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Cancer Letters Apr 2020Gliomas are intrinsic brain tumors that originate from neuroglial progenitor cells. Conventional therapies, including surgery, chemotherapy, and radiotherapy, have... (Review)
Review
Gliomas are intrinsic brain tumors that originate from neuroglial progenitor cells. Conventional therapies, including surgery, chemotherapy, and radiotherapy, have achieved limited improvements in the prognosis of glioma patients. Immunotherapy, a revolution in cancer treatment, has become a promising strategy with the ability to penetrate the blood-brain barrier since the pioneering discovery of lymphatics in the central nervous system. Here we detail the current management of gliomas and previous studies assessing different immunotherapies in gliomas, despite the fact that the associated clinical trials have not been completed yet. Moreover, several drugs that have undergone clinical trials are listed as novel strategies for future application; however, these clinical trials have indicated limited efficacy in glioma. Therefore, additional studies are warranted to evaluate novel therapeutic approaches in glioma treatment.
Topics: Brain Neoplasms; Disease Management; Glioma; Humans; Immunotherapy; Prognosis
PubMed: 32044356
DOI: 10.1016/j.canlet.2020.02.002 -
Advances in Experimental Medicine and... 2023This chapter provides a comprehensive overview of malignant gliomas, the most common primary brain tumor in adults. These tumors are varied in their cellular origin,... (Review)
Review
This chapter provides a comprehensive overview of malignant gliomas, the most common primary brain tumor in adults. These tumors are varied in their cellular origin, genetic profile, and morphology under the microscope, but together they share some of the most dismal prognoses of all neoplasms in the body. Although there is currently no cure for malignant glioma, persistent efforts to improve outcomes in patients with these tumors have led to modest increases in survival, and researchers worldwide continue to strive toward a deeper understanding of the factors that influence glioma development and response to treatment. In addition to well-established epidemiology, clinical manifestations, and common histopathologic and radiologic features of malignant gliomas, this section considers recent advances in molecular biology that have led to a more nuanced understanding of the genetic changes that characterize the different types of malignant glioma, as well as their implications for treatment. Beyond the traditional classification of malignant gliomas based on histopathological features, this chapter incorporates the World Health Organization's 2016 criteria for the classification of brain tumors, with special focus on disease-defining genetic alterations and newly established subcategories of malignant glioma that were previously unidentifiable based on microscopic examination alone. Traditional therapeutic modalities that form the cornerstone of treatment for malignant glioma, such as aggressive surgical resection followed by adjuvant chemotherapy and radiation therapy, and the studies that support their efficacy are reviewed in detail. This provides a foundation for additional discussion of novel therapeutic methods such as immunotherapy and convection-enhanced delivery, as well as new techniques for enhancing extent of resection such as fluorescence-guided surgery.
Topics: Adult; Humans; Glioma; Brain Neoplasms; Immunotherapy; Chemotherapy, Adjuvant
PubMed: 37452933
DOI: 10.1007/978-3-031-23705-8_1 -
Cancer Discovery Mar 2021Diffuse gliomas represent a heterogeneous group of universally lethal brain tumors characterized by minimally effective genotype-targeted therapies. Recent advances have... (Review)
Review
Diffuse gliomas represent a heterogeneous group of universally lethal brain tumors characterized by minimally effective genotype-targeted therapies. Recent advances have revealed that a remarkable level of genetic, epigenetic, and environmental heterogeneity exists within each individual glioma. Together, these interconnected layers of intratumoral heterogeneity result in extreme phenotypic heterogeneity at the cellular level, providing for multiple mechanisms of therapeutic resistance and forming a highly adaptable and resilient disease. In this review, we discuss how glioma intratumoral heterogeneity and malignant cellular state plasticity drive resistance to existing therapies and look to a future in which these challenges may be overcome. SIGNIFICANCE: Glioma intratumoral heterogeneity and malignant cell state plasticity represent formidable hurdles to the development of novel targeted therapies. However, the convergence of genotypically diverse glioma cells into a limited set of epigenetically encoded transcriptional cell states may present an opportunity for a novel therapeutic strategy we call "State Selective Lethality." In this approach, cellular states (as opposed to genetic perturbations/mutations) are the subject of therapeutic targeting, and plasticity-mediated resistance is minimized through the design of cell state "trapping agents."
Topics: Animals; Biological Variation, Population; Biomarkers, Tumor; Clinical Decision-Making; Combined Modality Therapy; Disease Management; Disease Susceptibility; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Glioma; Humans; Neoplasm Grading; Neoplasm Staging; Prognosis; Treatment Outcome; Tumor Microenvironment
PubMed: 33558264
DOI: 10.1158/2159-8290.CD-20-1474 -
Nature Reviews. Neurology Jul 2019The WHO 2007 glioma classification system (based primarily on tumour histology) resulted in considerable interobserver variability and substantial variation in patient... (Review)
Review
The WHO 2007 glioma classification system (based primarily on tumour histology) resulted in considerable interobserver variability and substantial variation in patient survival within grades. Furthermore, few risk factors for glioma were known. Discoveries over the past decade have deepened our understanding of the molecular alterations underlying glioma and have led to the identification of numerous genetic risk factors. The advances in molecular characterization of glioma have reframed our understanding of its biology and led to the development of a new classification system for glioma. The WHO 2016 classification system comprises five glioma subtypes, categorized by both tumour morphology and molecular genetic information, which led to reduced misclassification and improved consistency of outcomes within glioma subtypes. To date, 25 risk loci for glioma have been identified and several rare inherited mutations that might cause glioma in some families have been discovered. This Review focuses on the two dominant trends in glioma science: the characterization of diagnostic and prognostic tumour markers and the identification of genetic and other risk factors. An overview of the many challenges still facing glioma researchers is also included.
Topics: Biomarkers, Tumor; Brain Neoplasms; Glioma; Humans
PubMed: 31227792
DOI: 10.1038/s41582-019-0220-2 -
Frontiers in Immunology 2022In cancer, neutrophils are an important part of the tumour microenvironment (TME). Previous studies have shown that circulating and infiltrating neutrophils are... (Review)
Review
In cancer, neutrophils are an important part of the tumour microenvironment (TME). Previous studies have shown that circulating and infiltrating neutrophils are associated with malignant progression and immunosuppression in gliomas. However, recent studies have shown that neutrophils have an antitumour effect. In this review, we focus on the functional roles of neutrophils in the circulation and tumour sites in patients with glioma. The mechanisms of neutrophil recruitment, immunosuppression and the differentiation of neutrophils are discussed. Finally, the potential of neutrophils as clinical biomarkers and therapeutic targets is highlighted. This review can help us gain a deeper and systematic understanding of the role of neutrophils, and provide new insights for treatment in gliomas.
Topics: Glioma; Humans; Immunosuppression Therapy; Neutrophil Infiltration; Neutrophils; Tumor Microenvironment
PubMed: 35860278
DOI: 10.3389/fimmu.2022.927233 -
International Journal of Molecular... Nov 2022Glioma is the most common type of primary CNS tumor, composed of cells that resemble normal glial cells. Recent genetic studies have provided insight into the... (Review)
Review
Glioma is the most common type of primary CNS tumor, composed of cells that resemble normal glial cells. Recent genetic studies have provided insight into the inter-tumoral heterogeneity of gliomas, resulting in the updated 2021 WHO classification of gliomas. Thorough understanding of inter-tumoral heterogeneity has already improved the prognosis and treatment outcomes of some types of gliomas. Currently, the challenge for researchers is to study the intratumoral cell heterogeneity of newly defined glioma subtypes. Cancer stem cells (CSCs) present in gliomas and many other tumors are an example of intratumoral heterogeneity of great importance. In this review, we discuss the modern concept of glioma stem cells and recent single-cell sequencing-driven progress in the research of intratumoral glioma cell heterogeneity. The particular emphasis was placed on the recently revealed variations of the cell composition of the subtypes of the adult-type diffuse gliomas, including astrocytoma, oligodendroglioma and glioblastoma. The novel data explain the inconsistencies in earlier glioma stem cell research and also provide insight into the development of more effective targeted therapy and the cell-based immunotherapy of gliomas. Separate sections are devoted to the description of single-cell sequencing approach and its role in the development of cell-based immunotherapies for glioma.
Topics: Humans; Glioma; Oligodendroglioma; Glioblastoma; Astrocytoma; Neoplastic Stem Cells
PubMed: 36430704
DOI: 10.3390/ijms232214224 -
Signal Transduction and Targeted Therapy Nov 2023Glioma is the most prevalent brain tumor, presenting with limited treatment options, while patients with malignant glioma and glioblastoma (GBM) have poor prognoses. The...
Glioma is the most prevalent brain tumor, presenting with limited treatment options, while patients with malignant glioma and glioblastoma (GBM) have poor prognoses. The physical obstacle to drug delivery imposed by the blood‒brain barrier (BBB) and glioma stem cells (GSCs), which are widely recognized as crucial elements contributing to the unsatisfactory clinical outcomes. In this study, we found a small molecule, gambogic amide (GA-amide), exhibited the ability to effectively penetrate the blood-brain barrier (BBB) and displayed a notable enrichment within the tumor region. Moreover, GA-amide exhibited significant efficacy in inhibiting tumor growth across various in vivo glioma models, encompassing transgenic and primary patient-derived xenograft (PDX) models. We further performed a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen to determine the druggable target of GA-amide. By the combination of the cellular thermal shift assay (CETSA), the drug affinity responsive target stability (DARTS) approach, molecular docking simulation and surface plasmon resonance (SPR) analysis, WD repeat domain 1 (WDR1) was identified as the direct binding target of GA-amide. Through direct interaction with WDR1, GA-amide promoted the formation of a complex involving WDR1, MYH9 and Cofilin, which accelerate the depolymerization of F-actin to inhibit the invasion of patient-derived glioma cells (PDCs) and induce PDC apoptosis via the mitochondrial apoptotic pathway. In conclusion, our study not only identified GA-amide as an effective and safe agent for treating glioma but also shed light on the underlying mechanisms of GA-amide from the perspective of cytoskeletal homeostasis.
Topics: Humans; Molecular Docking Simulation; Cell Line, Tumor; Glioma; Cytoskeleton; Amides; Microfilament Proteins
PubMed: 37935665
DOI: 10.1038/s41392-023-01666-3 -
Current Neurology and Neuroscience... Apr 2023Pediatric low-grade gliomas and glioneuronal tumors (pLGG) account for approximately 30% of pediatric CNS neoplasms, encompassing a heterogeneous group of tumors of... (Review)
Review
PURPOSE OF REVIEW
Pediatric low-grade gliomas and glioneuronal tumors (pLGG) account for approximately 30% of pediatric CNS neoplasms, encompassing a heterogeneous group of tumors of primarily glial or mixed neuronal-glial histology. This article reviews the treatment of pLGG with emphasis on an individualized approach incorporating multidisciplinary input from surgery, radiation oncology, neuroradiology, neuropathology, and pediatric oncology to carefully weigh the risks and benefits of specific interventions against tumor-related morbidity. Complete surgical resection can be curative for cerebellar and hemispheric lesions, while use of radiotherapy is restricted to older patients or those refractory to medical therapy. Chemotherapy remains the preferred first-line therapy for adjuvant treatment of the majority of recurrent or progressive pLGG.
RECENT FINDINGS
Technologic advances offer the potential to limit volume of normal brain exposed to low doses of radiation when treating pLGG with either conformal photon or proton RT. Recent neurosurgical techniques such as laser interstitial thermal therapy offer a "dual" diagnostic and therapeutic treatment modality for pLGG in specific surgically inaccessible anatomical locations. The emergence of novel molecular diagnostic tools has enabled scientific discoveries elucidating driver alterations in mitogen-activated protein kinase (MAPK) pathway components and enhanced our understanding of the natural history (oncogenic senescence). Molecular characterization strongly supplements the clinical risk stratification (age, extent of resection, histological grade) to improve diagnostic precision and accuracy, prognostication, and can lead to the identification of patients who stand to benefit from precision medicine treatment approaches. The success of molecular targeted therapy (BRAF inhibitors and/or MEK inhibitors) in the recurrent setting has led to a gradual and yet significant paradigm shift in the treatment of pLGG. Ongoing randomized trials comparing targeted therapy to standard of care chemotherapy are anticipated to further inform the approach to upfront management of pLGG patients.
Topics: Child; Humans; Glioma; Molecular Targeted Therapy; Brain; Brain Neoplasms
PubMed: 36881254
DOI: 10.1007/s11910-023-01257-3 -
Journal of Neurosurgical Sciences Aug 2019Low grade gliomas (LGGs) are WHO grade II tumors that affect mostly adult patients and include diffuse astrocytomas and oligodendrogliomas. New diagnostic criteria based... (Review)
Review
Low grade gliomas (LGGs) are WHO grade II tumors that affect mostly adult patients and include diffuse astrocytomas and oligodendrogliomas. New diagnostic criteria based on histology and molecular characterization with IDH mutation status and 1p/19q codeletion status have provided further categorization of these tumors and additional insights into prognosis and treatment response. In general, the current management of LGG favors maximum upfront resection with consideration of combined chemoradiation for patients deemed "high risk." In this review, we summarize the defining molecular features, important prognostic factors, recommended pre-operative imaging work-up, as well as therapeutic management of WHO Grade II low grade gliomas in adults.
Topics: Astrocytoma; Brain Neoplasms; Glioma; Humans; Mutation; Neoplasm Grading; Prognosis
PubMed: 30916536
DOI: 10.23736/S0390-5616.19.04701-5 -
Nature Reviews. Cancer Jan 2020Altered cellular metabolism is a hallmark of gliomas. Propelled by a set of recent technological advances, new insights into the molecular mechanisms underlying glioma... (Review)
Review
Altered cellular metabolism is a hallmark of gliomas. Propelled by a set of recent technological advances, new insights into the molecular mechanisms underlying glioma metabolism are rapidly emerging. In this Review, we focus on the dynamic nature of glioma metabolism and how it is shaped by the interaction between tumour genotype and brain microenvironment. Recent advances integrating metabolomics with genomics are discussed, yielding new insight into the mechanisms that drive glioma pathogenesis. Studies that shed light on interactions between the tumour microenvironment and tumour genotype are highlighted, providing important clues as to how gliomas respond to and adapt to their changing tissue and biochemical contexts. Finally, a road map for the discovery of potential new glioma drug targets is suggested, with the goal of translating these new insights about glioma metabolism into clinical benefits for patients.
Topics: Animals; Biomarkers; Brain Neoplasms; Disease Management; Disease Susceptibility; Drug Discovery; Energy Metabolism; Genetic Variation; Glioma; Humans; Metabolomics; Molecular Targeted Therapy; Signal Transduction
PubMed: 31806884
DOI: 10.1038/s41568-019-0226-5