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首页> 外文期刊>British Journal of Cancer >Caspase-8 expression is predictive of tumour response to death receptor 5 agonist antibody in Ewing's sarcoma
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Caspase-8 expression is predictive of tumour response to death receptor 5 agonist antibody in Ewing's sarcoma

机译：Caspase-8表达可预测肿瘤对尤文氏肉瘤死亡受体5激动剂抗体的反应

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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.
机译：背景：尽管对化疗的初始反应良好，但仍有30％的尤因肉瘤（EWS）局部肿瘤患者复发性疾病，预后不良。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，并鉴定预测性生物标志物来应对这一挑战。方法：细胞活力测定，药物剂量反应，免疫印迹，基因转移拯救，小鼠肿瘤模型以及肿瘤生长和Kaplan-Meier生存曲线的统计比较。结果：这项研究表明，许多EWS细胞系对死亡受体DR5抗体具有选择性敏感性，并且对DR4抗体具有更强的抵抗力。这些细胞系的临床前评估表明它们在体外对人DR5激动剂抗体conatumumab敏感，可诱导caspase-8快速激活和凋亡。我们还发现对conatumumab的敏感性与caspase-8的表达相关。此外，caspase-8的催化活性对于赋予这种敏感性既必要又足够。在体内，conatumumab对EWS细胞系和具有较高caspase-8表达的患者源异种移植物具有活性，但对具有较低caspase-8表达的异种移植物无效。结论：这些研究表明，conatumumab作为抗EWS的治疗剂和caspase-8作为敏感性的预测生物标志物的潜力。

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