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@ARTICLE{Koch:155320,
      author       = {Koch, Marilin Sophia and Czemmel, Stefan and Lennartz,
                      Felix and Beyeler, Sarah and Rajaraman, Srinath and
                      Przystal, Justyna Magdalena and Govindarajan, Parameswari
                      and Canjuga, Denis and Neumann, Manfred and Rizzu, Patrizia
                      and Zwirner, Stefan and Hoetker, Michael Stefan and Zender,
                      Lars and Walter, Bianca and Tatagiba, Marcos and Raineteau,
                      Olivier and Heutink, Peter and Nahnsen, Sven and Tabatabai,
                      Ghazaleh},
      title        = {{E}xperimental glioma with high b{HLH} expression harbor
                      increased replicative stress and are sensitive toward {ATR}
                      inhibition.},
      journal      = {Neuro-oncology advances},
      volume       = {2},
      number       = {1},
      issn         = {2632-2498},
      address      = {Oxford},
      publisher    = {Oxford University Press},
      reportid     = {DZNE-2021-00587},
      pages        = {vdaa115},
      year         = {2020},
      note         = {ISSN 2632-2498 not unique: **2 hits**.},
      abstract     = {The overexpression of (basic)helix-loop-helix ((b)HLH)
                      transcription factors (TFs) is frequent in malignant glioma.
                      We investigated molecular effects upon disruption of the
                      (b)HLH network by a dominant-negative variant of the E47
                      protein (dnE47). Our goal was to identify novel molecular
                      subgroup-specific therapeutic strategies.Glioma cell lines
                      LN229, LNZ308, and GS-2/GS-9 were lentivirally transduced.
                      Functional characterization included immunocytochemistry,
                      immunoblots, cytotoxic, and clonogenic survival assays in
                      vitro, and latency until neurological symptoms in vivo.
                      Results of cap analysis gene expression and RNA-sequencing
                      were further validated by immunoblot, flow cytometry, and
                      functional assays in vitro.The induction of dnE47-RFP led to
                      cytoplasmic sequestration of (b)HLH TFs and antiglioma
                      activity in vitro and in vivo. Downstream molecular events,
                      ie, alterations in transcription start site usage and in the
                      transcriptome revealed enrichment of cancer-relevant
                      pathways, particularly of the DNA damage response (DDR)
                      pathway. Pharmacologic validation of this result using
                      ataxia telangiectasia and Rad3 related (ATR) inhibition led
                      to a significantly enhanced early and late apoptotic effect
                      compared with temozolomide alone.Gliomas overexpressing
                      (b)HLH TFs are sensitive toward inhibition of the ATR
                      kinase. The combination of ATR inhibition plus temozolomide
                      or radiation therapy in this molecular subgroup are
                      warranted.},
      keywords     = {CAGE (Other) / DDR (Other) / E47 (Other) / RNA-Seq (Other)
                      / bHLH transcription factors (Other)},
      cin          = {AG Rizzu / AG Heutink 1},
      ddc          = {610},
      cid          = {I:(DE-2719)1210009 / I:(DE-2719)1210002},
      pnm          = {345 - Population Studies and Genetics (POF3-345) / 342 -
                      Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-345 / G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33134924},
      pmc          = {pmc:PMC7592426},
      doi          = {10.1093/noajnl/vdaa115},
      url          = {https://pub.dzne.de/record/155320},
}