The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant—but not IDH1–wild-type—glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.

Diffuse gliomas comprise the most common malignant brain tumors in adults and include glioblastomas (GBM) and World Health Organization (WHO) grade II and grade III tumors, sometimes referred to as lower-grade gliomas (LGGs). Genetic tumor profiling is used for disease classification and to guide therapy 1 , 2 , but involves brain surgery for tissue collection and repeated tumor biopsies may be necessary for accurate genotyping over the course of the disease 3 – 10 . While detection of circulating tumor DNA (ctDNA) in blood remains challenging for patients with primary brain tumors 11 , 12 , sequencing of cerebrospinal fluid (CSF) ctDNA may provide an alternative to genotype glioma at lower morbidity and cost 13 , 14 . We therefore evaluated the representation of the glioma genome in CSF from 85 glioma patients who underwent a lumbar puncture for evaluation of neurological signs or symptoms. Tumor-derived DNA was detected in CSF from 42/85 (49.4 %) patients and was associated with disease burden and adverse outcome. The genomic landscape of glioma in CSF contained a broad spectrum of genetic alterations and closely resembled the genome in tumor biopsies. Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH2 1 , 2 , were shared in all matched ctDNA-positive CSF/tumor pairs, whereas we observed considerable evolution in growth factor receptor signaling pathways. The ability to monitor evolution of the glioma genome through a minimally invasive technique could advance the clinical development and use of genotype-directed therapies for glioma, one of the most aggressive human cancers.

Purpose: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood. Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. Results: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR ¼ 2.6, P ¼ 0.02), and likely preceded the acquisition of alkylating therapyassociated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAFmutant gliomas, response to agents targeting the RAF/MEK/ ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. Conclusions: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

The embryonic development of the olfactory nerve includes the differentiation of cells within the olfactory placode, migration of cells into the mesenchyme from the placode, and extension of axons by the olfactory sensory neurons (OSNs). The coalition of both placode-derived migratory cells and OSN axons within the mesenchyme is collectively termed the “migratory mass.” Here we address the sequence and coordination of the events that give rise to the migratory mass. Using neuronal and developmental markers, we show subpopulations of neurons emerging from the placode by embryonic day (E) 10, a time at which the migratory mass is largely cellular and only a few isolated OSN axons are seen, prior to the first appearance of OSN axon fascicles at E11. These neurons also precede the emergence of the gonadotropin-releasing hormone neurons and ensheathing glia which are also resident in the mesenchyme as part of the migratory mass beginning at about E11. The data reported here begin to establish a spatiotemporal framework for the migration of molecularly heterogeneous placode-derived cells in the mesenchyme. The precocious emigration of the early arriving neurons in the mesenchyme suggests they may serve as “guidepost cells” that contribute to the establishment of a scaffold for the extension and coalescence of the OSN axons.

The embryonic development of the olfactory nerve includes the differentiation of cells within the olfactory placode, migration of cells into the mesenchyme from the placode, and extension of axons by the olfactory sensory neurons (OSNs). The coalition of both placode‐derived migratory cells and OSN axons within the mesenchyme is collectively termed the “migratory mass.” Here we address the sequence and coordination of the events that give rise to the migratory mass. Using neuronal and developmental markers, we show subpopulations of neurons emerging from the placode by embryonic day (E)10, a time at which the migratory mass is largely cellular and only a few isolated OSN axons are seen, prior to the first appearance of OSN axon fascicles at E11. These neurons also precede the emergence of the gonadotropin‐releasing hormone neurons and ensheathing glia which are also resident in the mesenchyme as part of the migratory mass beginning at about E11. The data reported here begin to establish a spatiotemporal framework for the migration of molecularly heterogeneous placode‐derived cells in the mesenchyme. The precocious emigration of the early arriving neurons in the mesenchyme suggests they may serve as “guidepost cells” that contribute to the establishment of a scaffold for the extension and coalescence of the OSN axons. J. Comp. Neurol. 518:4825–4811, 2010. © 2010 Wiley‐Liss, Inc.