The promise of DNA damage response inhibitors for the treatment of glioblastoma.
The promise of DNA damage response inhibitors for the treatment of glioblastoma.
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DOI：
10.1093/noajnl/vdab015
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
de Groot JF
中科院分区：
文献类型：
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作者：
Majd NK;Yap TA;Koul D;Balasubramaniyan V;Li X;Khan S;Gandy KS;Yung WKA;de Groot JF
胶质母细胞瘤（GBM），最具侵袭性的原发性脑肿瘤，预后很差。尽管我们对GBM的基因组和表观基因组改变的了解越来越多，但在过去的二十年中，标准疗法和结果并没有发生显着变化。因此，迫切需要开发用于GBM的新疗法。GBM的肿瘤间和肿瘤内异质性、由于血脑屏障导致的肿瘤中药物浓度不足、导致对常规疗法耐药的冗余信号传导途径以及免疫抑制性肿瘤微环境都阻碍了GBM新疗法的开发。鉴于GBM中DNA损伤途径改变的频率很高，研究人员将精力集中在靶向关键酶，包括聚（ADP-核糖）聚合酶（PARP），DNA依赖性蛋白激酶，共济失调毛细血管扩张突变，共济失调毛细血管扩张和Rad 3相关。GBM治疗的支柱，电离辐射和烷化剂化疗，产生DNA损伤，通过上调和激活DNA损伤反应（DDR）酶修复。因此，使用PARP和其他DDR抑制剂使GBM细胞更容易受到常规治疗的影响是一个深入研究的领域。在这篇综述中，我们强调了GBM中DDR抑制剂背后越来越多的数据，重点是假定的预测反应的生物标志物。我们还讨论了成功开发DDR抑制剂用于GBM的挑战，包括颅内位置和DDR药物与当前护理标准的预测重叠毒性，并提出了克服这些障碍的有希望的策略。
Glioblastoma (GBM), the most aggressive primary brain tumor, has a dismal prognosis. Despite our growing knowledge of genomic and epigenomic alterations in GBM, standard therapies and outcomes have not changed significantly in the past two decades. There is therefore an urgent unmet need to develop novel therapies for GBM. The inter- and intratumoral heterogeneity of GBM, inadequate drug concentrations in the tumor owing to the blood–brain barrier, redundant signaling pathways contributing to resistance to conventional therapies, and an immunosuppressive tumor microenvironment, have all hindered the development of novel therapies for GBM. Given the high frequency of DNA damage pathway alterations in GBM, researchers have focused their efforts on pharmacologically targeting key enzymes, including poly(ADP-ribose) polymerase (PARP), DNA-dependent protein kinase, ataxia telangiectasia-mutated, and ataxia telangiectasia and Rad3-related. The mainstays of GBM treatment, ionizing radiation and alkylating chemotherapy, generate DNA damage that is repaired through the upregulation and activation of DNA damage response (DDR) enzymes. Therefore, the use of PARP and other DDR inhibitors to render GBM cells more vulnerable to conventional treatments is an area of intense investigation. In this review, we highlight the growing body of data behind DDR inhibitors in GBM, with a focus on putative predictive biomarkers of response. We also discuss the challenges involved in the successful development of DDR inhibitors for GBM, including the intracranial location and predicted overlapping toxicities of DDR agents with current standards of care, and propose promising strategies to overcome these hurdles.