Caspase-8 expression is predictive of tumour response to death receptor 5 agonist antibody in Ewing's sarcoma |
| |
Authors: | Zhigang Kang Seth D Goldstein Yunkai Yu Paul S Meltzer David M Loeb Liang Cao |
| |
Institution: | 1.Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA;2.Basic Science Program, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA;3.Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA |
| |
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. |
| |
Keywords: | Ewing''s sarcoma predictive biomarker death receptor 5 conatumumab caspase-8 |
|
|