Glioblastoma (GBM) is one of the most lethal human cancers. Genomic analyses are defining the molecular architecture of GBM, uncovering relevant subsets of patients whose disease may require ...different treatments. Many pharmacological targets have been revealed, promising to transform patient care through targeted therapies. However, for most patients, clinical responses to targeted inhibitors are either not apparent or not durable. In this review, we address the challenge of developing more effective, molecularly guided approaches for the treatment of GBM patients. We summarize the current state of knowledge regarding molecular classifiers and examine their benefit for stratifying patients for treatment. We survey the molecular landscape of the disease, discussing the challenges raised by acquired drug resistance. Furthermore, we analyze the biochemical features of GBM, suggesting a next generation of drug targets, and we examine the contribution of tumor heterogeneity and its implications. We conclude with an analysis of the experimental approaches and their potential benefit to patients.
The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO ...classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M–mutant; RELA fusion–positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma—a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.
Glioblastoma multiforme (GBM), the most common intracranial tumor in adults, is characterized by extensive heterogeneity at the cellular and molecular levels. This insidious feature arises inevitably ...in almost all cancers and has great significance for the general outcome of the malignancy, because it confounds our understanding of the disease and also intrinsically contributes to the tumor's aggressiveness and poses an obstacle to the design of effective therapies. The classic view that heterogeneity arises as the result of a tumor's "genetic chaos" and the more contemporary cancer stem cell (CSC) hypothesis tend to identify a single cell population as the therapeutic target: the prevailing clone over time in the first case and the CSC in the latter. However, there is growing evidence that the different tumor cell populations may not be simple bystanders. Rather, they can establish a complex network of interactions between each other and with the tumor microenvironment that eventually strengthens tumor growth and increases chances to escape therapy. These differing but complementary ideas about the origin and maintenance of tumor heterogeneity and its importance in GBM are reviewed here.
Aerobic glycolysis (the Warburg effect) is a core hallmark of cancer, but the molecular mechanisms underlying it remain unclear. Here, we identify an unexpected central role for mTORC2 in cancer ...metabolic reprogramming where it controls glycolytic metabolism by ultimately regulating the cellular level of c-Myc. We show that mTORC2 promotes inactivating phosphorylation of class IIa histone deacetylases, which leads to the acetylation of FoxO1 and FoxO3, and this in turn releases c-Myc from a suppressive miR-34c-dependent network. These central features of activated mTORC2 signaling, acetylated FoxO, and c-Myc levels are highly intercorrelated in clinical samples and with shorter survival of GBM patients. These results identify a specific, Akt-independent role for mTORC2 in regulating glycolytic metabolism in cancer.
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•mTORC2 is required for the growth of GBM cells in glucose•mTORC2 controls glycolytic metabolism by regulating the cellular level c-Myc•mTORC2 signaling acetylates FoxO1 and FoxO3 to upregulate c-Myc•mTORC2, acetylated FoxO, and c-Myc axis confer shorter survival in patients
Cancer cells depend on metabolic reprogramming for survival, undergoing profound shifts in nutrient sensing, nutrient uptake and flux through anabolic pathways, in order to drive nucleotide, lipid, ...and protein synthesis and provide key intermediates needed for those pathways. Although metabolic enzymes themselves can be mutated, including to generate oncometabolites, this is a relatively rare event in cancer. Usually, gene amplification, overexpression, and/or downstream signal transduction upregulate rate‐limiting metabolic enzymes and limit feedback loops, to drive persistent tumor growth. Recent molecular‐genetic advances have revealed discrete links between oncogenotypes and the resultant metabolic phenotypes. However, more comprehensive approaches are needed to unravel the dynamic spatio‐temporal regulatory map of enzymes and metabolites that enable cancer cells to adapt to their microenvironment to maximize tumor growth. Proteomic and metabolomic analyses are powerful tools for analyzing a repertoire of metabolic enzymes as well as intermediary metabolites, and in conjunction with other omics approaches could provide critical information in this regard. Here, we provide an overview of cancer metabolism, especially from an omics perspective and with a particular focus on the genomically well characterized malignant brain tumor, glioblastoma. We further discuss how metabolomics could be leveraged to improve the management of patients, by linking cancer cell genotype, epigenotype, and phenotype through metabolic reprogramming.
Cancer cells depend on metabolic reprogramming for survival, undergoing profound shifts in nutrient sensing, nutrient uptake, and flux through anabolic pathways to drive nucleotide, lipid, and protein synthesis, and to provide key intermediates needed for those pathways. Here, we provide an overview of cancer metabolism, especially from an omics perspective and with a particular focus on the genomically well characterized malignant brain tumor, glioblastoma. We further discuss how metabolomics could be leveraged to improve the management of patients, by linking cancer cell genotype, epigenotype, and phenotype through metabolic reprogramming.
Highlights • Oncogenes reprogram the cellular metabolism needed for rapid tumor growth. • mTORC2 is a central regulator of cancer metabolic reprogramming. • mTORC2 coordinates cancer metabolism ...through AKT-dependent and AKT-independent mechanisms. • c-Myc is a crucial effector of mTORC2-dependent metabolic reprogramming.
Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, providing a precise genomic view of tumors. Complementary biochemical and biophysical ...perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood. Here, we show that the lysophosphatidylcholine acyltransferase LPCAT1 functionally links specific genetic alterations in cancer with aberrant metabolism and plasma membrane remodeling to drive tumor growth. Growth factor receptor-driven cancers are found to depend on LPCAT1 to shape plasma membrane composition through enhanced saturated phosphatidylcholine content that is, in turn, required for the transduction of oncogenic signals. These results point to a genotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers.
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•Persistent EGFR signaling activates membrane lipid remodeling through LPCAT1•LPCAT1 regulates phospholipid saturation and oncogenic growth factor signaling•LPCAT1 is frequently amplified in cancer and associated with poor patient survival•Membrane phospholipid remodeling generates an actionable dependency across cancers
Persistent growth factor receptor signaling and metabolic reprograming are hallmarks of cancer. Bi et al. show that LPCAT1-mediated phospholipid remodeling supports the sustained oncogenic activity of growth factor receptors on plasma membrane of tumor cells, suggesting an actionable dependency in a wide variety of cancers.
Liquid biopsies, based on cell free DNA (cfDNA) and proteins, have shown the potential to detect early stage cancers of diverse tissue types. However, most of these studies were retrospective, using ...individuals previously diagnosed with cancer as cases and healthy individuals as controls. Here, we developed a liquid biopsy assay, named the hepatocellular carcinoma screen (HCCscreen), to identify HCC from the surface antigen of hepatitis B virus (HBsAg) positive asymptomatic individuals in the community population. The training cohort consisted of individuals who had liver nodules and/or elevated serum α-fetoprotein (AFP) levels, and the assay robustly separated those with HCC from those who were non-HCC with a sensitivity of 85% and a specificity of 93%. We further applied this assay to 331 individuals with normal liver ultrasonography and serum AFP levels. A total of 24 positive cases were identified, and a clinical follow-up for 6–8 mo confirmed four had developed HCC. No HCC cases were diagnosed from the 307 test-negative individuals in the follow-up during the same time-scale. Thus, the assay showed 100% sensitivity, 94% specificity, and 17% positive predictive value in the validation cohort. Notably, each of the four HCC cases was at the early stage (<3 cm) when diagnosed. Our study provides evidence that the use of combined detection of cfDNA alterations and protein markers is a feasible approach to identify early stage HCC from asymptomatic community populations with unknown HCC status.
Epidermal growth factor receptor (EGFR) gene amplification and mutations are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive tumor growth ...are not well understood. Here, through integrated epigenome and transcriptome analyses of cell lines, genotyped clinical samples, and TCGA data, we show that EGFR mutations remodel the activated enhancer landscape of GBM, promoting tumorigenesis through a SOX9 and FOXG1-dependent transcriptional regulatory network in vitro and in vivo. The most common EGFR mutation, EGFRvIII, sensitizes GBM cells to the BET-bromodomain inhibitor JQ1 in a SOX9, FOXG1-dependent manner. These results identify the role of transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy.
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•Oncogenic EGFRvIII mutation remodels the enhancer landscape in GBM•EGFRvIII induces SOX9 and FOXG1 transcription in GBM•SOX9 and FOXG1 collaborate to activate an oncogenic gene regulatory program•EGFRvIII-dependent transcription sensitizes GBM cells to JQ1
Epidermal growth factor receptor (EGFR) gene amplification and mutations are the most common oncogenic events in glioblastoma (GBM). Through an integrative genomics analysis, Liu et al., identify a role for transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy.
Small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to their inability to achieve sufficient drug levels in the CNS. Targeting ...non-oncogene tumor co-dependencies provides an alternative approach, particularly if drugs with high brain penetration can be identified. Here we demonstrate that the highly lethal brain cancer glioblastoma (GBM) is remarkably dependent on cholesterol for survival, rendering these tumors sensitive to Liver X receptor (LXR) agonist-dependent cell death. We show that LXR-623, a clinically viable, highly brain-penetrant LXRα-partial/LXRβ-full agonist selectively kills GBM cells in an LXRβ- and cholesterol-dependent fashion, causing tumor regression and prolonged survival in mouse models. Thus, a metabolic co-dependency provides a pharmacological means to kill growth factor-activated cancers in the CNS.
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•Glioblastoma (GBM) cells rely on exogenous cholesterol for survival•GBM cells suppress cholesterol and liver X receptor (LXR) ligand synthesis•A brain-penetrant LXR agonist kills GBM cells in a cholesterol-dependent fashion
Villa et al. show that glioblastomas (GBM) are reliant on cholesterol uptake and highly sensitive to liver X receptor (LXR) agonist LXR-623, a full LXRβ and partial LXRα agonist. LXR-623 shows brain penetration and causes tumor regression in a GBM mouse model, reducing cholesterol and inducing cell death.
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