Explore the vast range of titles available.

In this review, we discuss the use of the alkylating agent temozolomide (TMZ) in the treatment of IDH-mutant gliomas. We describe the challenges associated with TMZ in clinical (drug resistance and tumor recurrence) and preclinical settings (variabilities associated with in vitro models) in treating IDH-mutant glioma. Lastly, we summarize the emerging therapeutic targets that can potentially be used in combination with TMZ.

Mutations in IDH1 and IDH2 (encoding isocitrate dehydrogenase 1 and 2) drive the development of gliomas and other human malignancies. Mutant IDH1 induces epigenetic changes that promote tumorigenesis, but the scale and reversibility of these changes are unknown. Here, using human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant-IDH1-induced epigenomic reprogramming. We characterize the reversibility of the alterations in DNA methylation, the histone landscape, and transcriptional reprogramming that occur following IDH1 mutation. We discover genome-wide coordinate changes in the localization and intensity of multiple histone marks and chromatin states. Mutant IDH1 establishes a CD24 + population with a proliferative advantage and stem-like transcriptional features. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented high-resolution molecular portraits of mutant-IDH1-dependent epigenomic reprogramming. These findings have substantial implications for understanding of mutant IDH function and for optimizing therapeutic approaches to targeting IDH-mutant tumors. This study uses human astrocytes and glioma tumorspheres to generate an atlas of mutant-IDH1-induced epigenomic reprogramming. The findings have implications for understanding mutant IDH function and for optimizing approaches to target IDH-mutant tumors.

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 (m1DH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the m1DH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of m1DH1 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 m1DH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.

Mutation of isocitrate dehydrogenase 1 (IDH1) is shown to induce DNA hypermethylation and to remodel the epigenome to resemble that of gliomas with the CpG island methylator phenotype. Cancer induction by isocitrate dehydrogenase mutation Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 have been identified in gliomas, the most common form of brain tumour, and in other cancers including leukaemias. The mutated enzymes produce 2-hydroxyglutarate (2HG), which is a potential oncometabolite. Three papers in this issue of Nature examine the mechanisms through which IDH mutations promote cancers. Lu et al . show that 2HG-producing IDH mutants can prevent the histone demethylation that is required for progenitor cells to differentiate, potentially contributing to tumour-cell accumulation. Turcan et al . show that IDH1 mutation in primary human astrocytes induces DNA hypermethylation and reshapes the methylome to resemble that of the CIMP phenotype, a common feature of gliomas and other solid tumours. Koivunen et al . show that the ( R )-enantiomer of 2HG (but not the ( S )-enantiomer) can stimulate the activity of the EGLN prolyl 4-hydroxylases, leading to diminished levels of hypoxia-inducible factor (HIF), which in turn can enhance cell proliferation. These papers establish a framework for understanding gliomagenesis and highlight the interplay between genomic and epigenomic changes in human cancers. Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology 1 , 2 , 3 . Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 ( IDH1 ), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.

Cancer-associated IDH mutants that produce 2-hydroxyglutarate are shown to prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. Cancer induction by isocitrate dehydrogenase mutation Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 have been identified in gliomas, the most common form of brain tumour, and in other cancers including leukaemias. The mutated enzymes produce 2-hydroxyglutarate (2HG), which is a potential oncometabolite. Three papers in this issue of Nature examine the mechanisms through which IDH mutations promote cancers. Lu et al . show that 2HG-producing IDH mutants can prevent the histone demethylation that is required for progenitor cells to differentiate, potentially contributing to tumour-cell accumulation. Turcan et al . show that IDH1 mutation in primary human astrocytes induces DNA hypermethylation and reshapes the methylome to resemble that of the CIMP phenotype, a common feature of gliomas and other solid tumours. Koivunen et al . show that the ( R )-enantiomer of 2HG (but not the ( S )-enantiomer) can stimulate the activity of the EGLN prolyl 4-hydroxylases, leading to diminished levels of hypoxia-inducible factor (HIF), which in turn can enhance cell proliferation. These papers establish a framework for understanding gliomagenesis and highlight the interplay between genomic and epigenomic changes in human cancers. Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate 1 , 2 , 3 , 4 , 5 , 6 . Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro . Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.

Targeting the epigenome has been considered a compelling treatment modality for several cancers, including gliomas. Nearly 80% of the lower-grade gliomas and secondary glioblastomas harbor recurrent mutations in isocitrate dehydrogenase (IDH). Mutant IDH generates high levels of 2-hydroxyglutarate (2-HG) that inhibit various components of the epigenetic machinery, including histone and DNA demethylases. The encouraging results from current epigenetic therapies in hematological malignancies have reinvigorated the interest in solid tumors and gliomas, both preclinically and clinically. Here, we summarize the recent advancements in epigenetic therapy for lower-grade gliomas and discuss the challenges associated with current treatment options. A particular focus is placed on therapeutic mechanisms underlying favorable outcome with epigenetic-based drugs in basic and translational research of gliomas. This review also highlights emerging bridges to combination treatment with respect to epigenetic drugs. Given that epigenetic therapies, particularly DNA methylation inhibitors, increase tumor immunogenicity and antitumor immune responses, appropriate drug combinations with immune checkpoint inhibitors may lead to improvement of treatment effectiveness of immunotherapy, ultimately leading to tumor cell eradication.

Epigenetic drugs are used for the clinical treatment of hematologic malignancies; however, their therapeutic potential in solid tumors is still under investigation. Current evidence suggests that epigenetic drugs may lead to antitumor immunity by increasing antigen presentation and may enhance the therapeutic effect of immune checkpoint inhibitors. Here, we highlight their impact on the tumor epigenome and discuss the recent evidence that epigenetic agents may optimize the immune microenvironment and promote antiviral response.

Branched-chain amino acid transaminase 1, the enzyme that initiates the catabolism of branched-chain amino acids, is involved in glioma pathogenesis, making it a potential therapeutic target. Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of α-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro , as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.

Timothy Chan and colleagues report exome and genome sequencing of 60 adenoid cystic carcinoma (ACC) tumor-normal pairs. They identify multiple pathways recurrently disrupted in ACC and provide evidence that KDM6A and PIK3CA are functionally relevant candidate ACC driver genes. Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2 , CREBBP and KDM6A , suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB - NFIB translocations and somatic mutations in MYB -associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.

The development of breast cancer metastasis is accompanied by dynamic transcriptome changes and dramatic alterations in nuclear and chromatin structure. The basis of these changes is incompletely understood. The DNA methylome of primary breast cancers contribute to transcriptomic heterogeneity and different metastatic behavior. Therefore we sought to characterize methylome remodeling during regional metastasis. We profiled the DNA methylome and transcriptome of 44 matched primary breast tumors and regional metastases. Striking subtype-specific patterns of metastasis-associated methylome remodeling were observed, which reflected the molecular heterogeneity of breast cancers. These divergent changes occurred primarily in CpG island (CGI)-poor areas. Regions of methylome reorganization shared by the subtypes were also observed, and we were able to identify a metastasis-specific methylation signature that was present across the breast cancer subclasses. These alterations also occurred outside of CGIs and promoters, including sequences flanking CGIs and intergenic sequences. Integrated analysis of methylation and gene expression identified genes whose expression correlated with metastasis-specific methylation. Together, these findings significantly enhance our understanding of the epigenetic reorganization that occurs during regional breast cancer metastasis across the major breast cancer subtypes and reveal the nature of methylome remodeling during this process.