TMIC-45. DIFFUSION OF D-2-HYDROXYGLUTARATE FROM IDH1 MUTANT GLIOMAS IN THE BRAIN. Issue 11 (6th November 2017)

• Record Type: Journal Article
• Authors: Horbinski, Craig; Hartung, Grant; Liu, Benjamin; Mirkov, Snezana; Tangen, Kevin; Unruh, Dusten; Sarkaria, Jann; Linninger, Andreas
• Is Part Of: Neuro-oncology. Volume 19:Issue 11(2017)supplement 6
• Page Start: vi253
• Page End: vi253
• Publication Date: 2017-11-06
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/nox168.1033
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Approximately 20-30% of diffusely infiltrative gliomas in adults contain a point mutation in isocitrate dehydrogenase 1 (IDH1mut), which leads to production of D-2-hydroxyglutarate (D2HG). Production of D2HG is so efficient that D2HG concentrations often reach 30 mM within IDH1mut gliomas. Yet, while up to 100 µM D2HG can be detected in the circulating cerebrospinal fluid of IDH1mut glioma patients, the amount of D2HG to which nonneoplastic cells are exposed within and surrounding an IDH1mut glioma is unknown and difficult to measure directly in patients or animal models. Thus, to date, the majority of research on D2HG has focused on its effects inside tumor cells, with very little known about its role in the tumor microenvironment. Liquid chromatography-mass spectrometry (LC-MS) analysis indicates that patient-derived IDH1mut glioma cells release approximately 3.7-6.7 pg D2HG per cell per week in culture. Extrapolating this to an average-sized tumor (30 ml glioma volume and 1x108 cells/ml tumor, the latter based on a previously published estimate of tumor cell density), the rate of D2HG release by an IDH1mut glioma (SA) is calculated to be 3.2-5.8x10-12 moles/ml/sec. Mathematical models of D2HG production and diffusion around an IDH1mut glioma were independently generated based on intracerebral fluid dynamics and previously reported D2HG concentrations in the cerebrospinal fluid. These models estimate an SA of 2.9-17.0x10-12 moles/ml/sec, in good agreement with the LC-MS data generated from in vitro models. In even the most conservative of these diffusion models, the extracellular concentration of D2HG exceeds 3 mM within a 2 cm radius from the center of an IDH1mut glioma. This has profound implications for understanding how D2HG may alter the microenvironmental landscape in IDH1mut gliomas.