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@ARTICLE{Tzaridis:130693,
      author       = {T. Tzaridis and T. Milde$^*$ and K. Pajtler$^*$ and S.
                      Bender$^*$ and D. Jones$^*$ and S. Müller and A.
                      Wittmann$^*$ and M. Schlotter$^*$ and A. E. Kulozik and P.
                      Lichter$^*$ and V. Peter Collins and O. Witt$^*$ and M.
                      Kool$^*$ and A. Korshunov$^*$ and S. Pfister$^*$ and H.
                      Witt$^*$},
      title        = {{L}ow-dose {A}ctinomycin-{D} treatment re-establishes the
                      tumoursuppressive function of {P}53 in {RELA}-positive
                      ependymoma.},
      journal      = {OncoTarget},
      volume       = {7},
      number       = {38},
      issn         = {1949-2553},
      address      = {[S.l.]},
      publisher    = {Impact Journals LLC},
      reportid     = {DKFZ-2017-05771},
      pages        = {61860 - 61873},
      year         = {2016},
      abstract     = {Ependymomas in children can arise throughout all
                      compartments of the central nervous system (CNS). Highly
                      malignant paediatric ependymoma subtypes are Group A tumours
                      of the posterior fossa (PF-EPN-A) and RELA-fusion positive
                      (ST-EPN-RELA) tumours in the supratentorial compartment. It
                      was repeatedly reported in smaller series that accumulation
                      of p53 is frequently observed in ependymomas and that
                      immunohistochemical staining correlates with poor clinical
                      outcome, while TP53 mutations are rare. Our TP53 mutation
                      analysis of 130 primary ependymomas identified a mutation
                      rate of only $3\%.$ Immunohistochemical analysis of 398
                      ependymomas confirmed previous results correlating the
                      accumulation of p53 with inferior outcome. Among the
                      p53-positive ependymomas, the vast majority exhibited a RELA
                      fusion leading to the hypothesis that p53 inactivation might
                      be linked to RELA positivity.In order to assess the
                      potential of p53 reactivation through MDM2 inhibition in
                      ependymoma, we evaluated the effects of Actinomycin-D and
                      Nutlin-3 treatment in two preclinical ependymoma models
                      representing the high-risk subtypes PF-EPN-A and
                      ST-EPN-RELA. The IC-50 of the agent as determined by
                      metabolic activity assays was in the lower nano-molar range
                      (0.2-0.7 nM). Transcriptome analyses of high-dose (100 nM),
                      low-dose (5 nM) and non-treated cells revealed re-expression
                      of p53 dependent genes including p53 upregulated modulator
                      of apoptosis (PUMA) after low-dose treatment. At the protein
                      level, we validated the Actinomycin-D induced upregulation
                      of PUMA, and of p53 interaction partners MDM2 and p21.
                      Proapoptotic effects of low-dose application of the agent
                      were confirmed by flow cytometry. Thus, Actinomycin-D could
                      constitute a promising therapeutic option for ST-EPN-RELA
                      ependymoma patients, whose tumours frequently exhibit p53
                      inactivation.},
      cin          = {B062 / G340 / B060 / G380 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)G340-20160331 /
                      I:(DE-He78)B060-20160331 / I:(DE-He78)G380-20160331 /
                      I:(DE-He78)L101-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27556362},
      pmc          = {pmc:PMC5308696},
      doi          = {10.18632/oncotarget.11452},
      url          = {https://inrepo02.dkfz.de/record/130693},
}