Investigator: Marla Tipping, Providence College

Mentor: Kristi Wharton, Brown University

Scientific Theme: Cancer

Abstract: Gliomas are the most common and fatal form of brain cancer. In an effort to better understand the biology of these rapidly proliferating, and aggressively invasive tumors, Drosophila researchers have attempted to reproduce the human glioma phenotype in the fruit fly. One group was able to successfully generate gliomas by enhancing the activity of a known oncogene, Epidermal Growth Factor Receptor (EGFR), implicated in glioblastoma formation. This result suggests that the process of glial cell tumorigenesis is likely conserved in the fly, and presents the fly as a promising model for the study of these tumors. Recently 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 on cells harboring mutant IDH proteins. This proposal aims to model the IDH mutant phenotype in Drosophila glial cells with the goal to characterize their metabolic status, and elucidate changes in IDH enzymatic activity and protein interaction network. These aims will be achieved by 1) careful analysis of altered proliferation and cellular metabolism in Drosophila Idh1 mutant glia, and 2) investigation of Idh1 protein function via identifying proteins interacting with Idh1 mutants, as well as analysis of Idh1 mutant enzymatic activity. Results of this study will reveal novel targets for treatment and enhance our ability to treat these aggressive tumors at the level of cellular metabolism.

Human Health Relevance: Modeling the Isocitrate dehydrogenase (IDH) mutant phenotype in Drosophila will allow for more extensive genetic and molecular study of IDH derived gliomas. The investigation of both IDH mutant enzyme activity, interactions, and metabolic status will identify potential new targets for the treatment of these aggressive tumors.