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@ARTICLE{Schramm:143817,
      author       = {K. Schramm$^*$ and M. Iskar$^*$ and B. Statz$^*$ and N.
                      Jäger$^*$ and D. Haag$^*$ and M. Słabicki$^*$ and S. M.
                      Pfister$^*$ and M. Zapatka$^*$ and J. Gronych$^*$ and D. T.
                      W. Jones$^*$ and P. Lichter$^*$},
      title        = {{DECIPHER} pooled sh{RNA} library screen identifies
                      {PP}2{A} and {FGFR} signaling as potential therapeutic
                      targets for {DIPG}s.},
      journal      = {Neuro-Oncology},
      volume       = {21},
      number       = {7},
      issn         = {1523-5866},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2019-01379},
      pages        = {867-877},
      year         = {2019},
      abstract     = {Diffuse intrinsic pontine gliomas (DIPGs) are highly
                      aggressive pediatric brain tumors that are characterized by
                      a recurrent mutation (K27M) within the histone H3 encoding
                      genes H3F3A or HIST1H3A/B/C. These mutations have been shown
                      to induce a global reduction in the repressive histone
                      modification H3K27me3, which together with widespread
                      changes in DNA methylation patterns results in an extensive
                      transcriptional reprogramming hampering the identification
                      of single therapeutic targets based on a molecular
                      rationale.We applied a large-scale gene knockdown approach
                      using a pooled shRNA library in combination with
                      next-generation sequencing in order to identify
                      DIPG-specific vulnerabilities. The therapeutic potential of
                      specific inhibitors of candidate targets was validated in a
                      secondary drug screen.We identified fibroblast growth factor
                      receptor (FGFR) signaling and the serine/threonine protein
                      phosphatase 2A (PP2A) as top depleted hits in
                      patient-derived DIPG cell cultures and validated their
                      lethal potential by FGF ligand depletion and genetic
                      knockdown of the PP2A structural subunit PPP2R1A. Further,
                      pharmacological inhibition of FGFR and PP2A signaling
                      through ponatinib and LB-100 treatment, respectively,
                      exhibited strong tumor-specific anti-proliferative and
                      apoptotic activity in cultured DIPG cells.Our findings
                      suggest FGFR and PP2A signaling as potential new therapeutic
                      targets for the treatment of DIPGs.},
      cin          = {B060 / B062 / B360},
      ddc          = {610},
      cid          = {I:(DE-He78)B060-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)B360-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30943283},
      doi          = {10.1093/neuonc/noz057},
      url          = {https://inrepo02.dkfz.de/record/143817},
}