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@ARTICLE{Ltsch:169022,
      author       = {D. Lötsch and D. Kirchhofer and B. Englinger and L. Jiang
                      and K. Okonechnikov$^*$ and D. Senfter$^*$ and A. Laemmerer
                      and L. Gabler and C. Pirker and A. M. Donson and P. Bannauer
                      and P. Korbel and C. N. Jaunecker and J.-M. Hübner$^*$ and
                      L. Mayr and S. Madlener and M. T. Schmook and G. Ricken and
                      K. Maaß$^*$ and M. Grusch and K. Holzmann and B.
                      Grasl-Kraupp and S. Spiegl-Kreinecker and J. Hsu and C.
                      Dorfer and K. Rössler and A. A. Azizi and N. K. Foreman and
                      A. Peyrl and C. Haberler and T. Czech and I. Slavc and M. G.
                      Filbin and K. W. Pajtler$^*$ and M. Kool$^*$ and W. Berger
                      and J. Gojo$^*$},
      title        = {{T}argeting fibroblast growth factor receptors to combat
                      aggressive ependymoma.},
      journal      = {Acta neuropathologica},
      volume       = {142},
      number       = {2},
      issn         = {1432-0533},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2021-01190},
      pages        = {339-360},
      year         = {2021},
      note         = {#LA:B062#/2021 Aug;142(2):339-360},
      abstract     = {Ependymomas (EPN) are central nervous system tumors
                      comprising both aggressive and more benign molecular
                      subtypes. However, therapy of the high-risk subtypes
                      posterior fossa group A (PF-A) and supratentorial
                      RELA-fusion positive (ST-RELA) is limited to gross total
                      resection and radiotherapy, as effective systemic treatment
                      concepts are still lacking. We have recently described
                      fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as
                      oncogenic drivers of EPN. However, the underlying molecular
                      mechanisms and their potential as therapeutic targets have
                      not yet been investigated in detail. Making use of
                      transcriptomic data across 467 EPN tissues, we found that
                      FGFR1 and FGFR3 were both widely expressed across all
                      molecular groups. FGFR3 mRNA levels were enriched in ST-RELA
                      showing the highest expression among EPN as well as other
                      brain tumors. We further identified high expression levels
                      of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all
                      EPN subtypes while FGF9 was elevated in ST-EPN.
                      Interrogation of our EPN single-cell RNA-sequencing data
                      revealed that FGFR3 was further enriched in cycling and
                      progenitor-like cell populations. Corroboratively, we found
                      FGFR3 to be predominantly expressed in radial glia cells in
                      both mouse embryonal and human brain datasets. Moreover, we
                      detected alternative splicing of the FGFR1/3-IIIc variant,
                      which is known to enhance ligand affinity and FGFR
                      signaling. Dominant-negative interruption of FGFR1/3
                      activation in PF-A and ST-RELA cell models demonstrated
                      inhibition of key oncogenic pathways leading to reduced cell
                      growth and stem cell characteristics. To explore the
                      feasibility of therapeutically targeting FGFR, we tested a
                      panel of FGFR inhibitors in 12 patient-derived EPN cell
                      models revealing sensitivity in the low-micromolar to
                      nano-molar range. Finally, we gain the first clinical
                      evidence for the activity of the FGFR inhibitor nintedanib
                      in the treatment of a patient with recurrent ST-RELA.
                      Together, these preclinical and clinical data suggest FGFR
                      inhibition as a novel and feasible approach to combat
                      aggressive EPN.},
      keywords     = {Brain tumor (Other) / Ependymoma (Other) / FGFR (Other) /
                      Pediatric cancer (Other) / Small molecule inhibitors
                      (Other)},
      cin          = {B062 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34046693},
      doi          = {10.1007/s00401-021-02327-x},
      url          = {https://inrepo02.dkfz.de/record/169022},
}