Abstract 2917: Caspase-8 expression is predictive of tumor response to death receptor 5 agonist antibody conatumumab in Ewing's sarcoma

Abstract

Abstract Despite good initial response to cytotoxic chemotherapy, approximately 30% of Ewing's sarcoma (EWS) patients who present with localized tumors develop recurrent disease, which is associated with poor prognosis. Addressing this clinical challenge requires the development of targeted therapies. 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. Further analysis reveals the correlation of sensitivity to conatumumab with the expression of caspase-8, with its catalytic activity both necessary and sufficient to confer such sensitivity. In vivo, conatumumab has active against both EWS cell lines and a patient-derived xenograft with higher caspase-8 expression, but is not effective against another patient-derived xenograft with lower caspase-8 expression. These studies suggest the potential of conatumumab as a therapeutic agent against EWS and caspase-8 as a biomarker for correlative studies. Citation Format: Zhigang Kang, D Seth Goldstein, Yunkai Yu, Paul S. Meltzer, David M. Loeb, Liang Cao. Caspase-8 expression is predictive of tumor response to death receptor 5 agonist antibody conatumumab in Ewing's sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2917. doi:10.1158/1538-7445.AM2015-2917