Evidence map›Paper›PMID 40497637›Full record

ArticleNeuro-oncology2025

Novel GABAAR antagonists target networked gene hubs at the leading edge in high-grade gliomas.

Chloe Shard, Anya C Jones, Anahita Fouladzadeh, Helen M Palethorpe, Abbie Francis, Yasmin Boyle, Rebecca J Ormsby, Brittany Dewdney, Yen Yeow, Ishika Mahajan and 13 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuro-oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed.

  1. Review
  2. Review
  3. Article
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  5. Organoids glimpse: the nexus for diverse tumor heterogeneity.Frontiers in cell and developmental biology · 2026
    Review
  6. Article
  7. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors.

Chloe ShardCentre for Cancer Biology, South Australia Pathology and University of South Australia, Adelaide, South Australia, 5000, Australia.
Anya C JonesCentre for Child Health Research, The University of Western Australia, Western Australia, 6009, Australia.
Anahita FouladzadehCentre for Cancer Biology, South Australia Pathology and University of South Australia, Adelaide, South Australia, 5000, Australia.
Helen M PalethorpeCentre for Cancer Biology, South Australia Pathology and University of South Australia, Adelaide, South Australia, 5000, Australia.
Abbie FrancisCentre for Child Health Research, The University of Western Australia, Western Australia, 6009, Australia.
Yasmin BoyleCancer Centre, The Kids Research Institute Australia, Perth, Western Australia, 6009, Australia.
Rebecca J OrmsbyFlinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, 5001, Australia.
Brittany DewdneyCentre for Child Health Research, The University of Western Australia, Western Australia, 6009, Australia.
Yen YeowHarry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Perth, Western Australia, 6009, Australia.
Ishika MahajanCentre for Cancer Biology, South Australia Pathology and University of South Australia, Adelaide, South Australia, 5000, Australia.
Matthew BarkerCancer Centre, The Kids Research Institute Australia, Perth, Western Australia, 6009, Australia.
Irina KuznetsovaHarry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Perth, Western Australia, 6009, Australia.
Matthew E JonesHarry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Perth, Western Australia, 6009, Australia.
Ashwini PatilCombinatics, Chiba, 272-0824, Japan.
Sara RezaeiraveshCancer Centre, The Kids Research Institute Australia, Perth, Western Australia, 6009, Australia.
Zi Ying NgCancer Centre, The Kids Research Institute Australia, Perth, Western Australia, 6009, Australia.
Santosh I PoonnooseDepartment of Neurosurgery, Flinders Medical Centre, Adelaide, South Australia 5042, Australia.
Anthony BoscoAsthma and Airway Disease Research Center, University of Arizona, Tucson, Arizona, 85724, USA.
Santosh ValviBrain Tumour Research Programme, The Kids Research Institute Australia, Perth, Western Australia, 6009, Australia.ORCID 0000-0002-9655-0001
Alistair R R ForrestHarry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Perth, Western Australia, 6009, Australia.
Terrance G JohnsCentre for Child Health Research, The University of Western Australia, Western Australia, 6009, Australia.
Guillermo A GomezCentre for Cancer Biology, South Australia Pathology and University of South Australia, Adelaide, South Australia, 5000, Australia.
Emily V FletcherCentre for Child Health Research, The University of Western Australia, Western Australia, 6009, Australia.ORCID 0000-0002-9786-4221

Funding

Cancer Council of Western AustraliaCancer Council S.A. Beat Cancer ProjectCharlie Teo FoundationChildren's Leukemia & Cancer Research FoundationCure Brain Cancer FoundationMcCleary Murchland FellowshipNeurosurgical Research FoundationNeurosurgical Research Foundation Chris AdamsNHMRC 2021/GNT2013180NHMRC 2023/GNT2030541Perth Children's Hospital FoundationRobert Connor Dawes FoundationThe Kids Research Institute Australia AscendWestern Australian Future Health Research and Innovation Fund
6 · The paper itself

Abstract

backgroundIon channel activity underlying biological processes that drive high-grade gliomas (HGG) is largely unknown. We aimed to determine the networking of ion channel genes and validate their expression within HGG patient tumors, to identify ion channel-targeting drugs that would inhibit tumor-promoting processes.

methodsWe used weighted gene co-expression network analysis (WGCNA) of RNAseq data to identify ion channel gene hubs in diffuse midline glioma (DMG) and glioblastoma. Using scRNA-seq, spatial transcriptomics, and immunohistochemistry, we characterized the expression of identified hubs within patient tumors, validating their role by testing the efficacy of ion channel inhibitors alone or in combination with radiation and temozolomide on the growth and invasion of patient-derived glioblastoma explant organoids (GBOs).

resultsNetwork analysis revealed a preserved HGG "neuronal regulation" module, containing the greatest number of ion channels, with its corresponding genes concentrated at the tumor's leading edge. Hubs within this module included γ-Aminobutyric-acid type A receptor (GABAAR) genes GABRA1 (α1) and GABRG2 (γ2), which immunohistochemically colocalized with GABAergic synaptic markers at the leading edge. GBOs failed to retain this synaptic architecture but expressed a glioblastoma hub GABRA5 (α5), a component of extrasynaptic GABAARs. S44819, an α5-GABAAR antagonist strongly inhibited GBO invasion, with GABA(A)-compound 1b, a partial antagonist of GABAARs, robustly inhibiting GBO proliferation and invasion. Moreover, combined with standard-of-care (SOC) regimens, the anti-invasive properties of both compounds were enhanced in GBOs.

conclusionsOur co-expression network analysis identified key ion channels at the leading edge in HGGs, which can be targeted by GABAAR-acting drugs to disrupt tumor progression.

Indexed as

Brain NeoplasmsGene Expression Regulation, NeoplasticGene Regulatory NetworksGliomaReceptors, GABA-ABiomarkers, TumorCell ProliferationHumansNeoplasm GradingTumor Cells, CulturedBiomarkers, TumorReceptors, GABA-AGABAARshigh-grade gliomaleading edgesynapseWGCNA

Identifiers

PMID40497637
PMCPMC12908485

What OpenQuestion holds

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LicenceCC BY-NC
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.