Influence of DNA repair on PARP Inhibitor efficacy In GBM

在放射治疗(RT)期间和之后加入替莫唑胺(TMZ)可提高患者的存活率 患有新诊断的基底膜，是目前的护理标准。然而，TMZ的生存利益 治疗受到几乎所有患者对TMZ耐药性的发展的限制，而且有显著的 有兴趣确定分子增敏策略以提高TMZ的疗效。一件有希望的事 靶向修复TMZ诱导的DNA损伤的策略是抑制多聚ADP-核糖聚合酶 (PARP)。PARP间接参与了许多修复途径，先前的数据表明PARP 抑制剂基本上会使所有肿瘤对TMZ增敏。虽然我们在活体内的初步数据显示 原代GBM异种移植证实PARP抑制剂ABT-888在以下情况下具有强大的增敏作用 结合TMZ或TMZ/RT，我们的数据也证明了与PARP抑制剂联合治疗 只有对TMZ本身敏感的肿瘤才有效。同源重组缺陷(HR)- 介导的DNA修复与对TMZ和PARP抑制剂治疗的敏感性增加有关。在……里面 目的1、PARP抑制剂对TMZ的增敏作用与细胞内分子缺陷的关系 关键的HR修复基因将在主要的GBM异种移植模型中进行测试。提供的初步数据表明 辐射会影响TMZ抗性的出现，而TMZ抗性会产生不利影响 关于PARP抑制的疗效。在目标2中，PARP抑制、TMZ耐药性和 将探索辐射反应，以提供对潜在的抗性机制的更多洞察 PARP抑制剂对TMZ的增敏作用。最后，TMZ的敏感性受到以下因素的严格控制 MGMT修复蛋白通过启动子甲基化，并在目标3 MGMT甲基化，以及潜在的其他 AIM 1中定义的分子特征将用于选择参加临床试验的患者 ABT-888联合放化疗的疗效评价总的来说，这些研究可能 为PARP抑制剂联合放化疗个体化分子治疗提供合理依据 在新诊断的GBM患者中。

The addition of temozolomide (TMZ) during and after radiation therapy (RT) improved survival for patients with newly diagnosed GBM and is the current standard of care. However, the survival benefit of TMZ therapy is limited by the development of TMZ resistance in almost all patients, and there is significant interest in identifying molecular sensitizing strategies to improve the efficacy of TMZ. One promising strategy targeting the repair of TMZ-induced DNA damage is inhibition of poly-ADP-ribose polymerase (PARP). PARP is indirectly involved in numerous repair pathways, and previous data suggest that PARP inhibitors will sensitize essentially all tumors to TMZ. While our preliminary in vivo data in a panel of primary GBM xenografts confirms a robust sensitizing effect of the PARP inhibitor ABT-888 when combined with TMZ or TMZ/RT, our data also demonstrate that combination therapy with PARP inhibitors is only effective in tumors that are inherently sensitive to TMZ. Defects in homologous recombination (HR)- mediated DNA repair are associated with increased sensitivity to TMZ and to PARP inhibitor therapy. In Aim 1, the relationship between the TMZ-sensitizing effects of PARP inhibitors and molecular defects in key HR repair genes will be tested in primary GBM xenograft models. Preliminary data presented suggest that radiation can affect the emergence of TMZ resistance and that TMZ resistance can adversely impact on the efficacy of PARP inhibition. In Aim 2, the relationship between PARP inhibition, TMZ resistance and radiation responses will be explored to provide additional insight into potential mechanisms of resistance to the TMZ-sensitizing effects of PARP inhibitors. Finally, TMZ sensitivity is critically controlled by silencing of the MGMT repair protein by promoter methylation, and in Aim 3 MGMT methylation, and potentially other molecular features defined in Aim 1, will be used to select patients for enrollment on a clinical trial evaluating the efficacy of ABT-888 combined with chemo-radiotherapy. Collectively, these studies may provide a rational basis for customized molecular therapy with PARP inhibitors combined with chemo-radiotherapy in patients with newly diagnosed GBM.