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

Autor:	Laemmerer A; Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria., Lehmann C; IMBA - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna BioCenter (VBC), Vienna, Austria.; Vienna BioCenter (VBC), PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria., Mayr L; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria., Bruckner K; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.; Department of Neurosurgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Gabler L; Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; Department of Neurosurgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Senfter D; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria., Meyer P; Charles River Laboratories Germany GmbH, Freiburg, Germany., Balber T; Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.; Joint Applied Medicinal Radiochemistry Facility, University of Vienna, Medical University of Vienna, Vienna, Austria., Pirker C; Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Jaunecker CN; Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Kirchhofer D; Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Vician P; Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Griesser M; Department of Neurosurgery, Kepler University Hospital GmbH, Johannes Kepler University, Linz, Austria., Spiegl-Kreinecker S; Department of Neurosurgery, Kepler University Hospital GmbH, Johannes Kepler University, Linz, Austria., Schmook MT; Division of Neuroradiology and Musculoskeletal Radiology, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria., Traub-Weidinger T; Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria., Kuess P; Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria., Eckert F; Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria., Federico A; Hopp Children's Cancer Center (KiTZ), 69120 Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.; National Center for Tumor Diseases (NCT), Heidelberg, Germany., Madlener S; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria., Stepien N; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria., Robl B; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria., Baumgartner A; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria., Hainfellner JA; Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria., Dieckmann K; Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria., Dorfer C; Department of Neurosurgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Roessler K; Department of Neurosurgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Corsini NS; IMBA - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna BioCenter (VBC), Vienna, Austria., Holzmann K; Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Schmidt WM; Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria., Peyrl A; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria., Azizi AA; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria., Haberler C; Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria., Beck A; Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany., Pfister SM; Hopp Children's Cancer Center (KiTZ), 69120 Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.; National Center for Tumor Diseases (NCT), Heidelberg, Germany.; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany., Schueler J; Charles River Laboratories Germany GmbH, Freiburg, Germany., Loetsch-Gojo D; Department of Neurosurgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Knoblich JA; IMBA - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna BioCenter (VBC), Vienna, Austria.; Medical University of Vienna, Department of Neurology, Vienna, Austria., Berger W; Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Gojo J; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2024 Nov 18. Date of Electronic Publication: 2024 Nov 18.
DOI:	10.1093/neuonc/noae228
Abstrakt:	Background: 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. Methods: 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. Results: 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. Conclusion: Our preclinical and clinical data strongly support the further development of PARPis together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Databáze:	MEDLINE
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