Glioblastoma (GBM) is a primary malignancy of the central nervous system (CNS) that is nearly universally fatal. Our long-term goal is to understand the molecular mechanisms that underlie gliomagenesis and to use this information to develop better therapeutic modalities for GBM patients. Recent work has demonstrated that GBMs consist of several subgroups, each driven by different genetic alterations. The proneural subgroup of GBMs is a distinct class that includes tumors with isocitrate dehydrogenase (IDH) 1 and 2 mutation, PDGF pathway activation, and the glioma hypermethylator phenotype (G-CIMP). These alterations are potentially reversible and hold great promise as potential targets. However, the mechanisms of action underlying mutant IDH-mediated transformation remain unclear. Recently, our groups have shown that IDH mutation functions by remodeling the epigenome to establish G-CIMP and institute a block to differentiation. The central hypothesis of this application is that mutant IDH-induced epigenomic changes are critical events underlying the development of this subset of GBMs. The objective of this proposal is to understand the molecular foundations of mutant IDH-induced gliomagenesis and to evaluate the utility of targeting this alteration by pursuing 3 Specific Aims.
In Aim 1, we will elucidate the chromatin state dynamics underlying mutant IDH1- associated epigenetic reprogramming. The working hypothesis here is that IDH mutation acts by remodeling the epigenome and blocking differentiation, an effect that may be reversible. We will systematically elucidate the details of IDH1 mutation-induced chromatin state changes globally and at the level of individual effector genes. We will interrogate the reversibility of mutant IDH-induced effects.
In Aim 2, we will characterize oncogenic cooperativity between IDH1 mutation and IDH1 mutation-associated genetic alterations. Our data indicates that mutant IDH1 acts by promoting a dedifferentiated state, but does not transform cells alone. Our hypothesis here is that IDH1 mutation cooperates with other recurring genetic lesions to achieve transformation. We will define the tenants of this oncogenic context. We will investigate the ability of associated lesions to cooperate with mutant IDH1 in transformation using human astrocytes and the murine RCAS-TVA system.
In Aim 3, we will optimize targeting of mutant IDH1-dependent biological alterations with epigenetic therapy. Since IDH-induced changes are in principle reversible, we hypothesize that the effects of mutant IDH1 can be reversed using targeted small molecules, which will then enable tissue-specific factors to drive differentiation. Inhibition of mutant IDH1 alone using a mutant IDH1 inhibitor (AGI-5198) blocks 2-HG production but affects tumor growth only modestly. In contrast, DNMT and H3K9 methylase inhibitors (DAC, BIX) directly reverse pathologic methylation and are very potent against IDH mutant cells. We will use these two approaches to optimize a therapeutic strategy. Using both in vitro and mouse models, we will use DNA/ histone methylation inhibitors, alone and in combination with AGI-5198, to reverse the effects of mutant IDH1.

Public Health Relevance

Malignant glioma is a deadly disease of the central nervous system for which there is no cure. This fatal disease strikes patients in the United States and around the world. Our proposal will help illuminate the mechanisms underlying a novel, very frequently mutated gene in gliomas (isocitrate dehydrogenase). Our work will significantly contribute to our understanding of the fundamental biological basis of this tumor and help develop new approaches to treat this devastating disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Mietz, Judy
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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