Abstract B05: Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas

Abstract

Abstract Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) and the discovery of IDH1 mutations are major recent advances in glioma management and research. However, the mechanism underlying the selective intracellular accumulation of the 5-ALA derivative protoporphyrinogen IX (PpIX) and the metabolic effect of IDH1 mutations in malignant glioma cells are still not fully understood. Based on clinical experience, we hypothesized an association between enhanced 5-ALA fluorescence and IDH1 mutations in WHO grade III gliomas. Using genetically engineered malignant glioma cells harboring wild type (U87MG-IDH1WT) or mutant (U87MG-IDH1R132H) versions of IDH1, we confirmed a lag in 5-ALA metabolism and a temporary accumulation of PpIX in U87MG-IDH1R132H cells. To investigate the metabolic aspects of the mechanism responsible, we used liquid chromatography–mass spectrometry (LC-MS) to screen for tricarboxylic acid (TCA) cycle-related metabolite changes resulting from 5-ALA exposure. We observed low baseline levels of NADPH, an essential cofactor for the rate-limiting step of heme degradation, in U87MG-IDH1R132H cells. Abundant levels of NADPH are required to metabolize excessive 5-ALA, giving a plausible reason for the temporary enhanced 5-ALA fluorescence in mutant IDH1 cells. This hypothesis was supported by the results of metabolic screening in human malignant glioma samples. We discovered a relationship between enhanced 5-ALA fluorescence and IDH1 mutations in malignant gliomas and investigated the metabolic aspects of the mechanism responsible, identifying significantly different levels of NADPH between wild type and mutant IDH1 malignant glioma cells. Citation Format: Kim Ja Eun, Hye Rim Cho, Wen Jun Xu, Young-Hoon Kim, Ji Hoon Phi, Seung Hong Choi, Sunghyouk Park, Chul-Kee Park. Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B05.