ArticleNeuro-oncology2025
Alternative lengthening of telomere-based immortalization renders H3G34R-mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens.
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 10 papers.
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10 citing papers in PubMed.
- Twisting the End Game: How Telomere Chromatin Modifications Shape Telomere Maintenance.Aging cell · 2026Review
- SMARCAL1 is a targetable synthetic lethal therapeutic vulnerability in ATRX-deficient gliomas that use alternative lengthening of telomeres.Neuro-oncology · 2026Article
- Functional analysis of telomere maintenance mechanisms is more informative than immunohistochemistry for ATRX mutation interpretation in Gliomas.Acta neuropathologica communications · 2025Article
- Illuminating radiogenomic signatures in pediatric-type diffuse gliomas: insights into molecular, clinical, and imaging correlations. Part I: high-grade group.La Radiologia medica · 2025Review
- The Bermuda Triangle of paediatric brain cancers: epigenetics, developmental timing window and cell of origin.Cancer metastasis reviews · 2025Review
- A review of diffuse hemispheric glioma, H3 G34-mutant disease development, DNA repair, microenvironment, and treatments on the horizon.NPJ precision oncology · 2025Review
- Atypical R-loops in cancer: decoding molecular chaos for therapeutic gain.Journal of translational medicine · 2025Review
- Outcomes From a Contemporary Mono-Institutional Cohort of Histone-Mutant Diffuse Hemispheric Glioma: A Rare and Aggressive Pediatric-Type High-Grade Primary Brain Tumor.Brain tumor research and treatment · 2025Article
- A Review of Telomere Attrition in Cancer and Aging: Current Molecular Insights and Future Therapeutic Approaches.Cancers · 2025Review
- Preclinical evaluation of the potential PARP-imaging probe [carbonyl-EJNMMI radiopharmacy and chemistry · 2025Article
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40 authors.
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Abstract
backgroundDiffuse hemispheric glioma, H3 G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of alpha-thalassemia/mental retardation syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these 2 oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization, and consequently validate a targeted therapy approach.
methodsWe characterized patient-derived primary pediatric high-grade glioma (pHGG) models for telomere-maintenance mechanisms, DNA damage stress (including protein expression, pH2AX/Rad51 foci, cell-cycle arrest) and their sensitivity towards poly-ADP ribose polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modeling the disease. The anticancer activity of PARPi combinations in vivo was studied in Chorioallantoic Membrane (CAM) and orthotopic in vivo experiments. Finally, we treated a DHG-H3G34R_ATRX patient with PARPi combination therapy.
resultsWe elaborate that alternative lengthening of telomeres (ALT) is a key characteristic of DHG-H3G34R_ATRX. A dominant cooperative effect between H3G34R and ATRX loss in ALT activation also became apparent in iPSCs, which endogenously exert telomerase activity. In both, patient-derived DHG-H3G34R_ATRX models and H3G34R+/ATRX- iPSCs, the ALT-phenotype was associated with increased basal DNA damage stress, mediating synergistic susceptibility towards PARPi (talazoparib, niraparib) combinations with topoisomerase-I inhibitors (topotecan, irinotecan). In a first-of-its-kind case, treatment of a DHG-H3G34R_ATRX patient with the brain-penetrant PARP inhibitor niraparib and topotecan resulted in significant tumor reduction.
conclusionsOur preclinical and clinical data strongly support the further development of PARPi together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.
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