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

Alison O'Neill, Nilay Shah, Naamah Zitomersky, Marc Ladanyi, Neerav Shukla, Aykut Üren, David Loeb, Jeffrey Toretsky

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Article number450478
JournalSarcoma
Volume2013
DOIs
StatePublished - Mar 7 2013
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging

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