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Neurotherapeutics : the Journal of the... Apr 2017The impact of targeted therapies in glioma has been modest. All the therapies that have demonstrated a significant survival benefit for gliomas in Phase III trials,... (Review)
Review
The impact of targeted therapies in glioma has been modest. All the therapies that have demonstrated a significant survival benefit for gliomas in Phase III trials, including radiation, chemotherapy (temozolomide and PCV [procarbazine, lomustine, vincristine]), and tumor-treating fields, are based on nonspecific targeting of proliferating cells. Recent advances in the molecular understanding of gliomas suggest some potential reasons for the failure of more targeted therapies in gliomas. Specifically, the histologic-based glioma classification is composed of multiple different molecular subtypes with distinct biology, natural history, and prognosis. As a result of these insights, the diagnosis and classification of gliomas have recently been updated by the World Health Organization. However, these changes and other novel observations regarding glioma biomarkers and subtypes highlight several clinical challenges. First, the field is faced with the difficulty of reinterpreting the results of prior studies and retrospective data using the new classifications to clarify prognostic assessments and treatment recommendations for patients. Second, the new classifications and insights require rethinking the design and stratification of future clinical trials. Last, these observations provide the essential framework for the development and testing of new specific targeted therapies for particular glioma subtypes. This review aims to summarize the current literature regarding glioma subclassifications and their clinical relevance in this evolving field.
Topics: Brain Neoplasms; Gene Deletion; Gene Expression; Glioma; Humans; Molecular Targeted Therapy; Mutation; World Health Organization
PubMed: 28281173
DOI: 10.1007/s13311-017-0519-x -
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 -
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 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 -
Current Opinion in Pediatrics Feb 2019Pediatric low-grade gliomas (pLGGs) have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted... (Review)
Review
PURPOSE OF REVIEW
Pediatric low-grade gliomas (pLGGs) have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted therapies to be developed for these diverse tumors. At the same time, technological advances may redefine the late toxicities associated with radiation therapy. Understanding recent developments in pLGG therapy is essential to the management of these common pediatric tumors.
RECENT FINDINGS
It is now well understood that aberrations of the mitogen-activated protein kinase pathway are key to oncogenesis in low-grade gliomas. This understanding, along with the development of available targeted agents, have heralded a new era of understanding and treatment for these patients. Promising, sustained responses are now being seen in early phase trials among patients with multiply recurrent/progressive disease. Also, newer and highly conformal radiation approaches such as proton beam radiotherapy maintain efficacy of radiation but limit radiation-associated toxicities.
SUMMARY
Novel therapies offer the potential for tumor control with greatly reduced toxicities. However, late effects of these therapies are just now being explored. Improved radiation approaches and targeted agents have the potential to redefine traditional therapy for pLGG.
Topics: Child; Glioma; Humans; Neoplasm Grading
PubMed: 30531227
DOI: 10.1097/MOP.0000000000000717 -
Nature Reviews. Clinical Oncology Jul 2017Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These... (Review)
Review
Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers - together with classic histological features - in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.
Topics: Central Nervous System Neoplasms; Glioma; Humans; Molecular Biology; Practice Guidelines as Topic; World Health Organization
PubMed: 28031556
DOI: 10.1038/nrclinonc.2016.204 -
Nature Aug 2019Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of... (Comparative Study)
Comparative Study
Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.
Topics: Animals; Cerebellar Neoplasms; Cerebellum; Child; Evolution, Molecular; Female; Fetus; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Glioma; Humans; Medulloblastoma; Mice; Sequence Analysis, RNA; Single-Cell Analysis; Time Factors; Transcription, Genetic; Transcriptome
PubMed: 31043743
DOI: 10.1038/s41586-019-1158-7 -
BioMed Research International 2014
Topics: Brain Neoplasms; Glioma; Humans; Magnetic Resonance Imaging; Signal Transduction
PubMed: 25243142
DOI: 10.1155/2014/470523