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@ARTICLE{ElMalki:277130,
      author       = {K. El Malki and P. Wehling and F. Alt and R. Sandhoff$^*$
                      and S. Zahnreich and A. Ustjanzew and C. Wilzius$^*$ and M.
                      A. Brockmann and A. Wingerter and A. Russo$^*$ and O. Beck
                      and C. Sommer and M. Ottenhausen and K. B. M. Frauenknecht
                      and C. Paret$^*$ and J. Faber$^*$},
      title        = {{G}lucosylceramide {S}ynthase {I}nhibitors {I}nduce
                      {C}eramide {A}ccumulation and {S}ensitize {H}3{K}27 {M}utant
                      {D}iffuse {M}idline {G}lioma to {I}rradiation.},
      journal      = {International journal of molecular sciences},
      volume       = {24},
      number       = {12},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {DKFZ-2023-01292},
      pages        = {9905},
      year         = {2023},
      note         = {HI-TRON},
      abstract     = {H3K27M mutant (mut) diffuse midline glioma (DMG) is a
                      lethal cancer with no effective cure. The glycosphingolipids
                      (GSL) metabolism is altered in these tumors and could be
                      exploited to develop new therapies. We tested the effect of
                      the glucosylceramide synthase inhibitors (GSI) miglustat and
                      eliglustat on cell proliferation, alone or in combination
                      with temozolomide or ionizing radiation. Miglustat was
                      included in the therapy protocol of two pediatric patients.
                      The effect of H3.3K27 trimethylation on GSL composition was
                      analyzed in ependymoma. GSI reduced the expression of the
                      ganglioside GD2 in a concentration and time-dependent manner
                      and increased the expression of ceramide, ceramide
                      1-phosphate, sphingosine, and sphingomyelin but not of
                      sphingosine 1-phosphate. Miglustat significantly increased
                      the efficacy of irradiation. Treatment with miglustat
                      according to dose recommendations for patients with
                      Niemann-Pick disease was well tolerated with manageable
                      toxicities. One patient showed a mixed response. In
                      ependymoma, a high concentration of GD2 was found only in
                      the presence of the loss of H3.3K27 trimethylation. In
                      conclusion, treatment with miglustat and, in general,
                      targeting GSL metabolism may offer a new therapeutic
                      opportunity and can be administered in close proximity to
                      radiation therapy. Alterations in H3K27 could be useful to
                      identify patients with a deregulated GSL metabolism.},
      keywords     = {GD2 (Other) / H3K27 mutant diffuse midline glioma (Other) /
                      eliglustat (Other) / ependymoma (Other) / glycosphingolipids
                      (Other) / miglustat (Other) / trimethylation (Other)},
      cin          = {A411 / FM01},
      ddc          = {540},
      cid          = {I:(DE-He78)A411-20160331 / I:(DE-He78)FM01-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37373053},
      doi          = {10.3390/ijms24129905},
      url          = {https://inrepo02.dkfz.de/record/277130},
}