TY  - JOUR
AU  - Laemmerer, Anna
AU  - Lehmann, Christian
AU  - Mayr, Lisa
AU  - Bruckner, Katharina
AU  - Gabler, Lisa
AU  - Senfter, Daniel
AU  - Meyer, Philipp
AU  - Balber, Theresa
AU  - Pirker, Christine
AU  - Jaunecker, Carola N
AU  - Kirchhofer, Dominik
AU  - Vician, Petra
AU  - Griesser, Michelle
AU  - Spiegl-Kreinecker, Sabine
AU  - Schmook, Maria T
AU  - Traub-Weidinger, Tatjana
AU  - Kuess, Peter
AU  - Eckert, Franziska
AU  - Federico, Aniello
AU  - Madlener, Sibylle
AU  - Stepien, Natalia
AU  - Robl, Bernhard
AU  - Baumgartner, Alicia
AU  - Hainfellner, Johannes A
AU  - Dieckmann, Karin
AU  - Dorfer, Christian
AU  - Roessler, Karl
AU  - Corsini, Nina S
AU  - Holzmann, Klaus
AU  - Schmidt, Wolfgang M
AU  - Peyrl, Andreas
AU  - Azizi, Amedeo A
AU  - Haberler, Christine
AU  - Beck, Alexander
AU  - Pfister, Stefan M
AU  - Schueler, Julia
AU  - Loetsch-Gojo, Daniela
AU  - Knoblich, Jürgen A
AU  - Berger, Walter
AU  - Gojo, Johannes
TI  - Alternative lengthening of telomere-based immortalization renders H3G34R -mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens.
JO  - Neuro-Oncology
VL  - 27
IS  - 3
SN  - 1522-8517
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DKFZ-2024-02349
SP  - 811-827
PY  - 2025
N1  - 2025 Mar 7;27(3):811-827
AB  - Diffuse hemispheric glioma, H3G34R/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 two 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 polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modelling 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 a 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 a significant tumor reduction.Our preclinical and clinical data strongly support the further development of PARPis together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.
KW  - ATRX (Other)
KW  - DNA damage (Other)
KW  - Diffuse hemispheric glioma (Other)
KW  - H3G34R (Other)
KW  - PARP inhibitor (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39556024
DO  - DOI:10.1093/neuonc/noae228
UR  - https://inrepo02.dkfz.de/record/294574
ER  -