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 M. Loeb, Jeffrey Toretsky

Research output: Contribution to journalArticle

21 Citations (Scopus)

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

Fingerprint

Somatomedin Receptors
Ewing's Sarcoma
Up-Regulation
Clinical Trials
Mutation
Cell Line
Therapeutics
Tumor Cell Line
Sarcoma
Population
Neoplasms
Flow Cytometry
Stem Cells
Enzyme-Linked Immunosorbent Assay

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging

Cite this

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

In: Sarcoma, Vol. 2013, 450478, 07.03.2013.

Research output: Contribution to journalArticle

O'Neill, Alison ; Shah, Nilay ; Zitomersky, Naamah ; Ladanyi, Marc ; Shukla, Neerav ; Üren, Aykut ; Loeb, David M. ; Toretsky, Jeffrey. / 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. In: Sarcoma. 2013 ; Vol. 2013.
@article{c2739f3236a54946a83bde2e946a14b0,
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.",
author = "Alison O'Neill and Nilay Shah and Naamah Zitomersky and Marc Ladanyi and Neerav Shukla and Aykut {\"U}ren and Loeb, {David M.} and Jeffrey Toretsky",
year = "2013",
month = "3",
day = "7",
doi = "10.1155/2013/450478",
language = "English (US)",
volume = "2013",
journal = "Sarcoma",
issn = "1357-714X",
publisher = "Hindawi Publishing Corporation",

}

TY - JOUR

T1 - Insulin-like growth factor 1 receptor as a therapeutic target in ewing sarcoma

T2 - Lack of consistent upregulation or recurrent mutation and a review of the clinical trial literature

AU - O'Neill, Alison

AU - Shah, Nilay

AU - Zitomersky, Naamah

AU - Ladanyi, Marc

AU - Shukla, Neerav

AU - Üren, Aykut

AU - Loeb, David M.

AU - Toretsky, Jeffrey

PY - 2013/3/7

Y1 - 2013/3/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84874547199&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84874547199&partnerID=8YFLogxK

U2 - 10.1155/2013/450478

DO - 10.1155/2013/450478

M3 - Article

C2 - 23431249

AN - SCOPUS:84874547199

VL - 2013

JO - Sarcoma

JF - Sarcoma

SN - 1357-714X

M1 - 450478

ER -