TMIC-17. Novel GABAAR antagonists target networked gene hubs at the leading-edge in high-grade gliomas
Abstract The role of ion channel activity in high-grade glioma (HGG) pathophysiology remains poorly understood. Using weighted gene co-expression network analysis (WGCNA) of RNA-seq data, we identified a “neuronal regulation” module conserved across pediatric Diffuse Midline Glioma (DMG), non-brainstem HGG (NBS-HGG), and adult glioblastoma. Single-cell RNA-seq and spatial transcriptomics revealed this module is enriched at the leading edge. Significantly, we identified the γ-Aminobutyric acid type A receptor (GABAAR) genes, GABRA1 (α1) and GABRG2 (γ2), as central hubs within this module, whose expression in patient-resected tumour tissue co-localised with GABAergic synaptic markers. GABRA5 (α5), a component of non-synaptic GABAARs, was also upregulated in tumour cells in both patient tissue and glioblastoma organoids (GBOs). Pharmacologic targeting of GABAARs in GBOs using antagonists (S44819, GABA(A)-compound 1b) robustly suppressed tumour invasion and proliferation, with effects further enhanced by radiation and temozolomide. Our findings identify ion channel hubs at the glioma-invasive front as druggable vulnerabilities and highlight GABAAR-targeting as a promising strategy to disrupt tumour progression.
Authors
- Chloé Shard (ORCID: https://orcid.org/0000-0002-7408-9269)
- Yen Yeow (ORCID: https://orcid.org/0000-0002-2341-6354)
- Helen M. Palethorpe (ORCID: https://orcid.org/0000-0003-3803-5113)
- Guillermo Alberto Gomez (ORCID: https://orcid.org/0000-0002-0494-2404)
- Terrance G. Johns (ORCID: https://orcid.org/0000-0002-8874-4543)
- Anthony Bosco (ORCID: https://orcid.org/0000-0002-4335-615X)
- Santosh Poonnoose (ORCID: https://orcid.org/0000-0002-9486-4904)
- Emily V. Fletcher (ORCID: https://orcid.org/0000-0002-9786-4221)
- Anahita Fouladzadeh (ORCID: https://orcid.org/0000-0002-3981-4509)
- Zi Ying Ng
- Brittany Dewdney (ORCID: https://orcid.org/0000-0002-6362-369X)
- Santosh Valvi (ORCID: https://orcid.org/0000-0002-9655-0001)
- Matthew Jones (ORCID: https://orcid.org/0000-0002-5528-0826)
- Ishika Mahajan (ORCID: https://orcid.org/0000-0003-1640-7342)
- Ashwini Patil (ORCID: https://orcid.org/0000-0003-2132-3899)
- Alistair R. R. Forrest (ORCID: https://orcid.org/0000-0003-4543-1675)
- Abbie Francis (ORCID: https://orcid.org/0000-0002-4356-7686)
- Yasmin Boyle
- Rebecca J. Ormsby (ORCID: https://orcid.org/0000-0002-4256-7481)
- Anya C. Jones (ORCID: https://orcid.org/0000-0002-6649-4977)
- Irina Kuznetsova (ORCID: https://orcid.org/0000-0002-7501-1025)
- Matt Barker
- Sara Rezaeiravesh
Institutions
- The Kids Research Institute Australia (AU)
- The University of Western Australia (AU)
- Harry Perkins Institute of Medical Research (AU)
- Princess Margaret Hospital for Children (AU)
- Government of Western Australia Department of Health (AU)
- Brain Tumour Charity (GB)
- Flinders Medical Centre (AU)
- Adelaide Institute for Sleep Health (AU)
- Centre for Cancer Biology (AU)
- Dermatology Research Center (US)
- Perth Children's Hospital
- Cabinet Office (JP)
Publication Details
- Journal
- Neuro-Oncology
- Published
- 2025-11-01
- DOI
- https://doi.org/10.1093/neuonc/noaf201.1772
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00