Authors:	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
Title:	Glucosylceramide synthase inhibitors induce ceramide accumulation and sensitize H3K27 mutant diffuse midline glioma to irradiation
Online publication date:	13-Feb-2024
Year of first publication:	2023
Language:	english
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:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-9995
Version:	Published version
Publication type:	Zeitschriftenaufsatz
Document type specification:	Scientific article
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	International journal of molecular sciences 24 12
Pages or article number:	9905
Publisher:	MDPI
Publisher place:	Basel
Issue date:	2023
ISSN:	1422-0067
Publisher DOI:	10.3390/ijms24129905
Appears in collections:	DFG-491381577-G