However, the limitations of this study in terms of its retrospective nature and the antibodies used should be noted. receptor is primarily activated by its cognate ligands, insulin-like growth factor I (IGF-I) and II (IGF-II; 2- to 15-fold lower affinity), and to a much lower affinity by insulin. The ligands bind to the cysteine-rich domain of the studies have shown that IGF-1R is directly involved in Ewing’s sarcoma cell proliferation and survival [16, 40C42]. It has also been shown that results have been confirmed with the finding of IGF-1R expression in clinical samples of Ewing’s sarcoma and the Bardoxolone (CDDO) demonstration that lower levels of IGF-1R expression correlate with a lower tumor proliferative rate and a better prognosis [46]. However, the limitations of this study in terms of its retrospective nature and the antibodies used should be noted. Despite such limitations, this observation is important when planning clinical trials, where stratification of patients for biological variables may Bardoxolone (CDDO) be important. The evidence described above supports a role for drugs targeting IGF-1R signalling in Ewing’s sarcoma. Blockade of IGF-1R has been shown to cause inhibition of cancer cell proliferation, survival, and anchorage-independent growth and and studies have shown antitumor activity of several mAbs, resulting in inhibition of proliferation, apoptosis induction, and tumour growth inhibition [16, 48, 49]. There are a number of oral small CCNB2 molecule tyrosine kinase inhibitors in development. studies with a number of these agents have demonstrated inhibition of IGF-1R, high level of growth inhibition, survival reduction, complete pathway blockade, and xenograft tumor growth reduction [41, 50C52]. However, receptor downregulation was not observed with tyrosine kinase inhibitors, and this may partly account for their cytostatic, rather than cytotoxic effects against Ewing’s sarcoma xenografts [53]. Whether or not complete IGF-1R selectivity should be achieved is still under debate. Depending on the mechanism, inhibition of IGF-1R may target not only IGF-1R itself but also the hybrid receptors (especially those containing the fetal isoform insulin receptor-A) Bardoxolone (CDDO) which favour cancer cell proliferation and are activated by both IGFs. It has been shown that targeting IGF-1R increases the efficacy of other anticancer therapies. This is based on evidence that IGF-1R signalling protects tumour cells from many insults, including chemotherapeutic agents and ionizing radiation [54C56], thus limiting the efficacy of such therapy. Inhibition of IGF-1R signalling has been shown to increase the sensitivity of Ewing’s sarcoma cells to chemotherapy [51, 57, 58]. Combining IGF1-R with conventional therapy may have the advantage of lowering the effective dosage of radiotherapy and chemotherapy, minimizing side effects while maintaining efficacy. This is particularly important for paediatric patients. In addition to a potential role in combination with traditional cytotoxic regimens and with radiotherapy, there are data demonstrating involvement of IGF-1R in trastuzumab resistance [59, 60] and resistance to AKT/mTOR inhibitors [61]. It has been shown that IGF-1R blockade can restore sensitivity to these agents. An important issue in developing agents that specifically target IGF-1R is its high level of homology with the insulin receptor. There is a complete homology at the ATP-binding pocket and 84% homology within the intracellular kinase domain [62]. It is important to determine not only overlapping but also different biological effects of both receptors. Although both similarly activate PI3K and MAPK pathways [63, 64], subtle differences exist in the recruitment of certain docking proteins and intracellular mediators. These differences may be exploitable in terms of developing specific IGF-1R inhibitors. However, currently, there are no published data specifically addressing the role of the insulin receptor in Ewing’s sarcoma. 5. Clinical Experience with IGF-1R Targeted Treatments in Ewing’s Sarcoma At the time of this review, mAbs against IGF-1R represent the most clinically advanced means of inhibiting this.