarily involved in fetal development. It is highly expressed in the fetus where it is involved in fetal growth and tissue differentiation. However, postnatally, the expression of IGF2 decreases despite higher expression levels in the blood as compared with that of IGF1. In adults, the physiological function of IGF2 is poorly understood; however, the possibility of a metabolic function exists. Although the expression of IGF2 normally decreases in adults, it is overexpressed in a variety of cancers and associated with increased insulin-like growth factor 1 (IGF1R) receptor and insulin receptor (IR) activity. This subsequently increases the activity of downstream genes such as AKT, FOXO, and MAPK, resulting in enhanced proliferation, survival, and overall worse prognosis in patients overexpressing IGF2. As IGF1R activation has been found in several types of cancers, many different IGF1R-targeted therapies have been clinically evaluated, however, with only limited anti-cancer efficacy. In the present review, the physiological function of IGF2 will be outlined in relation to gene expression, imprinting, and signaling. Additionally, differences in physiological and aberrant signaling of IGF2 in cancer will be summarized.