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Updated: Jul 25, 2025
Live-3D-Cell Immunocytochemistry Assays of Pediatric Diffuse Midline Glioma
Published on: November 11, 2021
Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma
Khalifa El Malki1,2, Pia Wehling1,2, Francesca Alt1,2
1Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
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.
Insights
Targeting glycosphingolipid metabolism with glucosylceramide synthase inhibitors like miglustat shows promise for diffuse midline glioma. Miglustat enhanced radiation therapy efficacy and was well-tolerated in pediatric patients.
Area of Science:
- Oncology
- Biochemistry
- Cancer Therapeutics
Background:
- Diffuse midline glioma (DMG) with H3K27M mutations is a fatal pediatric cancer lacking effective treatments.
- Altered glycosphingolipid (GSL) metabolism is a hallmark of these tumors, presenting a potential therapeutic target.
Purpose of the Study:
- To investigate the efficacy of glucosylceramide synthase inhibitors (GSIs), miglustat and eliglustat, in treating H3K27M-mutant DMG.
- To evaluate the combination of GSIs with temozolomide or ionizing radiation.
- To explore the role of H3.3K27 trimethylation in GSL composition and its potential as a biomarker.
Main Methods:
- In vitro testing of GSIs (miglustat, eliglustat) on cell proliferation, alone and in combination with standard therapies.
- Analysis of GSL composition in ependymoma samples with varying H3.3K27 trimethylation status.
- Clinical observation of two pediatric patients treated with miglustat as part of their therapy.
Main Results:
- GSIs reduced ganglioside GD2 expression and increased ceramide, ceramide 1-phosphate, sphingosine, and sphingomyelin levels.
- Miglustat significantly enhanced the efficacy of ionizing radiation in preclinical models.
- Miglustat treatment was generally well-tolerated in pediatric patients, with manageable toxicities.
Conclusions:
- Targeting GSL metabolism with miglustat represents a promising therapeutic strategy for H3K27M-mutant DMG.
- Miglustat can be safely administered in conjunction with radiation therapy.
- H3K27 trimethylation status may serve as a biomarker for identifying patients with deregulated GSL metabolism.
