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

Brittany Dewdney; Panimaya Jeffreena Miranda; Mani Kuchibhotla; Ranjith Palanisamy; Caitlyn Richworth; Carol J Milligan; Zi Ying Ng; Lauren Ursich; Steve Petrou; Emily V Fletcher; Roger J Daly; Terry C C Lim Kam Sian; Santosh Valvi; Raelene Endersby; Terrance G Johns

doi:10.1093/noajnl/vdae187

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. eCollection 2024 Jan-Dec.

Authors

Brittany Dewdney^{1

2}, Panimaya Jeffreena Miranda^{1

2}, Mani Kuchibhotla², Ranjith Palanisamy², Caitlyn Richworth², Carol J Milligan³, Zi Ying Ng², Lauren Ursich², Steve Petrou^{4

3}, Emily V Fletcher^{1

2}, Roger J Daly⁵, Terry C C Lim Kam Sian⁶, Santosh Valvi^{7

1

2}, Raelene Endersby^{1

2}, Terrance G Johns^{1

2}

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.

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.