-
Biomedicine & Pharmacotherapy =... Sep 2023Glioblastoma (GBL) is the most common (60-70% of primary brain tumours) and the most malignant of the glial tumours. Although current therapies remain palliative, they... (Review)
Review
Glioblastoma (GBL) is the most common (60-70% of primary brain tumours) and the most malignant of the glial tumours. Although current therapies remain palliative, they have been proven to prolong overall survival. Within an optimal treatment regimen (incl. surgical resection, radiation therapy, and chemotherapy) temozolomide as the current anti-GBL first-line chemotherapeutic has increased the median overall survival to 14-15 months, and the percentage of patients alive at two years has been reported to rise from 10.4% to 26.5%. Though, the effectiveness of temozolomide chemotherapy is limited by the serious systemic, dose-related side effects. Therefore, the ponderation regarding novel treatment methods along with innovative formulations is crucial to emerging the therapeutic potential of the widely used drug simultaneously reducing the drawbacks of its use. Herein the complex temozolomide application restrictions present at different levels of therapy as well as, the currently proposed strategies aimed at reducing those limitations are demonstrated. Approaches increasing the efficacy of anti-GBL treatment are addressed. Our paper is focused on the most recent developments in the field of nano/biomaterials-based systems for temozolomide delivery and their functionalization towards more effective blood-brain-barrier crossing and/or tumour targeting. Appropriate designing accounting for the physical and chemical features of formulations along with distinct routes of administration is also discussed. In addition, considering the multiple resistance mechanisms, the molecular heterogeneity and the evolution of tumour the purposely selected delivery methods, the combined therapeutic approaches and specifically focused on GBL cells therapies are reviewed.
Topics: Humans; Temozolomide; Dacarbazine; Brain Neoplasms; Glioblastoma; Glioma; Antineoplastic Agents, Alkylating
PubMed: 37459661
DOI: 10.1016/j.biopha.2023.115174 -
International Journal of Molecular... Dec 2023Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose... (Review)
Review
Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma.
Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose metabolism. Moreover, oncogenic signaling pathways induce the expression of metabolic genes, increasing the metabolic enzyme activities and thus the critical biosynthetic pathways to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates that are essential to accomplish the biosynthetic needs of glioma cells. In this review, we aim to explore how dysregulated metabolic enzymes and their metabolites from primary metabolism pathways in glioblastoma (GBM) such as glycolysis and glutaminolysis modulate anabolic and catabolic metabolic pathways as well as pro-oncogenic signaling and contribute to the formation, survival, growth, and malignancy of glioma cells. Also, we discuss promising therapeutic strategies by targeting the key players in metabolic regulation. Therefore, the knowledge of metabolic reprogramming is necessary to fully understand the biology of malignant gliomas to improve patient survival significantly.
Topics: Humans; Glioblastoma; Glutamine; Metabolic Reprogramming; Glycolysis; Glioma; Signal Transduction; Apoptosis; Cell Proliferation
PubMed: 38139462
DOI: 10.3390/ijms242417633 -
Aging Sep 2023Glioma is the most frequent primary tumor of the central nervous system. The high heterogeneity of glioma tumors enables them to adapt to challenging environments,...
BACKGROUND
Glioma is the most frequent primary tumor of the central nervous system. The high heterogeneity of glioma tumors enables them to adapt to challenging environments, leading to resistance to treatment. Therefore, to detect the driving factors and improve the prognosis of glioma, it is essential to have a comprehensive understanding of the genomic heterogeneity, stemness, and immune microenvironment of glioma.
METHODS
We classified gliomas into various subtypes based on stemness, genomic heterogeneity, and immune microenvironment consensus clustering analysis. We identified risk hub genes linked to heterogeneous characteristics using WGCNA, LASSO, and multivariate Cox regression analysis and utilized them to create an effective risk model.
RESULTS
We thoroughly investigated the genomic heterogeneity, stemness, and immune microenvironment of glioma and identified the risk hub genes RAB42, SH2D4A, and GDF15 based on the TCGA dataset. We developed a risk model utilizing these genes that can reliably predict the prognosis of glioma patients. The risk signature showed a positive correlation with T cell exhaustion and increased infiltration of immunosuppressive cells, and a negative correlation with the response to immunotherapy. Moreover, we discovered that SH2D4A, one of the risk hub genes, could stimulate the migration and proliferation of glioma cells.
CONCLUSIONS
This study identified risk hub genes and established a risk model by analyzing the genomic heterogeneity, stemness, and immune microenvironment of glioma. Our findings will facilitate the diagnosis and prediction of glioma prognosis and may lead to potential treatment strategies for glioma.
Topics: Humans; Tumor Microenvironment; Genomics; Prognosis; Immunotherapy; Cluster Analysis; Glioma
PubMed: 37698534
DOI: 10.18632/aging.205018 -
Neuro-oncology May 2024High-grade glioma (HGG) is the most common cause of cancer death in children and the most common primary central nervous system tumor in adults. While pediatric HGG was... (Review)
Review
High-grade glioma (HGG) is the most common cause of cancer death in children and the most common primary central nervous system tumor in adults. While pediatric HGG was once thought to be biologically similar to the adult form of disease, research has shown these malignancies to be significantly molecularly distinct, necessitating distinct approaches to their clinical management. However, emerging data have shown shared molecular events in pediatric and adult HGG including the histone H3K27M mutation. This somatic missense mutation occurs in genes encoding one of two isoforms of the Histone H3 protein, H3F3A (H3.3), or HIST1H3B (H3.1), and is detected in up to 80% of pediatric diffuse midline gliomas and in up to 60% of adult diffuse gliomas. Importantly, the H3K27M mutation is associated with poorer overall survival and response to therapy compared to patients with H3 wild-type tumors. Here, we review the clinical features and biological underpinnings of pediatric and adult H3K27M mutant glioma, offering a groundwork for understanding current research and clinical approaches for the care of patients suffering with this challenging disease.
Topics: Humans; Glioma; Histones; Brain Neoplasms; Mutation; Child; Adult
PubMed: 37818718
DOI: 10.1093/neuonc/noad164 -
Theranostics 2023The CRISPR/Cas13a system offers the advantages of rapidity, precision, high sensitivity, and programmability as a molecular diagnostic tool for critical illnesses. One...
The CRISPR/Cas13a system offers the advantages of rapidity, precision, high sensitivity, and programmability as a molecular diagnostic tool for critical illnesses. One of the salient features of CRISPR/Cas13a-based bioassays is its ability to recognize and cleave the target RNA specifically. Simple and efficient approaches for RNA manipulation would enrich our knowledge of disease-linked gene expression patterns and provide insights into their involvement in the underlying pathomechanism. However, only a few studies reported the Cas13a-based reporter system for molecular diagnoses. A tiled crRNA pool targeting a particular RNA transcript was generated, and the optimally potential crRNA candidates were selected using bioinformatics modeling and biological validation methods. For imaging assessment of the anti-GBM effectiveness, we exploited a human GBM patient-derived xenograft model in nude mice. The most efficient crRNA sequence with a substantial cleavage impact on the target RNA as well as a potent collateral cleavage effect, was selected. In the xenografted GBM rodent model, the Cas13a-based reporter system enabled us imaging of the tumor growth. Furthermore, systemic treatments using this approach slowed tumor progression and increased the overall survival time in mice. Our work demonstrated the clinical potential of a Cas13a-based imaging method for the targeted degradation of specific RNAs in glioma cells, and suggested the feasibility of a tailored approach like Cas13a for the modulation of diagnosis and treatment options in glioma.
Topics: Humans; Animals; Mice; Clustered Regularly Interspaced Short Palindromic Repeats; Mice, Nude; Precision Medicine; CRISPR-Cas Systems; RNA; Glioma
PubMed: 37908718
DOI: 10.7150/thno.84429 -
Scientific Reports Jul 2023The disordered expression of ZNF143 is closely related to the malignant progression of tumours. However, the basic control mechanism of ZNF143 in glioma has not yet been...
The disordered expression of ZNF143 is closely related to the malignant progression of tumours. However, the basic control mechanism of ZNF143 in glioma has not yet been clarified. Therefore, we tried to find a new pathway to illustrate the function of ZNF143 in glioma. To explore the function of KPNA2 in the development of glioma, we used survival analysis by the Kaplan‒Meier method to assess the overall survival (OS) of patients with low and high KPNA2 expression in the TCGA and CGGA cohorts. Western blotting assays and RT‒PCR assays were utilized to determine the expression level of KPNA2 in glioma cells. The interaction between ZNF143 and KPNA2 was confirmed by ChIP assays. Proliferation was assessed by CCK-8 assays, and migration was evaluated by wound healing and Transwell assays. Apoptosis was determined by flow cytometry, and the expression level of YAP/TAZ was visualized using an immunofluorescence assay. The expression levels of LATS1, LATS2, YAP1, and p-YAP1 were determined. Patients with low KPNA2 expression showed a better prognosis than those with high KPNA2 expression. KPNA2 was found to be upregulated in human glioma cells. ZNF143 can bind to the promoter region of KPNA2. Downregulation of ZNF143 and KPNA2 can activate the Hippo signalling pathway and reduce YAP/TAZ expression in human glioma cells, thus inducing apoptosis of human glioma cells and weakening their proliferation, migration and invasion. In conclusion, ZNF143 mediates the Hippo/YAP signalling pathway and inhibits the growth and migration of glioma cells by regulating KPNA2.
Topics: Humans; Cell Proliferation; Cell Movement; Hippo Signaling Pathway; Glioma; Cell Line, Tumor; Trans-Activators; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins; alpha Karyopherins
PubMed: 37423952
DOI: 10.1038/s41598-023-38158-x -
Brain Research Bulletin Jul 2023The relationship between epilepsy and glioma has long been widely recognized, but the mechanisms of interaction remain unclear. This study aimed to investigate the...
OBJECTIVE
The relationship between epilepsy and glioma has long been widely recognized, but the mechanisms of interaction remain unclear. This study aimed to investigate the shared genetic signature and treatment strategies between epilepsy and glioma.
METHODS
We subjected hippocampal tissue samples from patients with epilepsy and glioma to transcriptomic analysis to identify differential genes and associated pathways, respectively. Weight gene co-expression network (WGCNA) analysis was performed to identify conserved modules in epilepsy and glioma and to obtain differentially expressed conserved genes. Prognostic and diagnostic models were built using lasso regression. We also focused on building transcription factor-gene interaction networks and assessing the proportion of immune invading cells in epilepsy patients. Finally, drug compounds were inferred using a drug signature database (DSigDB) based on core targets.
RESULTS
We discovered 88 differently conserved genes, most of which are involved in synaptic signaling and calcium ion pathways. We used lasso regression model to reduce 88 characteristic genes, and finally screened out 14 genes (EIF4A2, CEP170B, SNPH, EPHA4, KLK7, GNG3, MYOP, ANKRD29, RASD2, PRRT3, EFR3A, SGIP1, RAB6B, CNNM1) as the features of glioma prognosis model whose ROC curve is 0.9. Then, we developed a diagnosis model for epilepsy patients using 8 genes (PRRT3, RASD2, MYPOP, CNNM1, ANKRD29, GNG3, SGIP1, KLK7) with area under ROC curve (AUC) values near 1. According to the ssGSEA method, we observed an increase in activated B cells, eosinophils, follicular helper T cells and type 2T helper cells, and a decrease in monocytes in patients with epilepsy. Notably, the great majority of these immune cells showed a negative correlation with hub genes. To reveal the transcriptional-level regulation mechanism, we also built a TF-gene network. In addition, we discovered that patients with glioma-related epilepsy may benefit more from gabapentin and pregabalin.
CONCLUSION
This study reveals the modular conserved phenotypes of epilepsy and glioma and constructs effective diagnostic and prognostic markers. It provides new biological targets and ideas for the early diagnosis and effective treatment of epilepsy.
Topics: Humans; Epilepsy; Gabapentin; Area Under Curve; Cell Communication; Glioma
PubMed: 37192718
DOI: 10.1016/j.brainresbull.2023.110666 -
Biomedicine & Pharmacotherapy =... Jul 2023Diffuse intrinsic pontine glioma (DIPG) is a highly malignant brain tumor that mainly occurs in children with extremely low overall survival. Traditional therapeutic... (Review)
Review
Diffuse intrinsic pontine glioma (DIPG) is a highly malignant brain tumor that mainly occurs in children with extremely low overall survival. Traditional therapeutic strategies, such as surgical resection and chemotherapy, are not feasible mostly due to the special location and highly diffused features. Radiotherapy turns out to be the standard treatment method but with limited benefits of overall survival. A broad search for novel and targeted therapies is in the progress of both preclinical investigations and clinical trials. Extracellular vesicles (EVs) emerged as a promising diagnostic and therapeutic candidate due to their distinct biocompatibility, excellent cargo-loading-delivery capacity, high biological barrier penetration efficiency, and ease of modification. The utilization of EVs in various diseases as biomarker diagnoses or therapeutic agents is revolutionizing modern medical research and practice. In this review, we will briefly talk about the research development of DIPG, and present a detailed description of EVs in medical applications, with a discussion on the application of engineered peptides on EVs. The possibility of applying EVs as a diagnostic tool and drug delivery system in DIPG is also discussed.
Topics: Humans; Child; Brain Stem Neoplasms; Glioma; Drug Delivery Systems; Extracellular Vesicles; Cell Communication
PubMed: 37094548
DOI: 10.1016/j.biopha.2023.114630 -
CNS Neuroscience & Therapeutics Jul 2023Glioma is the most common primary intracranial malignancy in clinical practice, and in particular, IDH-wildtype glioblastoma has the worst prognosis. In recent years,... (Review)
Review
BACKGROUND
Glioma is the most common primary intracranial malignancy in clinical practice, and in particular, IDH-wildtype glioblastoma has the worst prognosis. In recent years, surgical resection combined with simultaneous radiotherapy and immune checkpoint inhibitors has made some progress, but the efficacy is still not satisfactory, which may be related to the low immunogenicity of glioma cells and the tumor immunosuppressive microenvironment.
METHODS
A comprehensive review of relevant literature was conducted to explore the mechanisms by which tumors suppress antitumor immune responses and produce escape, with a focus on the immune cells in the tumor microenvironment (TME).
RESULTS
The mechanisms involved in immune evasion of glioma cells are complex and involve with immune cell differentiation and function.
CONCLUSION
Our review emphasizes the need for a more profound comprehension of the mechanisms involved in immune response and immune evasion in glioma, to formulate more efficacious treatment modalities.
Topics: Humans; Immunotherapy; Glioma; Brain Neoplasms; Glioblastoma; Treatment Outcome; Tumor Microenvironment
PubMed: 37088950
DOI: 10.1111/cns.14217 -
Neuro-oncology May 2024H3 K27M-mutant diffuse glioma is a recently identified brain tumor associated with poor prognosis. As of 2016, it is classified by the World Health Organization as a... (Review)
Review
H3 K27M-mutant diffuse glioma is a recently identified brain tumor associated with poor prognosis. As of 2016, it is classified by the World Health Organization as a distinct form of grade IV glioma. Despite recognition as an important prognostic and diagnostic feature in diffuse glioma, radiation remains the sole standard of care and no effective systemic therapies are available for H3K27M mutant tumors. This review will detail treatment interventions applied to diffuse midline glioma and diffuse intrinsic pontine glioma (DIPG) prior to the identification of the H3 K27M mutation, the current standard-of-care for H3 K27M-mutant diffuse glioma treatment, and ongoing clinical trials listed on www.clinicaltrials.gov evaluating novel therapeutics in this population. Current clinical trials were identified using clinicaltrials.gov, and studies qualifying for this analysis were active or ongoing interventional trials that evaluated a therapy in at least 1 treatment arm or cohort comprised exclusively of patients with DIPG and H3 K27M-mutant glioma. Forty-one studies met these criteria, including trials evaluating H3 K27M vaccination, chimeric antigen receptor T-cell therapy, and small molecule inhibitors. Ongoing evaluation of novel therapeutics is necessary to identify safe and effective interventions in this underserved patient population.
Topics: Humans; Brain Neoplasms; Brain Stem Neoplasms; Diffuse Intrinsic Pontine Glioma; Glioma; Histones; Mutation; Prognosis
PubMed: 38102230
DOI: 10.1093/neuonc/noad220