将DNA修复抑制剂Dbait与放射疗法联合用于治疗高级别胶质瘤：临床前模型中的疗效和抗性蛋白生物标志物
Combining the DNA Repair Inhibitor Dbait With Radiotherapy for the Treatment of High Grade Glioma: Efficacy and Protein Biomarkers of Resistance in Preclinical Models.
作者信息
Biau Julian, Chautard Emmanuel, Berthault Nathalie, de Koning Leanne, Court Frank, Pereira Bruno, Verrelle Pierre, Dutreix Marie
机构信息
Centre de Recherche, Institut Curie, PSL Research University, Paris, France.
UMR3347, CNRS, Orsay, France.
出版信息
Front Oncol. 2019 Jun 19;9:549. doi: 10.3389/fonc.2019.00549. eCollection 2019.
High grade glioma relapses occur often within the irradiated volume mostly due to a high resistance to radiation therapy (RT). Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by RT. Here we evaluate the potential of Dbait to sensitize high grade glioma to RT. First, we demonstrated the radiosensitizer properties of Dbait in 6/9 tested cell lines. Then, we performed animal studies using six cell derived xenograft and five patient derived xenograft models, to show the clinical potential and applicability of combined Dbait+RT treatment for human high grade glioma. Using a RPPA approach, we showed that Phospho-H2AX/H2AX and Phospho-NBS1/NBS1 were predictive of Dbait efficacy in xenograft models. Our results provide the preclinical proof of concept that combining RT with Dbait inhibition of DNA repair could be of benefit to patients with high grade glioma.
高级别胶质瘤复发通常发生在放疗区域内，主要是因为对放射治疗（RT）具有高度抗性。Dbait（代表DNA链断裂诱饵）分子模拟双链断裂（DSB）并捕获DNA修复蛋白，从而抑制放疗诱导的DNA损伤修复。在此，我们评估Dbait使高级别胶质瘤对放疗敏感的潜力。首先，我们在9个测试细胞系中的6个中证明了Dbait的放射增敏特性。然后，我们使用6个细胞来源的异种移植模型和5个患者来源的异种移植模型进行动物研究，以展示联合Dbait+RT治疗人类高级别胶质瘤的临床潜力和适用性。使用RPPA方法，我们表明磷酸化H2AX/H2AX和磷酸化NBS1/NBS1可预测异种移植模型中Dbait的疗效。我们的结果提供了临床前概念验证，即放疗与Dbait抑制DNA修复相结合可能对高级别胶质瘤患者有益。
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