Dewdney Brittany, Miranda Panimaya Jeffreena, Kuchibhotla Mani, Palanisamy Ranjith, Richworth Caitlyn, Milligan Carol J, Ng Zi Ying, Ursich Lauren, Petrou Steve, Fletcher Emily V, Daly Roger J, Lim Kam Sian Terry C C, Valvi Santosh, Endersby Raelene, Johns Terrance G
Division of Paediatrics/Centre for Child Health Research, Medical School, University of Western Australia, Western Australia, Australia.
The Kids Research Institute, Perth, Western Australia, Australia.
Neurooncol Adv. 2024 Nov 19;6(1):vdae187. doi: 10.1093/noajnl/vdae187. eCollection 2024 Jan-Dec.
Glioblastoma, a lethal high-grade glioma, has not seen improvements in clinical outcomes in nearly 30 years. Ion channels are increasingly associated with tumorigenesis, and there are hundreds of brain-penetrant drugs that inhibit ion channels, representing an untapped therapeutic resource. The aim of this exploratory drug study was to screen an ion channel drug library against patient-derived glioblastoma cells to identify new treatments for brain cancer.
Seventy-two ion channel inhibitors were screened in patient-derived glioblastoma cells, and cell viability was determined using the ViaLight Assay. Cell cycle and apoptosis analysis were determined with flow cytometry using PI and Annexin V staining, respectively. Protein and phosphoprotein expression was determined using mass spectrometry and analyzed using gene set enrichment analysis. Kaplan-Meier survival analyses were performed using intracranial xenograft models of GBM6 and WK1 cells.
The voltage-gated sodium channel modulator, DPI-201-106, was revealed to reduce glioblastoma cell viability in vitro by inducing cell cycle arrest and apoptosis. Phosphoproteomics indicated that DPI-201-106 may impact DNA damage response (DDR) pathways. Combination treatment of DPI-201-106 with the CHK1 inhibitor prexasertib or the PARP inhibitor niraparib demonstrated synergistic effects in multiple patient-derived glioblastoma cells both in vitro and in intracranial xenograft mouse models, extending survival of glioblastoma-bearing mice.
DPI-201-106 enhances the efficacy of DDR inhibitors to reduce glioblastoma growth. As these drugs have already been clinically tested in humans, repurposing DPI-201-106 in novel combinatorial approaches will allow for rapid translation into the clinic.
胶质母细胞瘤是一种致命的高级别胶质瘤，近30年来临床疗效未见改善。离子通道与肿瘤发生的关联日益密切，有数百种可穿透血脑屏障的药物可抑制离子通道，这是一种尚未开发的治疗资源。这项探索性药物研究的目的是针对患者来源的胶质母细胞瘤细胞筛选离子通道药物库，以确定脑癌的新治疗方法。
在患者来源的胶质母细胞瘤细胞中筛选了72种离子通道抑制剂，并使用ViaLight检测法测定细胞活力。分别使用PI和膜联蛋白V染色通过流式细胞术测定细胞周期和凋亡分析。使用质谱法测定蛋白质和磷酸化蛋白质表达，并使用基因集富集分析进行分析。使用GBM6和WK1细胞的颅内异种移植模型进行Kaplan-Meier生存分析。
电压门控钠通道调节剂DPI-201-106被发现可通过诱导细胞周期停滞和凋亡来降低体外胶质母细胞瘤细胞的活力。磷酸化蛋白质组学表明DPI-201-106可能影响DNA损伤反应（DDR）途径。DPI-201-106与CHK1抑制剂prexasertib或PARP抑制剂尼拉帕利联合治疗在体外和颅内异种移植小鼠模型中的多种患者来源的胶质母细胞瘤细胞中均显示出协同作用，延长了荷胶质母细胞瘤小鼠的生存期。
DPI-201-106增强了DDR抑制剂降低胶质母细胞瘤生长的疗效。由于这些药物已经在人体中进行了临床试验，以新的联合方法重新利用DPI-201-106将能够快速转化为临床应用。
