After the formal demonstration of a direct association between IGF2BP3 and <i>IGF1R</i> mRNA using ribo-immunoprecipitation assay, we performed <i>in vitro</i> studies using A673 and TC-71 ES cell lines to demonstrate that IGF2BP3 loss promotes the downregulation of IGF1R and a decreased biological response to IGF1, represented by reduced migration and cell growth.
Repression of autocrine IGF1 by BET inhibitors led to significant inhibition of the IGF1R/AKT pathway critical to Ewing sarcoma cell proliferation and survival.
In addition, we will review the clinical experience with IGF1 targeted agents, ET-743 and epigenetically targeted therapies, the substantial amount of literature that supports their activity in Ewing sarcoma and the challenges remaining translating these therapies to the clinic.
We explored this paradox in a panel of ES cell lines and found their sensitivity to CP was unaffected by presence of IGF-1, countering a ligand blocking mechanism.
Clinical trials for patients with sarcoma have demonstrated impressive anti-tumor activity in cases where the IGF-1 pathway is activated, such as in Ewing sarcoma; however, acquired resistance has been common.
As has already occurred for malignancies such as breast or colon cancer, the "-omics-based" revolution has enhanced our understanding of the molecular changes responsible for Ewing's tumor formation and identified a number of potential targets (such as IGF-1R or mTOR) amenable to biological therapy.
However, three of three neuroepithelioma and one of two Ewing's sarcoma cell lines express IGF-I mRNA; therefore, in these tumors IGF-I may be an autocrine growth factor.