Gaucher's disease is characterized by intralysosomal storage of glucosylceramide due to a genetic deficiency of the enzyme glucosylceramidase. Gaucher’s disease can be treated using eliglustat and miglustat, two inhibitors of the glucosylceramide synthase (GSL). The conversion of ceramide to glucosylceramide is one of the first steps in the synthesis of glycosphingolipids which can be therefore inhibited by eliglustat and miglustat. Glycosphingolipids play a major role in brain development and have been involved in the pathology of brain tumors. Here we analyzed the glycosphingolipids composition and the effect of eliglustat in diffuse midline glioma (DMG), one of the deadliest cancers in the pediatric population.
We established and characterized primary cells from two pediatric DMG patients. Glycosphingolipids were analyzed by thin layer chromatography, liquid chromatography-coupled tandem mass spectrometry and flow cytometry. The effect of eliglustat on the cell proliferation was examined.
Immunohistochemistry analysis of DMG primary cells of both patients revealed glial origin (GFAP), high proliferative activity (Ki67) as well as the presence of H3 K27M mutant protein. The ganglioside GD2 was highly expressed. Neutral glycosphingolipids with 1 to 4 monosaccharides were also present in high concentration. Eliglustat completely abrogated the proliferation of the primary cells. Based on this promising data, treatment with miglustat of one patient has been started.
We show for the first time that inhibition of GSL effectively affects the survival of H3K27M-mutant DMG. Eliglusat and miglustat are released for the treatment of pediatric patients with Gaucher's disease and miglustat accumulates in the brain. Thus, targeting the glycosphingolipids metabolism with miglustat may accelerate the development of new therapies for brain tumors.
The authors.
Kinderkrebshilfe Mainz.
All authors have declared no conflicts of interest.