Caspase-8 expression is predictive of tumour response to death receptor 5 agonist antibody in Ewing's sarcoma.
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.
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.|Basic Science Program, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA.
Zhigang
Z
Kang
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
Seth D
SD
Goldstein
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Yunkai
Y
Yu
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Paul S
PS
Meltzer
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
David M
DM
Loeb
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Liang
L
Cao
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D011897:Random Allocation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000276:immunology*; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C554537:conatumumab; D053181:Caspase 8