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@ARTICLE{Laemmerer:294574,
      author       = {A. Laemmerer and C. Lehmann and L. Mayr and K. Bruckner and
                      L. Gabler and D. Senfter and P. Meyer and T. Balber and C.
                      Pirker and C. N. Jaunecker and D. Kirchhofer and P. Vician
                      and M. Griesser and S. Spiegl-Kreinecker and M. T. Schmook
                      and T. Traub-Weidinger and P. Kuess and F. Eckert and A.
                      Federico$^*$ and S. Madlener and N. Stepien and B. Robl and
                      A. Baumgartner and J. A. Hainfellner and K. Dieckmann and C.
                      Dorfer and K. Roessler and N. S. Corsini and K. Holzmann and
                      W. M. Schmidt and A. Peyrl and A. A. Azizi and C. Haberler
                      and A. Beck and S. M. Pfister$^*$ and J. Schueler and D.
                      Loetsch-Gojo and J. A. Knoblich and W. Berger and J. Gojo},
      title        = {{A}lternative lengthening of telomere-based immortalization
                      renders {H}3{G}34{R} -mutant diffuse hemispheric glioma
                      hypersensitive to {PARP} inhibitor combination regimens.},
      journal      = {Neuro-Oncology},
      volume       = {27},
      number       = {3},
      issn         = {1522-8517},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2024-02349},
      pages        = {811-827},
      year         = {2025},
      note         = {2025 Mar 7;27(3):811-827},
      abstract     = {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
                      $DHG-H3G34R_ATRX.$},
      keywords     = {ATRX (Other) / DNA damage (Other) / Diffuse hemispheric
                      glioma (Other) / H3G34R (Other) / PARP inhibitor (Other)},
      cin          = {B062 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39556024},
      doi          = {10.1093/neuonc/noae228},
      url          = {https://inrepo02.dkfz.de/record/294574},
}