Influence of DNA repair on PARP Inhibitor efficacy In GBM

DNA 修复对 GBM 中 PARP 抑制剂功效的影响

• 批准号: 8729252
• 负责人: Jann N. Sarkaria
• 金额: $ 27.68万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729252
• 关键词: Affect; Biological Models; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Cytotoxic Chemotherapy; DNA Damage; DNA Repair; DNA Repair Pathway; DNA repair protein; Data; Defect; Development; Disease; Enrollment; Genes; Glioblastoma; Human; Instruction; Lead; Lesion; Malignant neoplasm of brain; Mediating; Methylation; Modeling; Molecular; Molecular Profiling; Mutation; Newly Diagnosed; Nude Mice; O(6)-Methylguanine-DNA Methyltransferase; Pathway interactions; Patients; Phase; Phase II Clinical Trials; Play; Poly(ADP-ribose) Polymerases; Proteins; Radiation; Radiation therapy; Radio; Resistance; Role; Sampling; Testing; Treatment Protocols; Tumor Promoters; Xenograft Model; Xenograft procedure; arm; base; chemoradiation; chemotherapy; cytotoxic; homologous recombination; implantation; improved; in vivo; inhibitor/antagonist; insight; interest; molecular marker; patient population; preclinical study; promoter; radiation resistance; recombinational repair; repaired; resistance mechanism; response; standard of care; temozolomide; tumor

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.

放疗期间和放疗后加用替莫唑胺（TMZ）可改善患者的生存率 患有新诊断的GBM，是当前的护理标准。然而，TMZ的生存益处 治疗受到几乎所有患者中TMZ耐药性发展的限制， 在确定分子增敏策略，以提高TMZ的疗效的兴趣。一个有希望 靶向TMZ诱导的DNA损伤修复的策略是抑制聚ADP-核糖聚合酶 （PARP）。PARP间接参与许多修复途径，先前的数据表明PARP 抑制剂将使基本上所有肿瘤对TMZ敏感。虽然我们的初步体内数据在一组 原发性GBM异种移植物证实了PARP抑制剂ABT-888的强致敏作用， 与TMZ或TMZ/RT联合，我们的数据还表明，与PARP抑制剂联合治疗 仅对本身对TMZ敏感的肿瘤有效。同源重组（HR）缺陷- 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 目的1，研究PARP抑制剂的TMZ增敏作用与PARP中分子缺陷的关系。 将在原代GBM异种移植模型中测试关键的HR修复基因。初步数据显示， 辐射可以影响TMZ抗性的出现，TMZ抗性可以不利地影响 PARP抑制的功效。在目的2中，研究了PARP抑制、TMZ抗性和 辐射反应将被探索，以提供更多的洞察力的潜在机制的阻力， PARP抑制剂的TMZ致敏作用。最后，TMZ的敏感性受到沉默的关键控制。 MGMT通过启动子甲基化修复蛋白，且在Aim 3中MGMT甲基化，以及潜在地其它 目标1中定义的分子特征将用于选择临床试验的患者入组 评价ABT-888联合放化疗的疗效。总体而言，这些研究可能 为PARP抑制剂联合放化疗的定制化分子治疗提供合理依据 新诊断的GBM患者。