{
  "abstract": "Background Currently, an estimated 14,950 people live with oligodendroglioma in the United States. Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1mut/IDH2mut) and the absence of the two chromosomal arms, 1p and 19q. 1 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 glioma cell death.2–4 Methods TCGA and CCGA data were used to explore the association between acid ceramidase (AC) gene expression and patient survival. CCK8 viability assays were carried out to measure the sensitivity of glioma cell lines to acid ceramidase inhibitors. Western blot, flow cytometry, confocal microscopy, Raman spectroscopy and liquid chromatography-mass spectrometry analyses were performed for studying the mechanism of action of acid ceramidase inhibitors. The in vivo efficacy of the SABRAC drug, an irreversible inhibitor of AC, was evaluated in an orthotopic oligodendroglioma xenograft mice model using TS603 patient-derived oligodendroglioma cells.Results We report for the first time that the inhibition of acid ceramidase (AC) induces apoptosis and increases the survival of mice with IDH1mut oligodendroglioma. Exploring the mechanism of action of this drug, we found that SABRAC activates both extrinsic and intrinsic apoptosis in an ER stress-independent manner, suggesting 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. In addition, SABRAC demonstrated to increase MHC class I (MHC-I) surface levels in patient-derived glioma cells in a dose-dependent manner. MHC-I molecules present intracellular antigens to cytotoxic T cells, playing a crucial role in anti-tumor immune recognition, suggesting a potential role for acid ceramidase inhibitors in reducing immunosuppressive mechanisms.Conclusions We propose that AC as a candidate target in oligodendroglioma with IDH1mut and are conducting additional preclinical testing.References National Cancer Institute. Oligodendroglioma and Other IDH-Mutated Tumors: Diagnosis and Treatment. https://www.cancer.gov/rare-brain-spine-tumor/tumors/oligodendroglioma.Zaibaq F, Dowdy T, Larion M. Targeting the sphingolipid rheostat in gliomas. International Journal of Molecular Sciences. 2022;23. Preprint at https://doi.org/10.3390/ijms23169255.Dowdy T, et al. Sphingolipid pathway as a source of vulnerability in IDH1mut glioma. Cancers (Basel). 2020;12,1–16.Lita A, et al. IDH1 mutations induce organelle defects via dysregulated phospholipids. Nat Commun. 2021;12:614.Ethics Approval Intracranial orthotopic mouse models with an IDH1mut glioma cell line were established according to an approved animal study proposal NOB-008 by the NCI-Animal Use and Care Committee (ACUC).",
  "authors": [
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Helena Muley Vilamu"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Tyrone Dowdy"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Faris Zaibaq"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Michael Kruhlak"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Adrian Lita"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Aiguo Li"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Hua Song"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Meili Zhang"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Wei Zhang"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Lumin Zhang"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Mioara Larion"
    }
  ],
  "title": "1217 Dual effects of ceramidase inhibition in oligodendroglioma: apoptosis and immune modulation",
  "uid": "27cc5d9d-dcba-5258-ad94-7a03f26ed993"
}