Caspase-8 expression is predictive of tumour response to death receptor 5 agonist antibody in Ewing's sarcoma.
Caspase-8 expression is predictive of tumour response to death receptor 5 agonist antibody in Ewing's sarcoma.
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DOI：
10.1038/bjc.2015.298
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发表时间：
2015-09-15
影响因子：
8.8
通讯作者：
Cao L
中科院分区：
文献类型：
--
作者：
Kang Z;Goldstein SD;Yu Y;Meltzer PS;Loeb DM;Cao L
尽管最初对化疗的反应良好，但30%的尤文肉瘤(EWS)患者局部肿瘤发展为复发疾病，与预后不良相关。这项研究的目的是通过在体外和体内对死亡受体靶向药物进行临床前评估，并通过识别预测生物标记物来应对这一挑战。细胞活力分析、药物剂量反应、免疫印迹、基因转移挽救、小鼠肿瘤模型，以及肿瘤生长和Kaplan-Meier生存曲线的统计比较。这项研究表明，许多EWS细胞系对死亡受体DR5抗体选择性敏感，对DR4抗体更具抵抗力。临床前评估表明，这些细胞系对人DR5激动型抗体Conatumumab的体外敏感性，可诱导caspase-8的快速激活和细胞凋亡。我们还发现对conatumumab的敏感性与caspase-8的表达有关。此外，caspase-8的催化活性是赋予这种敏感性的必要条件和充分条件。在体内，Conatumumab对caspase-8表达较高的EWS细胞株和患者来源的异种移植瘤具有活性，但对另一种caspase-8表达较低的细胞株无效。这些研究表明Conatumab作为EWS的治疗剂和caspase-8作为敏感性的预测生物标记物的潜力。
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. 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. 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. These studies suggest the potential of conatumumab as a therapeutic agent against EWS and caspase-8 as a predictive biomarker for sensitivity.