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 EN

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.