Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation

Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation

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 eliglus...

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Bibliographic Details
Main Authors: Khalifa El Malki, Pia Wehling, Francesca Alt, Roger Sandhoff, Sebastian Zahnreich, Arsenij Ustjanzew, Carolin Wilzius, Marc A. Brockmann, Arthur Wingerter, Alexandra Russo, Olaf Beck, Clemens Sommer, Malte Ottenhausen, Katrin B. M. Frauenknecht, Claudia Paret, Jörg Faber
Format: Article
Language:English
Published: MDPI AG 2023-06-01
Series:International Journal of Molecular Sciences
Subjects:
H3K27 mutant diffuse midline glioma
ependymoma
miglustat
eliglustat
glycosphingolipids
GD2
Online Access:https://www.mdpi.com/1422-0067/24/12/9905
Description
Summary: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.
ISSN:1661-6596
1422-0067

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