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International Journal of Molecular... May 2021Malignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct... (Review)
Review
Malignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct tumor zones of this heterogeneous neoplasm develop their own microenvironment, in which subpopulations of cancer cells communicate. Adaptation to hypoxia in the center of the expanding tumor mass leads to the glycolytic and angiogenic switch, accompanied by upregulation of different glycolytic enzymes, transporters, and other metabolites. These processes render the tumor microenvironment more acidic, remodel the extracellular matrix, and create energy gradients for the metabolic communication between different cancer cells in distinct tumor zones. Escape mechanisms from hypoxia-induced cell death and energy deprivation are the result. The functional consequences are more aggressive and malignant behavior with enhanced proliferation and survival, migration and invasiveness, and the induction of angiogenesis. In this review, we go from the biochemical principles of aerobic and anaerobic glycolysis over the glycolytic switch, regulated by the key transcription factor hypoxia-inducible factor (HIF)-1α, to other important metabolic players like the monocarboxylate transporters (MCTs)1 and 4. We discuss the metabolic symbiosis model via lactate shuttling in the acidic tumor microenvironment and highlight the functional consequences of the glycolytic switch on glioma malignancy. Furthermore, we illustrate regulation by micro ribonucleic acids (miRNAs) and the connection between mutation status and glycolytic metabolism. Finally, we give an outlook about the diagnostic and therapeutic implications of the glycolytic switch and the relation to tumor immunity in malignant glioma.
Topics: Animals; Brain; Brain Chemistry; Brain Neoplasms; Carbonic Anhydrases; Glioma; Glycolysis; Humans; Hydrogen-Ion Concentration; Lactic Acid; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 34073734
DOI: 10.3390/ijms22115518 -
Neoplasia (New York, N.Y.) Mar 2015Malignant gliomas are the most common malignant primary brain tumors and one of the most challenging forms of cancers to treat. Despite advances in conventional... (Review)
Review
Malignant gliomas are the most common malignant primary brain tumors and one of the most challenging forms of cancers to treat. Despite advances in conventional treatment, the outcome for patients remains almost universally fatal. This poor prognosis is due to therapeutic resistance and tumor recurrence after surgical removal. However, over the past decade, molecular targeted therapy has held the promise of transforming the care of malignant glioma patients. Significant progress in understanding the molecular pathology of gliomagenesis and maintenance of the malignant phenotypes will open opportunities to rationally develop new molecular targeted therapy options. Recently, therapeutic strategies have focused on targeting pro-growth signaling mediated by receptor tyrosine kinase/RAS/phosphatidylinositol 3-kinase pathway, proangiogenic pathways, and several other vital intracellular signaling networks, such as proteasome and histone deacetylase. However, several factors such as cross-talk between the altered pathways, intratumoral molecular heterogeneity, and therapeutic resistance of glioma stem cells (GSCs) have limited the activity of single agents. Efforts are ongoing to study in depth the complex molecular biology of glioma, develop novel regimens targeting GSCs, and identify biomarkers to stratify patients with the individualized molecular targeted therapy. Here, we review the molecular alterations relevant to the pathology of malignant glioma, review current advances in clinical targeted trials, and discuss the challenges, controversies, and future directions of molecular targeted therapy.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Glioma; Humans; Molecular Targeted Therapy; Signal Transduction
PubMed: 25810009
DOI: 10.1016/j.neo.2015.02.002 -
BMJ (Clinical Research Ed.) Dec 1996
Clinical Trial Randomized Controlled Trial
Topics: Brain Neoplasms; Clinical Trials as Topic; Glioma; Humans; Quality of Life; Surveys and Questionnaires
PubMed: 8978218
DOI: 10.1136/bmj.313.7071.1500 -
Neuro-oncology Mar 2016The shared goal of all parties developing therapeutics against malignant gliomas is to positively impact the lives of people affected by these cancers. Clinical outcome... (Review)
Review
The shared goal of all parties developing therapeutics against malignant gliomas is to positively impact the lives of people affected by these cancers. Clinical outcome assessment (COA) tools, including measures of patient-reported outcome, performance outcome, clinician-reported outcome, and observer-reported outcome, allow patient-focused assessments to complement traditional efficacy measures such as overall survival and radiographic endpoints. This review examines the properties of various COA measures used in malignant glioma clinical trials to date and cross references their content to the priority signs, symptoms, and functional limitations defined through a community survey conducted by the National Brain Tumor Society. The overarching goal of this initiative is to identify COA measures that are feasible and have appropriate psychometric properties for use in this patient population as well as highlight where further development is needed.
Topics: Animals; Brain Neoplasms; Clinical Trials as Topic; Glioma; Humans; Outcome Assessment, Health Care; Quality of Life; Surveys and Questionnaires
PubMed: 26989128
DOI: 10.1093/neuonc/nov291 -
Swiss Medical Weekly 2011Glioblastomas (World Health Organisation (WHO) grade IV) and anaplastic gliomas (astrocytomas, oligoastrocytomas, oligodendrogliomas) (WHO grade III) are collectively... (Review)
Review
Glioblastomas (World Health Organisation (WHO) grade IV) and anaplastic gliomas (astrocytomas, oligoastrocytomas, oligodendrogliomas) (WHO grade III) are collectively referred to as malignant gliomas. The diagnosis of malignant glioma may be suspected based on clinical history and neuroimaging findings, but histological confirmation remains the diagnostic "gold standard". Molecular markers such as 1p/19q codeletion and isocitrate dehydrogenase (IDH) mutation provide important diagnostic and prognostic information. O-methylguanylmethyltransferase (MGMT) promoter methylation is another favourable prognostic marker and predicts benefit from alkylating agent chemotherapy in glioblastoma. Additionally, the extent of neurosurgical resection is a prognostic factor. Radiotherapy of the involved brain region or chemotherapy using the alkylating agent, temozolomide, are common therapeutic options for patients with anaplastic glioma. In contrast, temozolomide plus radiotherapy is the standard of care for most patients with glioblastoma. The increasing population of elderly patients with glioblastoma represents a particular challenge, with surgery followed by radiotherapy as the standard of care. Contemporary clinical studies focus on the role of angiogenesis. Specifically, pivotal phase III studies exploring the antibody to vascular endothelial growth factor (VEGF), bevacizumab, and the αvβ3/5 antagonist, cilengitide, in the management of newly diagnosed glioblastoma have completed enrolment. Moreover, a broad spectrum of other experimental treatment approaches, including immunotherapy with vaccines against glioma-associated antigens, are currently being explored in phase I/II clinical trials.
Topics: Biomarkers, Tumor; Central Nervous System Neoplasms; Glioblastoma; Humans; Neoplasm Recurrence, Local; Oligodendroglioma
PubMed: 21607882
DOI: 10.4414/smw.2011.13210 -
Neurosurgery Jun 2021Cognitive decline is common among patients with low- and high-grade glioma and can significantly impact quality of life. Although cognitive outcomes have been studied... (Review)
Review
Cognitive decline is common among patients with low- and high-grade glioma and can significantly impact quality of life. Although cognitive outcomes have been studied after therapeutic interventions such as surgery and radiation, it is important to understand the impact of the disease process itself prior to any interventions. Neurocognitive domains of interest in this disease context include intellectual function and premorbid ability, executive function, learning and memory, attention, language function, processing speed, visuospatial function, motor function, and emotional function. Here, we review oncologic factors associated with more neurocognitive impairment, key neurocognitive tasks relevant to glioma patient assessment, as well as the relevance of the human neural connectome in understanding cognitive dysfunction in glioma patients. A contextual understanding of glioma-functional network disruption and its impact on cognition is critical in the surgical management of eloquent area tumors.
Topics: Adult; Brain Neoplasms; Cognition; Cognitive Dysfunction; Glioma; Humans; Neuropsychological Tests; Neurosurgeons; Quality of Life
PubMed: 33289504
DOI: 10.1093/neuros/nyaa400 -
International Journal of Molecular... Sep 2018Gliomas are highly invasive brain tumors with short patient survival. One major pathogenic factor is aberrant tumor metabolism, which may be targeted with different... (Review)
Review
Gliomas are highly invasive brain tumors with short patient survival. One major pathogenic factor is aberrant tumor metabolism, which may be targeted with different specific and unspecific agents. Drug repurposing is of increasing interest in glioma research. Drugs interfering with the patient's metabolism may also influence glioma metabolism. In this review, we outline definitions and methods for drug repurposing. Furthermore, we give insights into important candidates for a metabolic drug repurposing, namely metformin, statins, non-steroidal anti-inflammatory drugs, disulfiram and lonidamine. Advantages and pitfalls of drug repurposing will finally be discussed.
Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Drug Repositioning; Energy Metabolism; Glioma; Humans; Molecular Targeted Therapy; Treatment Outcome
PubMed: 30223473
DOI: 10.3390/ijms19092768 -
International Journal of Molecular... Nov 2022Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant tumor of the central nervous system. GBM has a very low 5-year survival rate and...
Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant tumor of the central nervous system. GBM has a very low 5-year survival rate and reaching merely a median of ~15 months even with aggressive treatments. PPARγ (Peroxisome proliferator- activated receptor gamma) agonists (ciglitazone), while being widely used on patients of type 2 diabetes mellitus, also have approved anticancer effects. Their action mechanisms on malignant glioma are not fully understood. The aim of this study is to investigate the potential therapeutic effect of PPARγ agonists on maligant glioma. Glioma cell line and in-vivo/ex-vivo animal model intervened by ciglitazone were used to assess the associated mechanism and therapeutic effect. Our results from in vivo and ex vivo experiments showed that ciglitazone not only inhibited tumor growth and its associated angiogenesis, but it also reduced colony formation and migration of tumors. Ciglitazone inhibited the phosphorylation of STAT3 (signal transducer and activator of transcription 3) (at the point of tyrosine 705 by increasing both the amount and activity of SHP-2 (Src homology region 2-containing protein tyrosine phosphatase 2) proteins, based on evidence obtained from immunoprecipitation and immunohistochemistry. Furthermore, ciglitazone activated proteasomes and lysosomes to degrade cell-cycle-related proteins like Cyclin D1, Cyclin E, CDK2 (Cyclin-dependent kinase 2), and CDK4 (Cyclin-dependent kinase 4). Ciglitazone triggered expressions of LC3 (Microtubule-associated protein 1A/1B-light chain 3) and formation of acidic vesicular organelles (AVOs), both of which were implicated in the autophagy pathway. In conclusion, ciglitazone showed the multiple actions to regulate the growth of glioma, which appeared to be a potential candidate for treating malignant glioma.
Topics: Animals; PPAR gamma; Diabetes Mellitus, Type 2; Thiazolidinediones; Glioma; Hypoglycemic Agents; Cell Cycle Proteins; Glioblastoma; Microtubule-Associated Proteins; Cell Line, Tumor
PubMed: 36362294
DOI: 10.3390/ijms232113510 -
Journal of Cellular and Molecular... Apr 2022With the emergence of the molecular era and retreat of the histology epoch in malignant glioma, it is becoming increasingly necessary to research...
With the emergence of the molecular era and retreat of the histology epoch in malignant glioma, it is becoming increasingly necessary to research diagnostic/prognostic/therapeutic biomarkers and their related regulatory mechanisms. While accumulating studies have investigated coding gene-associated biomarkers in malignant glioma, research on comprehensive coding and noncoding RNA-associated biomarkers is lacking. Furthermore, few studies have illustrated the cross-talk signalling pathways among these biomarkers and mechanisms in detail. Here, we identified DEGs and ceRNA networks in malignant glioma and then constructed Cox/Lasso regression models to further identify the most valuable genes through stepwise refinement. Top-down comprehensive integrated analysis, including functional enrichment, SNV, immune infiltration, transcription factor binding site, and molecular docking analyses, further revealed the regulatory maps among these genes. The results revealed a novel and accurate model (AUC of 0.91 and C-index of 0.84 in the whole malignant gliomas, AUC of 0.90 and C-index of 0.86 in LGG, and AUC of 0.75 and C-index of 0.69 in GBM) that includes twelve ncRNAs, 1 miRNA and 6 coding genes. Stepwise logical reasoning based on top-down comprehensive integrated analysis and references revealed cross-talk signalling pathways among these genes that were correlated with the circadian rhythm, tumour immune microenvironment and cellular senescence pathways. In conclusion, our work reveals a novel model where the newly identified biomarkers may contribute to a precise diagnosis/prognosis and subclassification of malignant glioma, and the identified cross-talk signalling pathways would help to illustrate the noncoding RNA-associated epigenetic regulatory mechanisms of glioma tumorigenesis and aid in targeted therapy.
Topics: Biomarkers, Tumor; Brain Neoplasms; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Glioma; Humans; MicroRNAs; Molecular Docking Simulation; RNA, Long Noncoding; Tumor Microenvironment
PubMed: 35194922
DOI: 10.1111/jcmm.17244 -
Cancer Control : Journal of the Moffitt... 2004Despite advances in surgery, radiation therapy, and chemotherapy, only modest improvement has been achieved in the survival of patients with malignant gliomas. (Review)
Review
BACKGROUND
Despite advances in surgery, radiation therapy, and chemotherapy, only modest improvement has been achieved in the survival of patients with malignant gliomas.
METHODS
The authors review the immunologic aspects of gliomas, potential targets for therapy, and issues surrounding current immunotherapeutic strategies directed against malignant gliomas.
RESULTS
The blood-brain barrier and the purported immunological privilege of the brain are not necessarily insurmountable obstacles to effective immunotherapy for brain tumors. Preclinical studies suggest a number of potential therapeutic avenues. Translational studies offer the prospect of providing substantial new information about immunological trafficking in the nervous system and suggesting the most fruitful approaches to immunotherapy for malignant gliomas.
CONCLUSIONS
More effective adjuvant treatments for malignant gliomas are needed. The applicability of immunological approaches in the treatment of these tumors warrants continued study.
Topics: Animals; Antigens, Neoplasm; Blood-Brain Barrier; Brain; Cancer Vaccines; Clinical Trials as Topic; Dendritic Cells; Drug Delivery Systems; Genes, erbB-1; Glioma; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immune Tolerance; Immunotherapy; Interleukin-2; Mutation; Treatment Outcome
PubMed: 15153842
DOI: 10.1177/107327480401100306