Abstract 17: Metabolic analysis of IDH mutant gliomas in Drosophila

Abstract

Abstract Metabolic reprogramming is a common hallmark shared by nearly all proliferating cancer cells and has emerged as an exciting new direction in cancer research. Many signaling pathways have been implicated in mechanisms leading to the shift of metabolic programs in tumors, but more recently a small number of metabolic enzymes have also been identified in this process. Genes encoding the metabolic enzymes Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) were found to be mutated in up to 70% of low-grade and medium grade gliomas, and in 15-20% of adult acute leukemia samples. These findings were the first to link the IDH gene to tumorigenesis. IDH1 and IDH2 function to irreversibly catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Although these are important metabolic enzymes, little is known about the metabolic impact harboring mutant IDH protein has on cells. Our goal is to model the IDH mutant phenotype in Drosophila glial cells for further characterization of both metabolic status, and IDH enzymatic activity. To this end, we have generated Drosophila cell lines and transformant flies that express the most commonly identified IDH mutations under control of the UAS-Gal4 system. We have also investigated the metabolic flux of Drosophila cell lines expressing IDH mutant protein, and loss of IDH function, and glycolytic enzyme expression analysis. Currently, we are investigating the metabolic flux analysis (MFA) using labeled metabolites as well as comparing the protein interactions of the wild type to the mutant IDH cells. The results of these investigations will identify potential new targets for the treatment of aggressive gliomas at the level of cellular metabolism. Citation Format: Michaela Brown, Jenna Buccetti, Marla Tipping. Metabolic analysis of IDH mutant gliomas in Drosophila. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 17.