Targeting IDH1-Mutated Oligodendroglioma with Acid Ceramidase Inhibitors

Authors

• H Muley Vilamu
• T Dowdy
• F Zaibaq
• H Song
• M Zhang
• W Zhang
• Z Wong
• M Larion

Abstract

Currently, an estimated 14,950 people lives with oligodendroglioma in the United States. Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1mut/IDH2mut). Previously, we reported that in IDH1mut gliomas, D-2HG, the product of IDH1 mutant enzyme produces an increase in monounsaturated fatty acid levels that are incorporated into ceramides, tilting the S1P-to-ceramide rheostat toward apoptosis. Herein, we exploited this imbalance to further induce and IDHmut-specific glioma cell death.

Using TCGA and CCGA data, we found that high acid ceramidase (AC) expression is associated with worse patient survival, and that AC expression is significantly lower in IDHmut gliomas, especially in oligodendroglioma, compared to IDHwt gliomas. We also reported for the first time that the inhibition of AC induces apoptosis and increases the survival of mice with IDH1mut oligodendroglioma. We demonstrated an IDH1mut-specific cytotoxicity of SABRAC, an irreversible and specific AC inhibitor, in patient-derived oligodendroglioma cells. Exploring the mechanism of action of this drug, we found that SABRAC activates both extrinsic and intrinsic apoptosis in an ER stress-independent manner, pointing to a direct action of AC-related ceramides in mitochondria permeability. The activation of apoptosis detected under SABRAC treatment was associated with up to a 30-fold increase in some ceramide levels and its derivatives from the salvage pathway.

We propose that AC as a novel therapeutic target in oligodendroglioma with IDH1mut and we are conducting additional preclinical testing.

Scientific Focus Area: Cancer Biology

This page was last updated on Tuesday, August 6, 2024