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Alternative lengthening of telomere-based immortalization renders H3G34R-mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens

Diffuse 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 the...

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Main Authors: Lämmerer, Anna (Author) , Lehmann, Christian (Author) , Mayr, Lisa (Author) , Bruckner, Katharina (Author) , Gabler, Lisa (Author) , Senfter, Daniel (Author) , Meyer, Philipp (Author) , Balber, Theresa (Author) , Pirker, Christine (Author) , Jaunecker, Carola N (Author) , Kirchhofer, Dominik (Author) , Vician, Petra (Author) , Griesser, Michelle (Author) , Spiegl-Kreinecker, Sabine (Author) , Schmook, Maria T (Author) , Traub-Weidinger, Tatjana (Author) , Kuess, Peter (Author) , Eckert, Franziska (Author) , Federico, Aniello (Author) , Madlener, Sibylle (Author) , Stepien, Natalia (Author) , Robl, Bernhard (Author) , Baumgartner, Alicia (Author) , Hainfellner, Johannes A (Author) , Dieckmann, Karin (Author) , Dorfer, Christian (Author) , Roessler, Karl (Author) , Corsini, Nina S (Author) , Holzmann, Klaus (Author) , Schmidt, Wolfgang M (Author) , Peyrl, Andreas (Author) , Azizi, Amedeo A (Author) , Haberler, Christine (Author) , Beck, Alexander (Author) , Pfister, Stefan (Author) , Schueler, Julia (Author) , Lötsch-Gojo, Daniela (Author) , Knoblich, Jürgen A (Author) , Berger, Walter (Author) , Gojo, Johannes (Author)
Format: Article (Journal)
Language:English
Published: March 2025
In: Neuro-Oncology
Year: 2025, Volume: 27, Issue: 3, Pages: 811-827
ISSN:1523-5866
DOI:10.1093/neuonc/noae228
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1093/neuonc/noae228
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Author Notes:Anna Laemmerer, Christian Lehmann, Lisa Mayr, Katharina Bruckner, Lisa Gabler, Daniel Senfter, Philipp Meyer, Theresa Balber, Christine Pirker, Carola N. Jaunecker, Dominik Kirchhofer, Petra Vician, Michelle Griesser, Sabine Spiegl-Kreinecker, Maria T. Schmook, Tatjana Traub-Weidinger, Peter Kuess, Franziska Eckert, Aniello Federico, Sibylle Madlener, Natalia Stepien, Bernhard Robl, Alicia Baumgartner, Johannes A. Hainfellner, Karin Dieckmann, Christian Dorfer, Karl Roessler, Nina S. Corsini, Klaus Holzmann, Wolfgang M. Schmidt, Andreas Peyrl, Amedeo A. Azizi, Christine Haberler, Alexander Beck, Stefan M. Pfister, Julia Schueler, Daniela Lötsch-Gojo, Jürgen A. Knoblich, Walter Berger, and Johannes Gojo
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Summary:Diffuse 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.We 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.We 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.Our preclinical and clinical data strongly support the further development of PARPi together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.
Item Description:Veröffentlicht: 18. November 2024
Gesehen am 06.06.2025
Physical Description:Online Resource
ISSN:1523-5866
DOI:10.1093/neuonc/noae228

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