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@ARTICLE{Sigaud:180790,
      author       = {R. Sigaud$^*$ and L. Rösch$^*$ and C. Gatzweiler$^*$ and
                      J. Benzel$^*$ and L. von Soosten$^*$ and H. Peterziel$^*$
                      and F. Selt$^*$ and S. Najafi$^*$ and S. Ayhan$^*$ and X.
                      Gerloff$^*$ and N. Hofmann$^*$ and I. Büdenbender$^*$ and
                      L. Schmitt$^*$ and K. I. Foerster and J. Burhenne and W. E.
                      Haefeli and A. Korshunov$^*$ and F. Sahm$^*$ and C. M. van
                      Tilburg$^*$ and D. Jones$^*$ and S. Pfister$^*$ and D.
                      Knoerzer and B. L. Kreider and M. Sauter and K. Pajtler$^*$
                      and M. Zuckermann$^*$ and I. Oehme$^*$ and O. Witt$^*$ and
                      T. Milde$^*$},
      title        = {{T}he first-in-class {ERK} inhibitor ulixertinib shows
                      promising activity in {MAPK}-driven pediatric low-grade
                      glioma models.},
      journal      = {Neuro-Oncology},
      volume       = {25},
      number       = {3},
      issn         = {1522-8517},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2022-01552},
      pages        = {566-579},
      year         = {2023},
      note         = {#EA:B310#EA:B062#EA:B360#LA:B062#LA:B310# / 2023 Mar
                      14;25(3):566-579},
      abstract     = {Pediatric low-grade gliomas (pLGG) are the most common
                      pediatric central nervous system tumors, with driving
                      alterations typically occurring in the MAPK pathway. The
                      ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising
                      responses in adult patients with mitogen-activated protein
                      kinase (MAPK)-driven solid tumors.We investigated the
                      anti-tumoral activity of ulixertinib monotherapy as well as
                      in combination with MEK inhibitors (MEKi), BH3-mimetics, or
                      chemotherapy in pLGG. Patient-derived pLGG models reflecting
                      the two most common alterations in the disease,
                      KIAA1549:BRAF-fusion and BRAF V600E mutation (DKFZ-BT66 and
                      BT40, respectively) were used for in vitro and in vivo
                      (zebrafish embryos and mice) efficacy testing.Ulixertinib
                      inhibited MAPK pathway activity in both models, and reduced
                      cell viability in BT40 with clinically achievable
                      concentrations in the low nanomolar range. Combination
                      treatment of ulixertinib with MEKi or BH3-mimetics showed
                      strong evidence of anti-proliferative synergy in vitro.
                      Ulixertinib showed on-target activity in all tested
                      combinations. In vivo, sufficient penetrance of the drug
                      into brain tumor tissue in concentrations above the in vitro
                      IC50 and reduction of MAPK pathway activity was achieved. In
                      a preclinical mouse trial, ulixertinib mono- and combined
                      therapies slowed tumor growth and increased survival.These
                      data indicate a high clinical potential of ulixertinib for
                      the treatment of pLGG and strongly support its first
                      clinical evaluation in pLGG as single agent and in
                      combination therapy in a currently planned international
                      phase I/II umbrella trial.},
      keywords     = {BH3-mimetics (Other) / ERK inhibitor (Other) / MAPK
                      inhibitor (Other) / pediatric low-grade glioma (Other) /
                      synergism (Other)},
      cin          = {B310 / HD01 / B062 / B360 / B300 / B380},
      ddc          = {610},
      cid          = {I:(DE-He78)B310-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B062-20160331 / I:(DE-He78)B360-20160331 /
                      I:(DE-He78)B300-20160331 / I:(DE-He78)B380-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35882450},
      doi          = {10.1093/neuonc/noac183},
      url          = {https://inrepo02.dkfz.de/record/180790},
}