biostudies-literatureDharmaiah SNCATS NIH HHSNational Institutes of Health/National Cancer InstituteNational Center of Advancing Translational Sciences of the National Institutes of HealthNCI NIH HHS932-947https://www.ebi.ac.uk/biostudies/studies/S-EPMC12083236biostudies-literatureUnknown27(4)<h4>Background</h4>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.<h4>Methods</h4>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 standardNeuro-oncologyG-quadruplex stabilizer CX-5461 effectively combines with radiotherapy to target α-thalassemia/mental retardation X-linked-deficient malignant glioma.PMC12083236CA240338TL1 TR003169TL1TR003169 and UL1TR003167UL1 TR003167R01 CA240338Malgulwar PBHuse JTTadimeti VDharmaiah SSharin VChen BAFarooqi ASJohnson WEWhitfield BTAlvarez CfalseG-quadruplex stabilizer CX-5461 effectively combines with radiotherapy to target α-thalassemia/mental retardation X-linked-deficient malignant glioma.<h4>Background</h4>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.<h4>Methods</h4>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 standard2025-01-01T00:00:00Z2025 May2026-05-31T03:14:59.45Z2026-05-31T03:10:02.587ZS-EPMC120832363957000910.1093/neuonc/noae248