Faculty, Staff and Student Publications
Language
English
Publication Date
5-15-2025
DOI
10.1093/neuonc/noae248
PMID
39570009
PMCID
PMC12083236
PubMedCentral® Posted Date
11-21-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Background: Inactivation of α-thalassemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures, enhancing replication stress and genomic instability. Building on earlier work, we evaluated the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in ATRX-deficient preclinical glioma models.
Methods: Using the G4 stabilizer CX-5461, we treated patient-derived glioma stem cells (GSCs) in vitro and GSC flank and intracranial murine xenografts in vivo to evaluate efficacy as both a single agent and in combination with ionizing radiation (IR), the latter a central element of current treatment standards.
Results: CX-5461 promoted dose-sensitive lethality in ATRX-deficient GSCs relative to ATRX-intact controls. Mechanistic studies revealed that CX-5461 disrupted histone variant H3.3 deposition, enhanced replication stress and DNA damage, activated p53-independent apoptosis, and induced G2/M arrest to a greater extent in ATRX-deficient GSCs than in ATRX-intact counterparts. These data were corroborated in vivo, where CX-5461/IR treatment profoundly delayed tumor growth and prolonged survival in mice bearing ATRX-deficient flank xenografts. Histopathological analyses revealed decreased proliferation, increased apoptosis, and significant G4 induction, replication stress, and DNA damage in CX-5461-treated tumors, both alone and in combination with IR. Finally, despite suboptimal blood-brain-barrier penetration, systemic CX-5461 treatment induced tangible pharmacodynamic effects in ATRX-deficient intracranial GSC models.
Conclusions: In totality, our work substantively demonstrates efficacy and defines mechanisms of action for G4 stabilization as a novel therapeutic strategy targeting ATRX-deficient malignant glioma, laying the groundwork for clinical translation.
Keywords
Animals, Humans, G-Quadruplexes, Glioma, Mice, Brain Neoplasms, X-linked Nuclear Protein, Xenograft Model Antitumor Assays, alpha-Thalassemia, Tumor Cells, Cultured, Apoptosis, DNA Damage, X-Linked Intellectual Disability, Naphthyridines, Benzothiazoles, ATRX, CX-5461, glioma, G-quadruplex, radiation
Published Open-Access
yes
Recommended Citation
Dharmaiah, Sharvari; Malgulwar, Prit Benny; Johnson, William E; et al., "G-quadruplex Stabilizer Cx-5461 Effectively Combines With Radiotherapy to Target α-Thalassemia/Mental Retardation X-Linked-Deficient Malignant Glioma" (2025). Faculty, Staff and Student Publications. 5886.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5886
Graphical Abstract
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