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@ARTICLE{Valinciute:276078,
      author       = {G. Valinciute$^*$ and J. Ecker$^*$ and F. Selt$^*$ and T.
                      Hielscher$^*$ and R. Sigaud$^*$ and J. Ridinger$^*$ and V.
                      Thatikonda$^*$ and C. Gatzweiler$^*$ and S. Robinson and J.
                      Talbot and F. Bernardi and D. Picard$^*$ and M.
                      Blattner-Johnson$^*$ and S. Schmid$^*$ and D. T. Jones$^*$
                      and C. M. van Tilburg$^*$ and D. Capper$^*$ and M. Kool$^*$
                      and M. Remke$^*$ and I. Oehme$^*$ and S. M. Pfister$^*$ and
                      M. F. Roussel and O. Ayrault and O. Witt$^*$ and T.
                      Milde$^*$},
      title        = {{C}lass {I} {HDAC} inhibitor entinostat synergizes with
                      {PLK}1 inhibitors in {MYC}-amplified medulloblastoma cells.},
      journal      = {Journal of neuro-oncology},
      volume       = {163},
      number       = {1},
      issn         = {0167-594x},
      address      = {Dordrecht [u.a.]},
      publisher    = {Springer Science + Business Media B.V},
      reportid     = {DKFZ-2023-00984},
      pages        = {143-158},
      year         = {2023},
      note         = {#EA:B310#LA:B310# / 2023 May;163(1):143-158},
      abstract     = {We and others have demonstrated that MYC-amplified
                      medulloblastoma (MB) cells are susceptible to class I
                      histone deacetylase inhibitor (HDACi) treatment. However,
                      single drug treatment with HDACi has shown limited clinical
                      efficacy. We hypothesized that addition of a second compound
                      acting synergistically with HDACi may enhance efficacy.We
                      used a gene expression dataset to identify PLK1 as a second
                      target in MB cells and validated the relevance of PLK1 in
                      MB. We measured cell metabolic activity, viability, and
                      cycle progression in MB cells after treatment with
                      PLK1-specific inhibitors (PLK1i). Chou-Talalay synergy
                      calculations were used to determine the nature of class I
                      HDACi entinostat and PLK1i interaction which was validated.
                      Finally, the clinical potential of the combination was
                      assessed in the in vivo experiment.MYC-amplified tumor cells
                      are highly sensitive towards treatment with ATP-competitive
                      PLK1i as a monotherapy. Entinostat and PLK1i in combination
                      act synergistically in MYC-driven MB cells, exerting
                      cytotoxic effects at clinically relevant concentrations. The
                      downstream effect is exerted via MYC-related pathways,
                      pointing out the potential of MYC amplification as a
                      clinically feasible predictive biomarker for patient
                      selection. While entinostat significantly extended survival
                      of mice implanted with orthotopic MYC-amplified MB PDX,
                      there was no evidence of the improvement of survival when
                      treating the animals with the combination.The combination of
                      entinostat and PLK1i showed synergistic interaction in
                      vitro, but not in vivo. Therefore, further screening of
                      blood-brain barrier penetrating PLK1i is warranted to
                      determine the true potential of the combination as no
                      on-target activity was observed after PLK1i volasertib
                      treatment in vivo.},
      keywords     = {HDAC inhibitor (Other) / MYC (Other) / Medulloblastoma
                      (Other) / PLK1 inhibitor (Other)},
      cin          = {B310 / HD01 / C060 / B062 / ED01 / B360 / BE01},
      ddc          = {610},
      cid          = {I:(DE-He78)B310-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)C060-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)ED01-20160331 / I:(DE-He78)B360-20160331 /
                      I:(DE-He78)BE01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37183219},
      doi          = {10.1007/s11060-023-04319-1},
      url          = {https://inrepo02.dkfz.de/record/276078},
}