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@ARTICLE{Jungwirth:310296,
      author       = {G. Jungwirth$^*$ and J. Cao and Y. Pan and R. Warta and C.
                      Lotsch and M. Moustafa$^*$ and M. Knoll$^*$ and T. Yu and V.
                      Braun and L. Jassowicz and P. D. Trong and Z. Wang and A.
                      Younsi and M. Scherer and M. Bendszus and S. M. Krieg and A.
                      von Deimling$^*$ and J. Debus$^*$ and A. Abdollahi$^*$ and
                      A. Unterberg and F. Sahm$^*$ and C. Herold-Mende},
      title        = {{D}rug screening on tumor organoids exposes therapeutic
                      vulnerabilities of meningiomas to {HDAC}1/2i panobinostat.},
      journal      = {Science translational medicine},
      volume       = {18},
      number       = {839},
      issn         = {1946-6234},
      address      = {Washington, DC},
      publisher    = {AAAS},
      reportid     = {DKFZ-2026-00519},
      pages        = {eaea3115},
      year         = {2026},
      abstract     = {Managing aggressive meningiomas remains challenging because
                      of limited treatment options besides surgical tumor removal
                      and radiotherapy. To increase the repertoire of promising
                      therapies for aggressive meningiomas, we established a
                      multistep drug screening workflow, focusing on targetable
                      genes obtained from transcriptome data of highly aggressive
                      grade 3 meningiomas. In vitro screening of 107 targeted
                      drugs identified nine effective inhibitors. To study these
                      drugs in a more natural environment, we established a
                      standardized patient-derived tumor organoid (TO) model
                      preserving accurately the original tissue's genotype and
                      phenotype. Individual drug responses were assessed in TOs
                      from 60 meningioma cases characterized at the molecular
                      level. In particular, the US Food and Drug
                      Administration-approved epigenetic drug panobinostat
                      demonstrated high antimeningioma efficacy in $70\%$ of TOs,
                      mediated through histone deacetylase 1 and 2 (HDAC1/2)
                      inhibition. In addition, treatment in an orthotopic in vivo
                      model revealed improved survival. In search of the molecular
                      mechanism underlying a potentially intrinsic panobinostat
                      resistance, we identified up-regulation of the
                      HDAC8-transforming growth factor-β
                      (TGFβ)-epithelial-to-mesenchymal transition (EMT) axis in
                      the TO model, whereas subsequent HDAC8 depletion increased
                      the sensitivity to panobinostat. These data highlight the
                      utility of personalized drug screenings on TOs to identify
                      suitable drug targets and inhibitors for more effective
                      treatment of clinically aggressive meningiomas and to help
                      advance our understanding of counteracting resistance
                      mechanisms.},
      cin          = {HD01 / E210 / B300 / E050},
      ddc          = {500},
      cid          = {I:(DE-He78)HD01-20160331 / I:(DE-He78)E210-20160331 /
                      I:(DE-He78)B300-20160331 / I:(DE-He78)E050-20160331},
      pnm          = {319H - Addenda (POF4-319H)},
      pid          = {G:(DE-HGF)POF4-319H},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41779868},
      doi          = {10.1126/scitranslmed.aea3115},
      url          = {https://inrepo02.dkfz.de/record/310296},
}