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Neurotherapeutics : the Journal of the... Apr 2017Malignant glioma is the most common primary brain tumor and carries a grim prognosis, with a median survival of just over 14 months. Given the poor outcomes with... (Review)
Review
Malignant glioma is the most common primary brain tumor and carries a grim prognosis, with a median survival of just over 14 months. Given the poor outcomes with standard-of-care treatments, novel treatment strategies are needed. The concept of virotherapy for the treatment of malignant tumors dates back more than a century and can be divided into replication-competent oncolytic viruses and replication-deficient viral vectors. Oncolytic viruses are designed to selectively target, infect, and replicate in tumor cells, while sparing surrounding normal brain. A host of oncolytic viruses has been evaluated in early phase human trials with promising safety results, but none has progressed to phase III trials. Despite the 25 years that has passed since the initial publication of genetically engineered oncolytic viruses for the treatment of glioma, much remains to be learned about the use of this therapy, including its mechanism of action, optimal treatment paradigm, appropriate targets, and integration with adjuvant agents. Oncolytic viral therapy for glioma remains promising and will undoubtedly impact the future of patient care.
Topics: Adenoviridae; Animals; Brain Neoplasms; Clinical Trials as Topic; Genetic Vectors; Glioma; Humans; Oncolytic Virotherapy; Oncolytic Viruses; Paramyxoviridae; Parvovirus; Poliovirus; Reoviridae; Treatment Outcome; Virus Replication
PubMed: 28265902
DOI: 10.1007/s13311-017-0516-0 -
International Journal of Molecular... Nov 2018Glioblastoma multiforme is the most malignant and aggressive type of brain tumor, with a mean life expectancy of less than 15 months. This is due in part to the high... (Review)
Review
Glioblastoma multiforme is the most malignant and aggressive type of brain tumor, with a mean life expectancy of less than 15 months. This is due in part to the high resistance to apoptosis and moderate resistant to autophagic cell death in glioblastoma cells, and to the poor therapeutic response to conventional therapies. Autophagic cell death represents an alternative mechanism to overcome the resistance of glioblastoma to pro-apoptosis-related therapies. Nevertheless, apoptosis induction plays a major conceptual role in several experimental studies to develop novel therapies against brain tumors. In this review, we outline the different components of the apoptotic and autophagic pathways and explore the mechanisms of resistance to these cell death pathways in glioblastoma cells. Finally, we discuss drugs with clinical and preclinical use that interfere with the mechanisms of survival, proliferation, angiogenesis, migration, invasion, and cell death of malignant cells, favoring the induction of apoptosis and autophagy, or the inhibition of the latter leading to cell death, as well as their therapeutic potential in glioma, and examine new perspectives in this promising research field.
Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Biomarkers; Cell Transformation, Neoplastic; Clinical Trials as Topic; Drug Discovery; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioma; Humans; Molecular Targeted Therapy; Signal Transduction; Treatment Outcome
PubMed: 30486451
DOI: 10.3390/ijms19123773 -
Frontiers in Immunology 2020Glioma is the most malignant primary tumor of the central nervous system and is characterized by an extremely low overall survival. Recent breakthroughs in cancer... (Review)
Review
Glioma is the most malignant primary tumor of the central nervous system and is characterized by an extremely low overall survival. Recent breakthroughs in cancer therapy using immune checkpoint blockade have attracted significant attention. However, despite representing the most promising (immunotherapy) treatment for cancer, the clinical application of immune checkpoint blockade in glioma patients remains challenging due to the "cold phenotype" of glioma and multiple factors inducing resistance, both intrinsic and acquired. Therefore, comprehensive understanding of the tumor microenvironment and the unique immunological status of the brain will be critical for the application of glioma immunotherapy. More sensitive biomarkers to monitor the immune response, as well as combining multiple immunotherapy strategies, may accelerate clinical progress and enable development of effective and safe treatments for glioma patients.
Topics: Animals; Brain Neoplasms; Glioma; Humans; Immune Checkpoint Inhibitors; Molecular Targeted Therapy; Signal Transduction; Treatment Outcome; Tumor Microenvironment
PubMed: 33329549
DOI: 10.3389/fimmu.2020.578877 -
Cancer Cell Nov 2020Malignant gliomas are central nervous system tumors and remain among the most treatment-resistant cancers. Exome sequencing has revealed significant heterogeneity and... (Review)
Review
Malignant gliomas are central nervous system tumors and remain among the most treatment-resistant cancers. Exome sequencing has revealed significant heterogeneity and important insights into the molecular pathogenesis of gliomas. Mutations in chromatin modifiers-proteins that shape the epigenomic landscape through remodeling and regulation of post-translational modifications on chromatin-are very frequent and often define specific glioma subtypes. This suggests that epigenomic reprogramming may be a fundamental driver of glioma. Here, we describe the key chromatin regulatory pathways disrupted in gliomas, delineating their physiological function and our current understanding of how their dysregulation may contribute to gliomagenesis.
Topics: Biomarkers, Tumor; Brain Neoplasms; Epigenesis, Genetic; Epigenomics; Gene Expression Regulation, Neoplastic; Glioma; Humans; Exome Sequencing
PubMed: 32916125
DOI: 10.1016/j.ccell.2020.08.008 -
Neurotherapeutics : the Journal of the... Oct 2022Glioblastoma is the most common primary malignant brain tumor in adults and outcomes remain poor despite the current standard of care multimodal therapy. Oncolytic... (Review)
Review
Glioblastoma is the most common primary malignant brain tumor in adults and outcomes remain poor despite the current standard of care multimodal therapy. Oncolytic virotherapy utilizes engineered viruses to exert an anti-tumor effect via both direct oncolysis and stimulation of an immune response within the tumor microenvironment, turning tumors from "cold" to "hot." This has shown promise as a novel therapeutic modality and attempts to circumvent the challenges associated with traditional treatments. Many oncolytic viruses have been investigated in completed and ongoing clinical trials and while safety has been demonstrated, clinical outcomes have been variable, often with only a subgroup of patients showing a significant response. This review summarizes these studies, addresses relevant technical aspects of oncolytic virus administration, and highlights practical considerations to assist providers in appropriately caring for patients treated with oncolytic virotherapy. Additionally, future directions within the field that may help to maximize efficacy of this modality are discussed.
Topics: Humans; Oncolytic Virotherapy; Glioma; Oncolytic Viruses; Glioblastoma; Viruses; Tumor Microenvironment
PubMed: 35674873
DOI: 10.1007/s13311-022-01256-1 -
Cancer Mar 2017Glioblastoma is the most common malignant primary brain tumor. Despite standard-of-care treatment, consisting of maximal surgical resection followed by chemoradiation,... (Review)
Review
Glioblastoma is the most common malignant primary brain tumor. Despite standard-of-care treatment, consisting of maximal surgical resection followed by chemoradiation, both morbidity and mortality associated with this disease remain very poor. Therefore, there is an urgent need for more efficacious and well tolerated therapies. Advancing knowledge of the intricate interplay between malignant gliomas and the immune system, coupled with the recent launch of immunotherapy research for other cancers, has led to a veritable increase in immunotherapy investigation for glioblastoma and other malignant gliomas. This clinical review highlights the recent breakthroughs in cancer immunotherapy and the complex correlation of the immune system with primary brain tumors, with special attention to multiple immunotherapy modalities currently being investigated for malignant glioma, including peptide vaccines, dendritic cell vaccines, oncolytic viruses, chimeric T-cell receptors, and checkpoint inhibitors. Cancer 2017;123:734-50. © 2016 American Cancer Society.
Topics: Brain Neoplasms; Chemoradiotherapy; Dendritic Cells; Glioma; Humans; Immunotherapy; Oncolytic Viruses
PubMed: 27875627
DOI: 10.1002/cncr.30371 -
Frontiers in Immunology 2023Glioblastoma is the most common primary malignant tumor of the central nervous system, which has the characteristics of strong invasion, frequent recurrence, and rapid... (Review)
Review
Glioblastoma is the most common primary malignant tumor of the central nervous system, which has the characteristics of strong invasion, frequent recurrence, and rapid progression. These characteristics are inseparable from the evasion of glioma cells from immune killing, which makes immune escape a great obstacle to the treatment of glioma, and studies have confirmed that glioma patients with immune escape tend to have poor prognosis. The lysosomal peptidase lysosome family plays an important role in the immune escape process of glioma, which mainly includes aspartic acid cathepsin, serine cathepsin, asparagine endopeptidases, and cysteine cathepsins. Among them, the cysteine cathepsin family plays a prominent role in the immune escape of glioma. Numerous studies have confirmed that glioma immune escape mediated by lysosomal peptidases has something to do with autophagy, cell signaling pathways, immune cells, cytokines, and other mechanisms, especially lysosome organization. The relationship between protease and autophagy is more complicated, and the current research is neither complete nor in-depth. Therefore, this article reviews how lysosomal peptidases mediate the immune escape of glioma through the above mechanisms and explores the possibility of lysosomal peptidases as a target of glioma immunotherapy.
Topics: Humans; Peptide Hydrolases; Cysteine; Cathepsins; Glioma; Lysosomes
PubMed: 37398678
DOI: 10.3389/fimmu.2023.1154146 -
Current Opinion in Pharmacology Aug 2018Resistance of malignant glioma, including glioblastoma (GBM), to the chemotherapeutic temozolomide (TMZ) remains a key obstacle in treatment strategies. The gap junction... (Review)
Review
Resistance of malignant glioma, including glioblastoma (GBM), to the chemotherapeutic temozolomide (TMZ) remains a key obstacle in treatment strategies. The gap junction protein connexin43 (Cx43) has complex roles in the establishment, progression, and persistence of malignant glioma. Recent findings demonstrate that connexins play an important role in the microenvironment of malignant glioma and that Cx43 is capable of conferring chemotherapeutic resistance to GBM cells. Carboxyl-terminal Cx43 peptidomimetics show therapeutic promise in overcoming TMZ resistance via mechanisms that may include modulating junctional activity between tumor cells and peritumoral cells and/or downstream molecular signaling events mediated by Cx43 protein binding. High levels of intra-tumor and inter-tumor heterogeneity make it difficult to clearly define specific populations for Cx43-targeted therapy; hence, development of in vitro models that better mimic the microenvironment of malignant glioma, and the incorporation of patient-derived stem cells, could provide opportunities for patient-specific drug screening. This review summarizes recent advances in understanding the roles of Cx43 in malignant glioma, with a special focus on tumor microenvironment, TMZ resistance, and therapeutic opportunity offered by Cx43 peptidomimetics.
Topics: Antineoplastic Agents, Alkylating; Central Nervous System Neoplasms; Connexin 43; Drug Resistance, Neoplasm; Glioblastoma; Glioma; Humans; Molecular Targeted Therapy; Peptidomimetics; Signal Transduction; Temozolomide; Tumor Microenvironment
PubMed: 29803991
DOI: 10.1016/j.coph.2018.05.002 -
Frontiers in Immunology 2022Despite a generally better prognosis than high-grade glioma (HGG), recurrence and malignant progression are the main causes for the poor prognosis and difficulties in...
Despite a generally better prognosis than high-grade glioma (HGG), recurrence and malignant progression are the main causes for the poor prognosis and difficulties in the treatment of low-grade glioma (LGG). It is of great importance to learn about the risk factors and underlying mechanisms of LGG recurrence and progression. In this study, the transcriptome characteristics of four groups, namely, normal brain tissue and recurrent LGG (rLGG), normal brain tissue and secondary glioblastoma (sGBM), primary LGG (pLGG) and rLGG, and pLGG and sGBM, were compared using Chinese Glioma Genome Atlas (CGGA) and Genotype-Tissue Expression Project (GTEx) databases. In this study, 296 downregulated and 396 upregulated differentially expressed genes (DEGs) with high consensus were screened out. Univariate Cox regression analysis of data from The Cancer Genome Atlas (TCGA) yielded 86 prognostically relevant DEGs; a prognostic prediction model based on five key genes (HOXA1, KIF18A, FAM133A, HGF, and MN1) was established using the least absolute shrinkage and selection operator (LASSO) regression dimensionality reduction and multivariate Cox regression analysis. LGG was divided into high- and low-risk groups using this prediction model. Gene Set Enrichment Analysis (GSEA) revealed that signaling pathway differences in the high- and low-risk groups were mainly seen in tumor immune regulation and DNA damage-related cell cycle checkpoints. Furthermore, the infiltration of immune cells in the high- and low-risk groups was analyzed, which indicated a stronger infiltration of immune cells in the high-risk group than that in the low-risk group, suggesting that an immune microenvironment more conducive to tumor growth emerged due to the interaction between tumor and immune cells. The tumor mutational burden and tumor methylation burden in the high- and low-risk groups were also analyzed, which indicated higher gene mutation burden and lower DNA methylation level in the high-risk group, suggesting that with the accumulation of genomic mutations and epigenetic changes, tumor cells continued to evolve and led to the progression of LGG to HGG. Finally, the value of potential therapeutic targets for the five key genes was analyzed, and findings demonstrated that KIF18A was the gene most likely to be a potential therapeutic target. In conclusion, the prediction model based on these five key genes can better identify the high- and low-risk groups of LGG and lay a solid foundation for evaluating the risk of LGG recurrence and malignant progression.
Topics: Biomarkers, Tumor; Brain Neoplasms; Glioblastoma; Glioma; Humans; Immunotherapy; Kinesins; Neoplasm Grading; Neoplasm Recurrence, Local; Tumor Microenvironment
PubMed: 35677036
DOI: 10.3389/fimmu.2022.899710 -
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