With incidence rates up to 80%, isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II-III gliomas and secondary glioblastomas. Prior to its discovery in gliomas by Parsons et al. in 2008, this mutation had never before been linked to cancer. Subsequent studies have identified IDH1 and IDH2 mutations in several different tumor types suggesting that these genes are important players in cancer. The mechanism by which mutant IDH promotes tumor development has been under intense investigation and several key findings have significantly improved our understanding of the biology of this disease. IDH proteins function to generate reduced nicotinamide adenine dinucleotide phosphate (NADPH) from NADP+ by catalyzing the oxidative decarboxylation of isocitrate to ?-ketoglutarate (?-KG). These mutations inhibit the native function of the enzyme and instead confer a gain-of-function phenotype resulting in the conversion of ?- KG to 2-hydroxyglutarate (2-HG). 2-HG is a competitive inhibitor of multiple ?-KG-dependent enzymes, including transaminases, histone demethylases, and the TET family of 5-methylcytosine hydroxylases, which mediate DNA demethylation. As a result, gliomas harboring mutations in IDH exhibit increased dependence on glutaminase, defects in DNA repair, and manifest a DNA hypermethylation phenotype. Mutant IDH also compromises the citric acid cycle, which results in an enhanced dependence on mitochondrial metabolism. Interestingly, the presence of an IDH mutation was found to be an independent marker for better prognosis and it was discovered that tumors harboring mutations in IDH are more sensitive to conventional chemotherapy and radiotherapy. As such, we hypothesize that tumors harboring mutations in IDH have multiple vulnerabilities that can be therapeutically exploited. However, evaluating these strategies has been hindered by the lack of appropriate in vivo models. To fill this void, we developed a mouse model of mutant IDH1-driven glioma that mimics the human disease genetically, functionally, and histologically. Our results support the hypothesis that mutant IDH1 is a bona fide glioma oncogene and provide the first in vivo evidence that it promotes gliomagenesis. The model we have developed is ideal for assessing rational therapeutic strategies to combat this disease. In this study, we propose to use human glioma cells and our novel mouse models to evaluate the sensitivity of these gliomas to DNA demethylating agents in combination with mutant IDH1 inhibitors, to exploit their dependence on glutamine metabolism, and to target their enhanced requirement for oxidative phosphorylation. Demonstration of therapeutic efficacy in our novel glioma mouse model will further support translation to the clinic and has the potential to significantly improve the outcome for patients with this deadly disease.
Diffuse gliomas are the most common primary brain tumor in adults and are associated with a poor prognosis. We recently generated a glioma animal model driven by mutant isocitrate dehydrogenase 1 (IDH1), which is altered in a significant percentage of these brain tumors. In this study, we will use this animal model to evaluate the efficacy of several novel therapies that have the potential to significantly improve the outcome for patients with this deadly disease.
