title: Insulin-like growth factor 1 receptor as a therapeutic target in ewing sarcoma: lack of consistent upregulation or recurrent mutation and a review of the clinical trial literature.
abstract: The insulin-like growth factor 1 receptor (IGF-1R) has been considered an important therapeutic target in Ewing sarcoma (ES), generating a need to identify the subset of patients most likely to respond to IGF-1R inhibitors. We assessed IGF-1R expression in ES cell lines and patient tumors to understand the variable clinical responses to anti-IGF-1R therapy. Using ligand-binding displacement, we measured between 13,000 and 40,000 receptors per cell in ES cell lines. We used ELISA to quantify IGF-1R in patient tumors, which expressed 4.8%  ± 3.7 to 20.0%  ± 0.2 of the levels in a positive control cell line overexpressing IGF-1R. Flow cytometry showed markedly reduced IGF-1R expression in ES cell lines compared to a standard positive control cell line. The IGF1R gene was sequenced in 47 ES tumor samples and 8 ES cell lines; only one tumor sample showed a nonsynonymous mutation, R1353H, in a region with low functional impact. Finally, we assessed IGF-1R pathway activity in the ES stem cell (ESSC) population, to characterize its potential for resistance to anti-IGF-1R therapy, using Luminex technology. We found no significant differences in IGF-1R pathway activity between ESSCs and the total cell population. Overall, our findings suggest that IGF-1R as a therapeutic target in this sarcoma may require reevaluation.
authors: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
authors: Alison
authors: A
authors: O'Neill
authors: Nilay
authors: N
authors: Shah
authors: Naamah
authors: N
authors: Zitomersky
authors: Marc
authors: M
authors: Ladanyi
authors: Neerav
authors: N
authors: Shukla
authors: Aykut
authors: A
authors: Uren
authors: David
authors: D
authors: Loeb
authors: Jeffrey
authors: J
authors: Toretsky