Modeling the diffusion of D-2-hydroxyglutarate from IDH1 mutant gliomas in the central nervous system

Background. Among diffusely infiltrative gliomas in adults, 20%-30% contain a point mutation in isocitrate dehydrogenase 1 (IDH1^mut), which increases production of D-2-hydroxyglutarate (D2HG). This is so efficient that D2HG often reaches 30 mM within IDH1^mut gliomas. Yet, while up to 100 µM D2HG can be detected in the circulating cerebrospinal fluid of IDH1^mut glioma patients, the exposure of nonneoplastic cells within and surrounding an IDH1^mut glioma to D2HG is unknown and difficult to measure directly. Methods. Conditioned medium from patient-derived wild type IDH1 (IDH1^wt) and IDH1^mut glioma cells was analyzed for D2HG by liquid chromatography-mass spectrometry (LC-MS). Mathematical models of D2HG release and diffusion around an IDH1^mut glioma were independently generated based on fluid dynamics within the brain and on previously reported intratumoral and cerebrospinal D2HG concentrations. Results. LC-MS analysis indicates that patient-derived IDH1^mut glioma cells release 3.7-97.0 pg D2HG per cell per week. Extrapolating this to an average-sized tumor (30 mL glioma volume and 1 × 10⁸ cells/mL tumor), the rate of D2HG release by an IDH1^mut glioma (S_A) is estimated at 3.2-83.0 × 10⁻¹² mol/mL/sec. Mathematical models estimate an S_A of 2.9-12.9 × 10⁻¹² mol/mL/sec, within the range of the in vitro LC-MS data. In even the most conservative of these models, the extracellular concentration of D2HG exceeds 3 mM within a 2 cm radius from the center of an IDH1^mut glioma. Conclusions. The microenvironment of an IDH1^mut glioma is likely being exposed to high concentrations of D2HG, in the low millimolar range. This has implications for understanding how D2HG affects nonneoplastic cells in an IDH1^mut glioma.