Autoren:	El Malki, Khalifa Wehling, Pia Alt, Francesca Sandhoff, Roger Zahnreich, Sebastian Ustjanzew, Arsenij Wilzius, Carolin Brockmann, Marc A. Wingerter, Arthur Russo, Alexandra Beck, Olaf Sommer, Clemens Ottenhausen, Malte Frauenknecht, Katrin B. M. Paret, Claudia Faber, Jörg
Titel:	Glucosylceramide synthase inhibitors induce ceramide accumulation and sensitize H3K27 mutant diffuse midline glioma to irradiation
Online-Publikationsdatum:	13-Feb-2024
Erscheinungsdatum:	2023
Sprache des Dokuments:	Englisch
Zusammenfassung/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.
DDC-Sachgruppe:	610 Medizin 610 Medical sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 04 Medizin
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-9995
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Weitere Angaben zur Dokumentart:	Scientific article
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	International journal of molecular sciences 24 12
Seitenzahl oder Artikelnummer:	9905
Verlag:	MDPI
Verlagsort:	Basel
Erscheinungsdatum:	2023
ISSN:	1422-0067
DOI der Originalveröffentlichung:	10.3390/ijms24129905
Enthalten in den Sammlungen:	DFG-491381577-G