{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:25:36Z","timestamp":1790436336557,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T00:00:00Z","timestamp":1686182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"HI-TRON Mainz","award":["HITR-2021-14"],"award-info":[{"award-number":["HITR-2021-14"]}]},{"name":"HI-TRON Mainz","award":["SKFM_01_2022"],"award-info":[{"award-number":["SKFM_01_2022"]}]},{"name":"Stiftung Kinderkrebsforschung Mainz","award":["HITR-2021-14"],"award-info":[{"award-number":["HITR-2021-14"]}]},{"name":"Stiftung Kinderkrebsforschung Mainz","award":["SKFM_01_2022"],"award-info":[{"award-number":["SKFM_01_2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2013Pick 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.<\/jats:p>","DOI":"10.3390\/ijms24129905","type":"journal-article","created":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T02:59:57Z","timestamp":1686279597000},"page":"9905","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation"],"prefix":"10.3390","volume":"24","author":[{"given":"Khalifa","family":"El Malki","sequence":"first","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"University Cancer Center (UCT), University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Wehling","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"University Cancer Center (UCT), University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Alt","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"University Cancer Center (UCT), University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Sandhoff","sequence":"additional","affiliation":[{"name":"Lipid Pathobiochemistry, German Cancer Research Center, 69120 Heidelberg, Germany"},{"name":"Helmholtz-Institute for Translational Oncology Mainz (HI-TRON), 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8365-3258","authenticated-orcid":false,"given":"Sebastian","family":"Zahnreich","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Radiation Therapy, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1014-4521","authenticated-orcid":false,"given":"Arsenij","family":"Ustjanzew","sequence":"additional","affiliation":[{"name":"Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"University Cancer Center (UCT), University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"German Cancer Consortium (DKTK), Site Frankfurt\/Mainz, Germany, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Beck","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"University Cancer Center (UCT), University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Sommer","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Ottenhausen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1372-3297","authenticated-orcid":false,"given":"Katrin B. M.","family":"Frauenknecht","sequence":"additional","affiliation":[{"name":"Helmholtz-Institute for Translational Oncology Mainz (HI-TRON), 55131 Mainz, Germany"},{"name":"Institute of Neuropathology, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"National Center of Pathology (NCP), Laboratoire National de Sant\u00e9, 3555 Dudelange, Luxembourg"},{"name":"Luxembourg Center of Neuropathology (LCNP), Laboratoire National de Sant\u00e9, 3555 Dudelange, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9094-1634","authenticated-orcid":false,"given":"Claudia","family":"Paret","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"University Cancer Center (UCT), University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"Helmholtz-Institute for Translational Oncology Mainz (HI-TRON), 55131 Mainz, Germany"},{"name":"German Cancer Consortium (DKTK), Site Frankfurt\/Mainz, Germany, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Research Center of Immunotherapy (FZI), University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5432-8234","authenticated-orcid":false,"given":"J\u00f6rg","family":"Faber","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"University Cancer Center (UCT), University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"Helmholtz-Institute for Translational Oncology Mainz (HI-TRON), 55131 Mainz, Germany"},{"name":"German Cancer Consortium (DKTK), Site Frankfurt\/Mainz, Germany, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s00401-012-0998-0","article-title":"K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas","volume":"124","author":"Buczkowicz","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/ng.1102","article-title":"Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas","volume":"44","author":"Wu","year":"2012","journal-title":"Nat. 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