2. Academic Validation
  3. Ion channel modulator DPI-201-106 significantly enhances antitumor activity of DNA damage response inhibitors in glioblastoma

Ion channel modulator DPI-201-106 significantly enhances antitumor activity of DNA damage response inhibitors in glioblastoma

  • Neurooncol Adv. 2024 Nov 19;6(1):vdae187. doi: 10.1093/noajnl/vdae187.
Brittany Dewdney 1 2,  Panimaya Jeffreena Miranda 1 2,  Mani Kuchibhotla 2,  Ranjith Palanisamy 2,  Caitlyn Richworth 2,  Carol J Milligan 3,  Zi Ying Ng 2,  Lauren Ursich 2,  Steve Petrou 4 3,  Emily V Fletcher 1 2,  Roger J Daly 5,  Terry C C Lim Kam Sian 6,  Santosh Valvi 7 1 2,  Raelene Endersby 1 2,  Terrance G Johns 1 2
Affiliations

Affiliations

  • 1 Division of Paediatrics/Centre for Child Health Research, Medical School, University of Western Australia, Western Australia, Australia.
  • 2 The Kids Research Institute, Perth, Western Australia, Australia.
  • 3 Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • 4 Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
  • 5 Cancer Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
  • 6 Monash Proteomics and Metabolomics Platform, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
  • 7 Perth Children's Hospital, Perth, Western Australia, Australia.
PMID: 39659830 DOI: 10.1093/noajnl/vdae187
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

DNA damage; cell cycle; glioblastoma; ion channel.

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