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@ARTICLE{Vollmer:284402,
      author       = {J. Vollmer$^*$ and J. Ecker$^*$ and T. Hielscher$^*$ and G.
                      Valinciute$^*$ and J. Ridinger$^*$ and N. Jamaladdin$^*$ and
                      H. Peterziel$^*$ and C. M. van Tilburg$^*$ and I. Oehme$^*$
                      and O. Witt$^*$ and T. Milde$^*$},
      title        = {{C}lass {I} {HDAC} inhibition reduces {DNA} damage repair
                      capacity of {MYC}-amplified medulloblastoma cells.},
      journal      = {Journal of neuro-oncology},
      volume       = {164},
      number       = {3},
      issn         = {0167-594X},
      address      = {Dordrecht [u.a.]},
      publisher    = {Springer Science + Business Media B.V},
      reportid     = {DKFZ-2023-01991},
      pages        = {617-632},
      year         = {2023},
      note         = {#EA:B310#LA:B310# / 2023 Sep;164(3):617-632},
      abstract     = {MYC-driven Group 3 medulloblastoma (MB) (subtype II) is a
                      highly aggressive childhood brain tumor. Sensitivity of
                      MYC-driven MB to class I histone deacetylase inhibitors
                      (HDACi) has been previously demonstrated in vitro and in
                      vivo. In this study we characterize the transcriptional
                      effects of class I HDACi in MYC-driven MB and explore
                      beneficial drug combinations.MYC-amplified Group 3 MB cells
                      (HD-MB03) were treated with class I HDACi entinostat.
                      Changes in the gene expression profile were quantified on a
                      microarray. Bioinformatic assessment led to the
                      identification of pathways affected by entinostat treatment.
                      Five drugs interfering with these pathways (olaparib,
                      idasanutlin, ribociclib, selinexor, vinblastine) were tested
                      for synergy with entinostat in WST-8 metabolic activity
                      assays in a 5 × 5 combination matrix design. Synergy was
                      validated in cell count and flow cytometry experiments. The
                      effect of entinostat and olaparib on DNA damage was
                      evaluated by γH2A.X quantification in immunoblotting,
                      fluorescence microscopy and flow cytometry.Entinostat
                      treatment changed the expression of genes involved in 22
                      pathways, including downregulation of DNA damage response.
                      The PARP1 inhibitors olaparib and pamiparib showed synergy
                      with entinostat selectively in MYC-amplified MB cells,
                      leading to increased cell death, decreased viability and
                      increased formation of double strand breaks, as well as
                      increased sensitivity to additional induction of DNA damage
                      by doxorubicin. Non-MYC-amplified MB cells and normal human
                      fibroblasts were not susceptible to this triple
                      treatment.Our study identifies the combination of entinostat
                      with olaparib as a new potential therapeutic approach for
                      MYC-driven Group 3 MB.},
      keywords     = {DNA-damage (Other) / HDAC (Other) / MYC (Other) /
                      Medulloblastoma (Other) / Synergy (Other)},
      cin          = {B310 / HD01 / C060},
      ddc          = {610},
      cid          = {I:(DE-He78)B310-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)C060-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37783879},
      doi          = {10.1007/s11060-023-04445-w},
      url          = {https://inrepo02.dkfz.de/record/284402},
}