Caspase-8 expression is predictive of tumour response to death receptor 5 agonist antibody in Ewing's sarcoma

Zhigang Kang, Seth Daniel Goldstein, Yunkai Yu, Paul S. Meltzer, David M. Loeb, Liang Cao*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Background:Despite good initial response to chemotherapy, 30% of Ewing's sarcoma (EWS) patients with localised tumours develop recurrent disease, associated with poor prognosis. The aim of this study was to address this challenge by conducting preclinical evaluation of a death receptor targeted agent in vitro and in vivo, and by identifying predictive biomarkers.Methods:Cell viability assays, drug dose responses, immunoblots, rescue with gene transfer, mice tumour models, and statistical comparisons of tumour growth and Kaplan-Meier survival curves.Results:This study shows that many EWS cell lines are selectively sensitive to a death receptor DR5 antibody and are more resistant to a DR4 antibody. Preclinical evaluation of these cell lines indicates their sensitivity to human DR5 agonist antibody conatumumab in vitro, which induces rapid activation of caspase-8 and apoptosis. We also found that sensitivity to conatumumab correlates with expression of caspase-8. Furthermore, the catalytic activity of caspase-8 is both necessary and sufficient to confer this sensitivity. In vivo, conatumumab is active against an EWS cell line and a patient-derived xenograft with higher caspase-8 expression, but is not effective against another with lower caspase-8 expression.Conclusions:These studies suggest the potential of conatumumab as a therapeutic agent against EWS and caspase-8 as a predictive biomarker for sensitivity.

Original languageEnglish (US)
Pages (from-to)894-901
Number of pages8
JournalBritish Journal of Cancer
Volume113
Issue number6
DOIs
StatePublished - Sep 15 2015

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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