人们对重新利用聚腺苷二磷酸核糖聚合酶 1 (PARP-1) 抑制剂奥拉帕尼治疗新诊断或复发的异柠檬酸脱氢酶野生型胶质母细胞瘤越来越感兴趣。我们探讨腔内给药奥拉帕尼是否能在临床前高级神经胶质瘤模型中带来生存获益。原发性肿瘤 RNA 测序数据用于确定 PARP-1 作为胶质母细胞瘤浸润边缘的靶标。我们使用克隆生长测定、细胞周期分析和免疫细胞化学在体外评估了单独使用奥拉帕尼以及伴随基因毒性损伤所赋予的放射增敏作用，并在体内评估了手术后从温度敏感的聚合物浆料递送后的放射增敏作用。RNA测序证实PARP-1是一种放射增敏剂。胶质母细胞瘤浸润性疾病的可行治疗靶点。神经胶质瘤细胞急性暴露于奥拉帕尼会损害增殖并诱导与体外 DNA 损伤相关的晚期细胞凋亡，辐射会增强这种细胞凋亡。使用高级别胶质瘤原位同种异体移植物，与全身奥拉帕尼和标准胶质母细胞瘤治疗相比，间质奥拉帕尼递送联合放疗观察到长期总体生存获益。奥拉帕尼与替莫唑胺或依托泊苷联合给药可增加长期生存率，表明奥拉帕尼可作为 DNA 损伤敏化剂。总的来说，我们的数据支持局部奥拉帕尼给药与当前恶性胶质瘤治疗临床方案相结合的基本原理。© 2024。作者。

There is increased pan-cancer specific interest in repurposing the poly adenosine diphosphate-ribose polymerase-1 (PARP-1) inhibitor, olaparib, for newly diagnosed or recurrent isocitrate dehydrogenase wild type glioblastoma. We explore whether intra-cavity delivery of olaparib confers a survival benefit in a pre-clinical high-grade glioma model.Primary tumor RNA sequencing data was used to determine PARP-1 as a target in the glioblastoma infiltrative margin. We assessed radiosensitization conferred by olaparib alone and concomitant to genotoxic insults in vitro using clonal growth assays, cell cycle analysis and immunocytochemistry, and in vivo upon post-surgical delivery from a temperature-sensitive polymeric paste.RNA-sequencing confirmed PARP-1 as a viable therapy target in glioblastoma infiltrative disease. Acute exposure of glioma cells to olaparib impaired proliferation and induced late-stage apoptosis associated with DNA damage in vitro, potentiated by radiation. Using high-grade glioma orthotopic allografts, a long-term overall survival benefit was observed upon interstitial olaparib delivery concomitant with radiotherapy, compared to systemic olaparib and standard glioblastoma treatment. Combined delivery of olaparib with either temozolomide or etoposide increased long-term survival, suggestive of olaparib functioning as DNA damage sensitizer.Collectively, our data support a rationale for localized olaparib delivery concomitant with the current clinical regimen for malignant glioma treatment.© 2024. The Author(s).