Caspase-8 Expression is Predictive of Tumour Response to Death Receptor 5 Agonist Antibody in Ewing's Sarcoma

Overview

Journal Br J Cancer

Specialty Oncology

Date 2015 Aug 21

PMID 26291055

Citations 2

Authors

Zhigang Kang

Seth D Goldstein

Yunkai Yu

Paul S Meltzer

David M Loeb

Liang Cao

Affiliations

Soon will be listed here.

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.

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