Majd Nazanin, Yap Timothy A, Yung W K Alfred, de Groot John
Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J Immunother Precis Oncol. 2020 Nov 12;3(4):157-164. doi: 10.36401/JIPO-20-20. eCollection 2020 Nov.
Diffuse infiltrating gliomas are a clinically and molecularly heterogeneous group of tumors that are uniformly incurable. Despite our growing knowledge of genomic and epigenomic alterations in gliomas, standard treatments have not changed in the past 2 decades and remain limited to surgical resection, ionizing radiation, and alkylating chemotherapeutic agents. Development of novel therapeutics for diffuse gliomas has been challenging due to inter- and intra-tumoral heterogeneity, diffuse infiltrative nature of gliomas, inadequate tumor/drug concentration due to blood-brain barrier, and an immunosuppressive tumor microenvironment. Given the high frequency of DNA damage pathway alterations in gliomas, researchers have focused their efforts in targeting the DNA damage pathways for the treatment of gliomas. A growing body of data has shed light on the role of poly(ADP-ribose) polymerase (PARP) in combination with radiation and temozolomide in high-grade gliomas. Furthermore, a novel therapeutic strategy in low-grade glioma is the recent elucidation for a potential role of PARP inhibitors in gliomas with mutations. This review highlights the concepts behind targeting PARP in gliomas with a focus on putative predictive biomarkers of response. We further discuss the challenges involved in the successful development of PARP inhibitors in gliomas, including the intracranial location of the tumor and overlapping toxicities with current standards of care, and promising strategies to overcome these hurdles.
弥漫性浸润性胶质瘤是一组临床和分子特征均异质性的肿瘤，无一可治愈。尽管我们对胶质瘤的基因组和表观基因组改变的认识不断增加，但在过去20年里，标准治疗方法并未改变，仍然局限于手术切除、电离辐射和烷基化化疗药物。由于肿瘤间和肿瘤内的异质性、胶质瘤的弥漫浸润性、血脑屏障导致的肿瘤/药物浓度不足以及免疫抑制性肿瘤微环境，弥漫性胶质瘤新型治疗方法的开发一直具有挑战性。鉴于胶质瘤中DNA损伤途径改变的高频率，研究人员将精力集中在靶向DNA损伤途径以治疗胶质瘤上。越来越多的数据揭示了聚（ADP-核糖）聚合酶（PARP）与放疗和替莫唑胺联合应用于高级别胶质瘤中的作用。此外，低级别胶质瘤的一种新型治疗策略是最近阐明了PARP抑制剂在有特定突变的胶质瘤中的潜在作用。本综述重点介绍了在胶质瘤中靶向PARP背后的概念，重点关注假定的反应预测生物标志物。我们还进一步讨论了胶质瘤中PARP抑制剂成功开发所涉及的挑战，包括肿瘤的颅内位置以及与当前护理标准的毒性重叠，以及克服这些障碍的有前景的策略。
