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British Journal of Cancer Oct 2023Exosomes (Exos) can safely and effectively deliver therapeutic substances to glioma cells; however, their blood-brain barrier (BBB) crossing capacity remains limited....
BACKGROUND
Exosomes (Exos) can safely and effectively deliver therapeutic substances to glioma cells; however, their blood-brain barrier (BBB) crossing capacity remains limited. Focused ultrasound (FUS) can transiently, reversibly, and locally open the BBB, while the effects of FUS combined with Exos-miRNA on the treatment of glioma have not been explored to date.
METHODS
Exos were extracted by differential centrifugation and the efficacy of miR-1208-loaded Exos combined with FUS in the treatment of glioma was detected by CCK-8, colony formation, flow cytometry, transwell and tumour xenografts assays. The METTL3-mediated regulation of IGF2BP2 on mRNA stability of NUP214 was determined by MeRIP-qPCR, half-life and RIP assays.
RESULTS
We used Exos secreted by mesenchymal stem cells as carriers for the tumour suppressor gene miR-1208, and following FUS irradiation, more Exos carrying miR-1208 were allowed to pass through the BBB, and the uptake of miR-1208 in Exos by glioma cells was promoted, thereby achieving high-efficiency tumour-suppressive effects. Furthermore, the molecular mechanism underlying this effect was elucidated that miR-1208 downregulated the mA methylation level of NUP214 mRNA by negatively regulating the expression of METTL3, thereby NUP214 expression and TGF-β pathway activity were suppressed.
CONCLUSIONS
MiR-1208-loaded Exos combined with FUS is expected to become an effective glioma treatment and deserves further clinical evaluation.
Topics: Humans; Blood-Brain Barrier; Exosomes; Glioma; Mesenchymal Stem Cells; Methyltransferases; MicroRNAs; RNA-Binding Proteins
PubMed: 37580442
DOI: 10.1038/s41416-023-02393-w -
Nature Communications Jul 2023Accurate determination of the extent and grade of adult-type diffuse gliomas is critical to patient management. In clinical practice, contrast-enhancing areas of diffuse...
Accurate determination of the extent and grade of adult-type diffuse gliomas is critical to patient management. In clinical practice, contrast-enhancing areas of diffuse gliomas in magnetic resonance imaging (MRI) sequences are usually used to target biopsy, surgery, and radiation therapy, but there can be discrepancies between these areas and the actual tumor extent. Here we show that adding F-fluoro-ethyl-tyrosine positron emission tomography (FET-PET) to MRI sequences accurately locates the most malignant areas of contrast-enhancing gliomas, potentially impacting subsequent management and outcomes. We present a prospective analysis of over 300 serial biopsy specimens from 23 patients with contrast-enhancing adult-type diffuse gliomas using a hybrid PET-MRI scanner to compare T2-weighted and contrast-enhancing MRI images with FET-PET. In all cases, we observe and confirm high FET uptake in early PET acquisitions (5-15 min after F-FET administration) outside areas of contrast enhancement on MRI, indicative of high-grade glioma. In 30% cases, inclusion of FET-positive sites changes the biopsy result to a higher tumor grade.
Topics: Humans; Adult; Amino Acids; Glioma; Positron-Emission Tomography; Magnetic Resonance Imaging; Biological Transport
PubMed: 37516762
DOI: 10.1038/s41467-023-39731-8 -
Journal of Translational Medicine Dec 2023Glioblastoma (GBM) comprises 45.6% of all primary malignant brain cancers and is one of the most common and aggressive intracranial tumors in adults. Intratumoral... (Review)
Review
Glioblastoma (GBM) comprises 45.6% of all primary malignant brain cancers and is one of the most common and aggressive intracranial tumors in adults. Intratumoral heterogeneity with a wide range of proteomic, genetic, and epigenetic dysregulation contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. To date, numerous clinical trials have been developed to target the proteome and epigenome of high-grade gliomas with promising results. However, studying RNA modifications, or RNA epitranscriptomics, is a new frontier within neuro-oncology. RNA epitranscriptomics was discovered in the 1970s, but in the last decade, the extent of modification of mRNA and various non-coding RNAs has emerged and been implicated in transposable element activation and many other oncogenic processes within the tumor microenvironment. This review provides background information and discusses the therapeutic potential of agents modulating epitranscriptomics in high-grade gliomas. A particular emphasis will be placed on how combination therapies that include immune agents targeting hERV-mediated viral mimicry could improve the treatment of GBM.
Topics: Adult; Humans; Endogenous Retroviruses; Tumor Microenvironment; Proteomics; Glioma; Glioblastoma; Brain Neoplasms; RNA, Messenger
PubMed: 38071304
DOI: 10.1186/s12967-023-04725-z -
Aging Aug 2023Glioma is a general neurological tumor and circular RNAs (circRNAs) have been implicated in glioma development. However, the underlying mechanisms and circRNA biological...
Glioma is a general neurological tumor and circular RNAs (circRNAs) have been implicated in glioma development. However, the underlying mechanisms and circRNA biological functions responsible for the regulation of glioma progression remain unknown. In this study, we employ next-generation sequencing (NGS) to investigate altered circRNA expression in glioma tissues. Regulatory mechanisms were studied using luciferase reporter analyses, transwell migration, CCK8, and EdU analysis. Tumorigenesis and metastasis assays were utilized to determine the function of hsa_circ_0010889 in glioma. Our results showed that hsa_circ_0010889 expression increased in glioma cell lines and tissues, indicating that hsa_circ_0010889 may be involved in glioma progression. Downregulation of hsa_circ_0010889 inhibited glioma invasion and proliferation in both and experiments and luciferase report assays found that miR-590-5p and SATB1 were downstream targets for hsa_circ_0010889. SATB1 overexpression or miR-590-5p inhibition reversed glioma cells proliferation and migration post-silencing of hsa_circ_0010889. Taken together, our study demonstrates that hsa_circ_0010889 downregulation inhibits glioma progression through the miR-590-5p/SATB1 axis.
Topics: Humans; MicroRNAs; RNA, Circular; Down-Regulation; Matrix Attachment Region Binding Proteins; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Glioma; Transcription Factors; Cell Proliferation
PubMed: 37540226
DOI: 10.18632/aging.204907 -
Current Neurology and Neuroscience... Feb 2024The response assessment in Neuro-Oncology (RANO) criteria and its versions were developed by expert opinion consensus to standardize response evaluation in glioma... (Review)
Review
PURPOSE OF REVIEW
The response assessment in Neuro-Oncology (RANO) criteria and its versions were developed by expert opinion consensus to standardize response evaluation in glioma clinical trials. New patient-based data informed the development of updated response assessment criteria, RANO 2.0.
RECENT FINDINGS
In a recent study of patients with glioblastoma, the post-radiation brain MRI was a superior baseline MRI compared to the pretreatment MRI, and confirmation scans were only beneficial within the first 12 weeks of completion of radiation in newly diagnosed disease. Nonenhancing disease evaluation did not improve the correlation between progression-free survival and overall survival in newly diagnosed and recurrent settings. RANO 2.0 recommends a single common response criteria for high- and low-grade gliomas, regardless of the treatment modality being evaluated. It also provides guidance on the evaluation of nonenhancing tumors and tumors with both enhancing and nonenhancing components.
Topics: Humans; Brain Neoplasms; Glioma; Magnetic Resonance Imaging; Glioblastoma; Neuroimaging
PubMed: 38170429
DOI: 10.1007/s11910-023-01329-4 -
Genes & Genomics Sep 2023Glioma is the most common and devastating form of malignant brain tumor, with a poor prognosis. Extracellular matrix (ECM) organization is a crucial determinant of...
BACKGROUND
Glioma is the most common and devastating form of malignant brain tumor, with a poor prognosis. Extracellular matrix (ECM) organization is a crucial determinant of glioma invasion and progression. However, the clinical significance of ECM organization in glioma patients remains unclear.
OBJECTIVE
To evaluate the prognostic value of ECM organization-related genes in glioma patients and identify potential therapeutic targets.
METHODS
Bulk RNA-sequencing and corresponding clinical data for patients with glioma were downloaded from TCGA and GEO databases. Differentially expressed ECM organization genes were identified, and an ECM organization-related gene prognostic model was then generated. Furthermore, the prognostic model has validated in the Chinese Glioma Genome Atlas (CGGA) dataset. The role of TIMP1 in glioma cells by using various functional assays revealed their underlying mechanism in vitro.
RESULTS
We identified and validated a nine-gene signature (TIMP1, SERPINE1, PTX3, POSTN, PLOD3, PDPN, LOXL1, ITGA2, and COL8A1) related to ECM organization as a robust prognostic biomarker for glioma. Time-dependent ROC curve analysis confirmed the specificity and sensitivity of the signature. The signature was closely related to an immunosuppressive phenotype, and its combination with immune checkpoints served as a good predictor for patients' clinical outcomes. Notably, single-cell RNA sequencing analysis revealed high expression of TIMP1 in astrocytes and oligodendrocyte progenitor cells in glioma patients. Last, we show that TIMP1 regulates glioma cell growth and invasion via the AKT/GSK3β signaling pathway.
CONCLUSION
This study provides promising insights into predicting glioma prognosis and identifying a potential therapeutic target in TIMP1.
Topics: Humans; Biomarkers; Genes, Regulator; Glioma; Prognosis; Extracellular Matrix; Tissue Inhibitor of Metalloproteinase-1
PubMed: 37301776
DOI: 10.1007/s13258-023-01413-6 -
BMC Cancer Jan 2024Glioblastoma is the most frequent and a particularly malignant primary brain tumor with no efficacy-proven standard therapy for recurrence. It has recently been... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Glioblastoma is the most frequent and a particularly malignant primary brain tumor with no efficacy-proven standard therapy for recurrence. It has recently been discovered that excitatory synapses of the AMPA-receptor subtype form between non-malignant brain neurons and tumor cells. This neuron-tumor network connectivity contributed to glioma progression and could be efficiently targeted with the EMA/FDA approved antiepileptic AMPA receptor inhibitor perampanel in preclinical studies. The PerSurge trial was designed to test the clinical potential of perampanel to reduce tumor cell network connectivity and tumor growth with an extended window-of-opportunity concept.
METHODS
PerSurge is a phase IIa clinical and translational treatment study around surgical resection of progressive or recurrent glioblastoma. In this multicenter, 2-arm parallel-group, double-blind superiority trial, patients are 1:1 randomized to either receive placebo or perampanel (n = 66 in total). It consists of a treatment and observation period of 60 days per patient, starting 30 days before a planned surgical resection, which itself is not part of the study interventions. Only patients with an expected safe waiting interval are included, and a safety MRI is performed. Tumor cell network connectivity from resected tumor tissue on single cell transcriptome level as well as AI-based assessment of tumor growth dynamics in T2/FLAIR MRI scans before resection will be analyzed as the co-primary endpoints. Secondary endpoints will include further imaging parameters such as pre- and postsurgical contrast enhanced MRI scans, postsurgical T2/FLAIR MRI scans, quality of life, cognitive testing, overall and progression-free survival as well as frequency of epileptic seizures. Further translational research will focus on additional biological aspects of neuron-tumor connectivity.
DISCUSSION
This trial is set up to assess first indications of clinical efficacy and tolerability of perampanel in recurrent glioblastoma, a repurposed drug which inhibits neuron-glioma synapses and thereby glioblastoma growth in preclinical models. If perampanel proved to be successful in the clinical setting, it would provide the first evidence that interference with neuron-cancer interactions may indeed lead to a benefit for patients, which would lay the foundation for a larger confirmatory trial in the future.
TRIAL REGISTRATION
EU-CT number: 2023-503938-52-00 30.11.2023.
Topics: Humans; Glioblastoma; Quality of Life; Neoplasm Recurrence, Local; Seizures; Nitriles; Pyridones; Treatment Outcome; Double-Blind Method
PubMed: 38279087
DOI: 10.1186/s12885-024-11846-1 -
Journal of Neuro-oncology Jan 2024Malignant gliomas are a therapeutic challenge and remain nearly uniformly fatal. While new targeted chemotherapeutic agentsagainst malignant glioma have been... (Review)
Review
BACKGROUND
Malignant gliomas are a therapeutic challenge and remain nearly uniformly fatal. While new targeted chemotherapeutic agentsagainst malignant glioma have been developed in vitro, these putative therapeutics have not been translated into successful clinical treatments. The lack of clinical effectiveness can be the result of ineffective biologic strategies, heterogeneous tumor targets and/or the result of poortherapeutic distribution to malignant glioma cells using conventional nervous system delivery modalities (intravascular, cerebrospinal fluid and/orpolymer implantation), and/or ineffective biologic strategies.
METHODS
The authors performed a review of the literature for the terms "convection enhanced delivery", "glioblastoma", and "glioma". Selectclinical trials were summarized based on their various biological mechanisms and technological innovation, focusing on more recently publisheddata when possible.
RESULTS
We describe the properties, features and landmark clinical trials associated with convection-enhanced delivery for malignant gliomas.We also discuss future trends that will be vital to CED innovation and improvement.
CONCLUSION
Efficacy of CED for malignant glioma to date has been mixed, but improvements in technology and therapeutic agents arepromising.
Topics: Humans; Convection; Drug Delivery Systems; Brain Neoplasms; Glioma; Biological Products; Antineoplastic Agents
PubMed: 38261143
DOI: 10.1007/s11060-023-04552-8 -
Journal of Mathematical Biology Nov 2023Malignant gliomas are notoriously invasive, a major impediment against their successful treatment. This invasive growth has motivated the use of predictive partial...
Malignant gliomas are notoriously invasive, a major impediment against their successful treatment. This invasive growth has motivated the use of predictive partial differential equation models, formulated at varying levels of detail, and including (i) "proliferation-infiltration" models, (ii) "go-or-grow" models, and (iii) anisotropic diffusion models. Often, these models use macroscopic observations of a diffuse tumour interface to motivate a phenomenological description of invasion, rather than performing a detailed and mechanistic modelling of glioma cell invasion processes. Here we close this gap. Based on experiments that support an important role played by long cellular protrusions, termed tumour microtubes, we formulate a new model for microtube-driven glioma invasion. In particular, we model a population of tumour cells that extend tissue-infiltrating microtubes. Mitosis leads to new nuclei that migrate along the microtubes and settle elsewhere. A combination of steady state analysis and numerical simulation is employed to show that the model can predict an expanding tumour, with travelling wave solutions led by microtube dynamics. A sequence of scaling arguments allows us reduce the detailed model into simpler formulations, including models falling into each of the general classes (i), (ii), and (iii) above. This analysis allows us to clearly identify the assumptions under which these various models can be a posteriori justified in the context of microtube-driven glioma invasion. Numerical simulations are used to compare the various model classes and we discuss their advantages and disadvantages.
Topics: Humans; Glioma; Anisotropy; Computer Simulation; Diffusion; Travel
PubMed: 38015257
DOI: 10.1007/s00285-023-02025-0 -
International Journal of Molecular... Nov 2023Gliomas are aggressive malignant brain tumors, with poor prognosis despite available therapies, raising the necessity for finding new compounds with therapeutic action.... (Meta-Analysis)
Meta-Analysis Review
Gliomas are aggressive malignant brain tumors, with poor prognosis despite available therapies, raising the necessity for finding new compounds with therapeutic action. Numerous preclinical investigations evaluating resveratrol's anti-tumor impact in animal models of glioma have been reported; however, the variety of experimental circumstances and results have prevented conclusive findings about resveratrol's effectiveness. Several databases were searched during May 2023, ten publications were identified, satisfying the inclusion criteria, that assess the effects of resveratrol in murine glioma-bearing xenografts. To determine the efficacy of resveratrol, tumor volume and animal counts were retrieved, and the data were then subjected to a random effects meta-analysis. The influence of different experimental conditions and publication bias on resveratrol efficacy were evaluated. Comparing treated to untreated groups, resveratrol administration decreased the tumor volume. Overall, the effect's weighted standardized difference in means was -2.046 (95%CI: -3.156 to -0.936; -value < 0.001). The efficacy of the treatment was observed for animals inoculated with both human glioblastoma or rat glioma cells and for different modes of resveratrol administration. The combined administration of resveratrol and temozolomide was more effective than temozolomide alone. Reducing publication bias did not change the effectiveness of resveratrol treatment. The findings suggest that resveratrol slows the development of tumors in animal glioma models.
Topics: Humans; Rats; Mice; Animals; Temozolomide; Resveratrol; Cell Line, Tumor; Glioma; Brain Neoplasms; Models, Animal
PubMed: 38068922
DOI: 10.3390/ijms242316597