Combining the DNA Repair Inhibitor Dbait With Radiotherapy for the Treatment of High Grade Glioma: Efficacy and Protein Biomarkers of Resistance in Preclinical Models
Combining the DNA Repair Inhibitor Dbait With Radiotherapy for the Treatment of High Grade Glioma: Efficacy and Protein Biomarkers of Resistance in Preclinical Models
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DOI：
10.3389/fonc.2019.00549
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发表时间：
2019-06-19
影响因子：
4.7
通讯作者：
Dutreix, Marie
中科院分区：
文献类型：
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作者：
Biau, Julian;Chautard, Emmanuel;Dutreix, Marie
高级别胶质瘤复发通常发生在受照射的体积内，主要是由于对放射治疗（RT）的高耐药性。Dbait（代表DNA链断裂诱饵）分子模拟DSBs并捕获DNA修复蛋白，从而抑制rt诱导的DNA损伤的修复。在这里，我们评估了Dbait对rt致敏的潜力。首先，我们在6/9的测试细胞系中证明了Dbait的放射致敏特性。然后，我们使用6种细胞来源的异种移植物和5种患者来源的异种移植物模型进行动物研究，以展示Dbait+RT联合治疗人类高级别胶质瘤的临床潜力和适用性。使用RPPA方法，我们发现Phospho-H2AX/H2AX和Phospho-NBS1/NBS1在异种移植物模型中预测Dbait的疗效。我们的结果为RT联合Dbait抑制DNA修复可能对高级别胶质瘤患者有益的概念提供了临床前证明。
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.