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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 -
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 Treatment Options in Oncology Jul 2020Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a... (Review)
Review
Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a novel, locoregional, antineoplastic treatment modality with favorable efficacy and safety being demonstrated in the most aggressive type of malignant gliomas, glioblastoma (GBM). In 2 large randomized, controlled phase 3 trials, the addition of TTFields was associated with increased overall survival when combined with adjuvant temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM (ndGBM) and comparable overall survival compared with standard chemotherapy in patients with recurrent GBM (rGBM). TTFields target cancer cells by several mechanisms of action (MoA) including suppression of proliferation, migration and invasion, disruption of DNA repair and angiogenesis, antimitotic effects, and induction of apoptosis and immunogenic cell death. Having several MoAs makes TTFields an attractive modality to combine with standard, salvage, and novel treatment regimens (e.g., radiotherapy, chemotherapy, and immunotherapy). Treatment within the field of malignant gliomas is evolving to emphasize combinatorial approaches that work synergistically to improve patient outcomes. Here, we review the current use of TTFields in GBM, discuss MOA and treatment delivery, and consider the potential for its wider adoption in other gliomas.
Topics: Algorithms; Brain Neoplasms; Clinical Decision-Making; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Factor Analysis, Statistical; Glioblastoma; Glioma; Humans; Radiofrequency Ablation; Treatment Outcome
PubMed: 32734509
DOI: 10.1007/s11864-020-00773-5 -
CNS Neuroscience & Therapeutics Nov 2023Tumor-associated macrophages (TAMs) in the immune microenvironment play an important role in the increased drug resistance and recurrence of malignant glioma, but the...
AIMS
Tumor-associated macrophages (TAMs) in the immune microenvironment play an important role in the increased drug resistance and recurrence of malignant glioma, but the mechanism remains incompletely inventoried. The focus of this study was to investigate the distinctions of M2-like TAMs in the immune microenvironment between primary and recurrent malignant glioma and its influence in the recurrence.
METHODS
We employed single-cell RNA sequencing to construct a single-cell atlas for a total of 23,010 individual cells from 6 patients with primary or recurrent malignant glioma and identified 5 cell types, including TAMs and malignant cells. Immunohistochemical techniques and proteomics analysis were performed to investigate the role of intercellular interaction between malignant cells and TAMs in the recurrence of malignant glioma.
RESULTS
Six subgroups of TAMs were annotated and M2-like TAMs were found to increase in recurrent malignant glioma significantly. A pseudotime trajectory and a dynamic gene expression profiling during the recurrence of malignant glioma were reconstructed. Up-regulation of several cancer pathways and intercellular interaction-related genes are associated with the recurrence of malignant glioma. Moreover, the M2-like TAMs can activate the PI3K/Akt/HIF-1α/CA9 pathway in the malignant glioma cells via SPP1-CD44-mediated intercellular interaction. Interestingly, high expression of CA9 can trigger the immunosuppressive response in the malignant glioma, thus promoting the degree of malignancy and drug resistance.
CONCLUSION
Our study uncovers the distinction of M2-like TAMs between primary and recurrent glioma, which offers unparalleled insights into the immune microenvironment of primary and recurrent malignant glioma.
Topics: Humans; Proteomics; Phosphatidylinositol 3-Kinases; Single-Cell Gene Expression Analysis; Neoplasm Recurrence, Local; Macrophages; Glioma; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37194413
DOI: 10.1111/cns.14269 -
Seminars in Neurology Feb 2018Malignant glioma is a common type of brain tumor that remains largely incurable. Although a definitive cell of origin of gliomas remains elusive, numerous population... (Review)
Review
Malignant glioma is a common type of brain tumor that remains largely incurable. Although a definitive cell of origin of gliomas remains elusive, numerous population studies, sequencing efforts, and genetically engineered mouse models have contributed to our understanding of the early events that may lead to gliomagenesis. Herein we summarize our current knowledge on the population epidemiology of gliomas, heritable genetic risk factors, the somatic events that contribute to tumor evolution, and mouse models that have shed light on the glioma cell of origin. Future studies will increase our understanding of the sequence of early events within susceptible cells and their niche that trigger the path to malignant transformation. Such knowledge will allow us to design more effective treatment options to control tumor growth or screening methods for early detection.
Topics: Animals; Brain Neoplasms; Glioma; Humans
PubMed: 29548046
DOI: 10.1055/s-0037-1620238 -
Advances in Experimental Medicine and... 2017Glioma is the most common type of brain tumors and malignant glioma is extremely lethal, with patients' 5-year survival rate less than 10%. Treatment of gliomas poses... (Review)
Review
Glioma is the most common type of brain tumors and malignant glioma is extremely lethal, with patients' 5-year survival rate less than 10%. Treatment of gliomas poses remarkable clinical challenges, not only because of their particular localization but also because glioma cells possess several malignant biological features, including highly proliferative, highly invasive, highly angiogenic, and highly metabolic aberrant. All these features make gliomas highly recurrent and drug resistant. Finding new and effective molecular drug targets for glioma is an urgent and critical task for both basic and clinical research. Recent studies have proposed a type of non-voltage-gated calcium channels, namely, canonical transient receptor potential (TRPC) channels, to be newly emerged potential drug targets for glioma. They are heavily involved in the proliferation, migration, invasion, angiogenesis, and metabolism of glioma cells. Abundant evidence from both cell models and preclinical mouse models has demonstrated that inhibition of TRPC channels shows promising anti-glioma effect. In this chapter, we will give a comprehensive review on the current progress in the studies on TRPC channels and glioma and discuss their potential clinical implication in glioma therapy.
Topics: Animals; Brain Neoplasms; Glioma; Humans; Mice; TRPC Cation Channels
PubMed: 28508321
DOI: 10.1007/978-94-024-1088-4_14 -
Pharmacological Research Jun 2020Despite many endeavors to treat malignant gliomas in the last decades, the median survival of patients has not significantly improved. The infiltrative nature of... (Review)
Review
Despite many endeavors to treat malignant gliomas in the last decades, the median survival of patients has not significantly improved. The infiltrative nature of high-grade gliomas and the impermeability of the blood-brain barrier to the most therapeutic agents remain major hurdles, impeding an efficacious treatment. Theranostic platforms bridging diagnosis and therapeutic modalities aim to surmount the current limitations in diagnosis and therapy of glioma. Gold nanoparticles (AuNPs) due to their biocompatibility and tunable optical properties have widely been utilized for an assortment of theranostic purposes. In this Review, applications of AuNPs as imaging probes, drug/gene delivery systems, radiosensitizers, photothermal transducers, and multimodal theranostic agents in malignant gliomas are discussed. This Review also aims to provide a perspective on cancer theranostic applications of AuNPs in future clinical trials.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Drug Carriers; Gene Transfer Techniques; Genetic Therapy; Glioma; Gold Compounds; Humans; Immunotherapy; Metal Nanoparticles; Molecular Imaging; Photochemotherapy; Photothermal Therapy; Predictive Value of Tests; Theranostic Nanomedicine
PubMed: 32209363
DOI: 10.1016/j.phrs.2020.104753 -
Surgical Oncology Clinics of North... Oct 2022High-grade glioma is the most common malignant primary brain tumor in adults. Glioma infiltration renders it difficult to treat and likely to recur. Increasing the... (Review)
Review
High-grade glioma is the most common malignant primary brain tumor in adults. Glioma infiltration renders it difficult to treat and likely to recur. Increasing the extent of resection has been associated with improving progression-free survival and overall survival by several months. The introduction of 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery has allowed surgeons to better differentiate between neoplastic tissue and normal tissue, thus achieving greater extent of resection. The development of new intraoperative imaging modalities in combination with 5-ALA may provide additional benefits for glioma patients.
Topics: Adult; Aminolevulinic Acid; Brain Neoplasms; Diagnostic Imaging; Glioma; Humans; Surgery, Computer-Assisted
PubMed: 36243495
DOI: 10.1016/j.soc.2022.06.002 -
Topics in Magnetic Resonance Imaging :... Apr 2020Malignant gliomas constitute a smaller portion of brain tumors in children compared with adults. Nevertheless, they can be devastating tumors with poor prognosis. Recent... (Review)
Review
Malignant gliomas constitute a smaller portion of brain tumors in children compared with adults. Nevertheless, they can be devastating tumors with poor prognosis. Recent advances and improved understanding of the genetic and molecular characterization of pediatric brain tumors, including those of malignant gliomas, have led to the reclassification of many pediatric brain tumors and new entities have been defined. In this paper, we will present some of the more recent characterization and pertinent changes in pediatric high-grade gliomas, along with the conventional and advanced imaging features associated with these entities. Implications of the recent changes in pediatric malignant glioma classifications will also be discussed.
Topics: Adult; Brain; Brain Neoplasms; Child; Glioma; Humans; Magnetic Resonance Imaging; Pediatrics
PubMed: 32271285
DOI: 10.1097/RMR.0000000000000235 -
Cancer Science Jan 2018Malignant gliomas are primary tumors of the central nervous system characterized by diffuse infiltration into the brain and a high recurrence rate. Advances in... (Review)
Review
Malignant gliomas are primary tumors of the central nervous system characterized by diffuse infiltration into the brain and a high recurrence rate. Advances in comprehensive genomic studies have provided unprecedented insight into the genetic and molecular heterogeneity of these tumors and refined our understanding of their evolution from low to high grade. However, similar levels of phenotypic characterization are indispensable to understanding the complexity of malignant gliomas. Experimental glioma models have also achieved great progress in recent years. Advances in transgenic technologies and cell culture have allowed the establishment of mouse models that mirror the human disease with increasing fidelity and which support single-cell resolution for phenotypic analyses. Here we review the major types of preclinical glioma models, with an emphasis on how recent developments in experimental modeling have shed new light on two fundamental aspects of glioma phenotype, their cell of origin and their invasive potential.
Topics: Animals; Brain Neoplasms; Glioma; Humans; Mice; Mice, Transgenic; Neoplasm Invasiveness; Neoplasm Transplantation; Single-Cell Analysis
PubMed: 28796931
DOI: 10.1111/cas.13351