Understanding Glioblastoma Signaling, Heterogeneity, Invasiveness, and Drug Delivery Barriers

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 14256 - 14256

Published: Sept. 19, 2023

The most prevalent and aggressive type of brain cancer, namely, glioblastoma (GBM), is characterized by intra- inter-tumor heterogeneity strong spreading capacity, which makes treatment ineffective. A true therapeutic answer still in its infancy despite various studies that have made significant progress toward understanding the mechanisms behind GBM recurrence resistance. primary causes are attributed to diffusive nature; therefore, monitoring tumor’s may offer a set targets could improve clinical management prevent tumor relapse. Additionally, blood–brain barrier (BBB)-related poor drug delivery prevents effective concentrations within discussed. With emphasis on signaling heterogeneity, infiltration, computational modeling GBM, this review covers typical difficulties factors contributing resistance development discusses potential approaches.

Language: Английский

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A Custom DNA-Based NGS Panel for the Molecular Characterization of Patients With Diffuse Gliomas: Diagnostic and Therapeutic Applications

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: March 17, 2022

The management of patients with Central Nervous System (CNS) malignancies relies on the appropriate classification these tumors. Recently, World Health Organization (WHO) has published new criteria underlining importance an accurate molecular characterization CNS malignancies, in order to integrate information generated by histology. Next generation sequencing (NGS) allows single step multiple genes, generating a comprehensive and specific mutational profile tumor tissue. We developed custom NGS-based multi-gene panel (Glio-DNA panel) for identification correct glioma oncotype detection its essential aberrations. Specifically, Glio-DNA targets genetic chromosomal alterations involving ATRX chromatin remodeler (ATRX), cyclin dependent kinase inhibitor 2A (CDKN2A), isocitrate dehydrogenase (NADP+) 1 (IDH1) telomerase reverse transcriptase (TERT) promoter while also recognizing co-deletion 1p/19q, loss chromosome 10 gain 7. Furthermore, evaluates methylation level O-6-methylguanine-DNA methyltransferase (MGMT) gene that predicts temozolomide efficacy. As knowledge landscape each is mandatory define personalized therapeutic strategy, identifies "druggable" or "actionable" genes. To test specificity our panel, we used two reference mutated DNAs verifying NGS allele frequency measurement was highly sensitive. Subsequently, performed comparative analysis between conventional techniques - such as immunohistochemistry fluorescence situ hybridization 60 diffuse samples had been previously characterized. comparison testing showed high concordance, suggesting may replace time-consuming tests. Finally, different actionable genes matches potential targeted therapies available through clinical trials. In conclusion, demonstrates efficacy simultaneously detecting useful diagnosis, prognosis treatment adult glioma.

Language: Английский

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Alterations in Molecular Profiles Affecting Glioblastoma Resistance to Radiochemotherapy: Where Does the Good Go?

Cancers, Journal Year: 2022, Volume and Issue: 14(10), P. 2416 - 2416

Published: May 13, 2022

Glioblastoma multiforme (GBM) is a brain tumor characterized by high heterogeneity, diffuse infiltration, aggressiveness, and formation of recurrences. Patients with this kind suffer from cognitive, emotional, behavioral problems, beyond exhibiting dismal survival rates. Current treatment comprises surgery, radiotherapy, chemotherapy the methylating agent, temozolomide (TMZ). GBMs harbor intrinsic mutations involving major pathways that elicit cells to evade cell death, adapt genotoxic stress, regrow. Ionizing radiation TMZ induce, for most part, DNA damage repair, autophagy, stemness, senescence, whereas only small fraction GBM undergoes treatment-induced apoptosis. Particularly upon exposure, undergo cellular senescence. Increased repair attenuates agent-induced cytotoxicity; autophagy functions as pro-survival mechanism, protecting facilitating have energy grow. Stemness grants capacity repopulate tumor, senescence triggers an inflammatory microenvironment favorable transformation. Here, we highlight mutational background its interference response standard radiochemotherapy. We discuss relevant recent evidence obtained studies revealing molecular mechanisms lead these be resistant indicate some future perspectives on combating incurable tumor.

Language: Английский

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Every problem is embedded in a greater whole

Journal of Evaluation in Clinical Practice, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 23, 2024

Peter Drucker pointed out an important distinction between 'doing things right' and the right thing', which recognised that all problems are embedded in a context thus can only be understood within their unique contextual setting. Contemporary research practices clinical medicine often regards factors as potential confounders will bias effect estimates must avoided. However rigorous, devoid of ultimately deprives users understanding support make transferable to policy decisions or managing care individual patients-it stands way thing' 'real life' settings. Appreciating greater means one should not ignore interconnected interdependent systemic nature, is, every variable is simultaneously dependent independent. This reason for cascading effects feedback loops witnessed disease progression efforts. We discuss need researchers a-priori consider question well structural relationships variables under investigation, turn provides basis choosing most appropriate design. have moral imperative first 'do thing'-ask questions address needs our patients, then it right'-choose best method answer this contextually framed need. Only efforts meaningful lasting impacts on patient care.

Language: Английский

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A receptor-mediated landscape of druggable and targeted nanomaterials for gliomas

Materials Today Bio, Journal Year: 2023, Volume and Issue: 20, P. 100671 - 100671

Published: May 19, 2023

Gliomas are the most common type of brain cancer, and among them, glioblastoma multiforme (GBM) is prevalent (about 60% cases) aggressive primary tumor. The treatment GBM a major challenge due to pathophysiological characteristics disease, such as presence blood-brain barrier (BBB), which prevents regulates passage substances from bloodstream parenchyma, making many chemotherapeutics currently available not able reach in therapeutic concentrations, accumulating non-target organs, causing considerable adverse effects for patient. In this scenario, nanocarriers emerge tools capable improving bioavailability chemotherapeutics, addition their biodistribution enhancing uptake cells. This possible its nanometric size surface modification strategies, can actively target elements overexpressed by cells (such transmembrane receptors) related development, drug resistance, poor prognosis. review, an overview frequently receptors approaches chemotherapeutic delivery active targeting using will be presented.

Language: Английский

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A Systematic Review of the Metabolism of High-Grade Gliomas: Current Targeted Therapies and Future Perspectives

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 724 - 724

Published: Jan. 5, 2024

High-grade glial tumors (HGGs) exhibit aggressive growth patterns and high recurrence rates. The prevailing treatment approach comprises radiation therapy (RT), chemotherapy (CMT), surgical resection. Despite the progress made in traditional treatments, outlook for patients with HGGs remains bleak. Tumor metabolism is emerging as a potential target glioma therapies, promising that harnesses to tumor cells. However, efficacy of therapies targeting unclear, compelling comprehensive review. This study aimed assess outcome present trials on HGG metabolism. A search PubMed, Ovid MEDLINE, EMBASE was conducted until November 2023. method used pertinent Medical Subject Heading (MeSH) terminologies keywords referring “high-grade gliomas”, “metabolism”, “target therapies”, “monoclonal antibodies”, “overall survival”, “progression-free survival”. review analyzed studies focused human subjects. These included both randomized controlled (RCTs) non-randomized (NRCTs). Out 284 articles identified, 23 met inclusion criteria were thoroughly analyzed. Phase II most numerous (62%). Targeted metabolic predominantly recurrent (67%). common targeted pathways vascular endothelial factor (VEGF, 43%), epidermal receptor (HER, 22%), platelet-derived (PDGF, 17%), mammalian rapamycin (mTOR, 17%). In 39% studies, subject combined CMT (22%), RT (4%), or (13%). median OS widely ranged from 4 26.3 months, while PFS 1.5 13 months. systematic literature offers thorough exploration state HGGs. multitude underscores intricate nature addressing aspects these tumors. existing challenges, findings provide valuable insights, guiding future research endeavors. results serve foundation refining strategies enhancing patient outcomes within complex landscape

Language: Английский

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Characterization of prevalent tyrosine kinase inhibitors and their challenges in glioblastoma treatment

Frontiers in Chemistry, Journal Year: 2024, Volume and Issue: 11

Published: Jan. 8, 2024

Glioblastoma multiforme (GBM) is a highly aggressive malignant primary tumor in the central nervous system. Despite extensive efforts radiotherapy, chemotherapy, and neurosurgery, there remains an inadequate level of improvement treatment outcomes. The development large-scale genomic proteomic analysis suggests that GBMs are characterized by transcriptional heterogeneity, which responsible for therapy resistance. Hence, knowledge about genetic epigenetic heterogeneity GBM crucial developing effective treatments this form brain cancer. Tyrosine kinases (TKs) can act as signal transducers, regulate important cellular processes like differentiation, proliferation, apoptosis metabolism. Therefore, TK inhibitors (TKIs) have been developed to specifically target these kinases. TKIs categorized into allosteric non-allosteric inhibitors. Irreversible covalent bonds, lead longer-lasting effects. However, also increase risk off-target effects toxicity. therapeutics through computer-aided drug design (CADD) bioinformatic techniques enhance potential improve patients’ survival rates. continued exploration targets expected even more specific future.

Language: Английский

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Glioblastoma Neurovascular Progenitor Orchestrates Tumor Cell Type Diversity

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 24, 2024

Abstract Glioblastoma (GBM) is the deadliest form of primary brain tumor with limited treatment options. Recent studies have profiled GBM heterogeneity, revealing numerous axes variation that explain molecular and spatial features tumor. Here, we seek to bridge descriptive characterization cell type heterogeneity functional role individual populations within Our lens leverages a gene program-centric meta-atlas published transcriptomic identify commonalities between diverse tumors types in order decipher mechanisms drive them. This approach led discovery tumor-derived stem population mixed vascular neural features, termed neurovascular progenitor (NVP). Following situ validation NVP cells patient samples, characterized their function vivo. Genetic depletion resulted altered composition, fewer cycling cells, extended survival, underscoring critical role. Clonal analysis human organoid transplantation system demonstrated has dual potency, generating both neuronal cells. Although comprise small fraction tumor, these clonal analyses they strongly contribute total number generate defined subset whole study represents paradigm by which type-specific interrogation can be used therapeutically targetable vulnerabilities GBM.

Language: Английский

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Association of tumor treating fields (TTFields) therapy with overall survival in newly diagnosed glioblastoma

Clinical & Translational Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Neurotransmitters: Potential Targets in Glioblastoma

Cancers, Journal Year: 2022, Volume and Issue: 14(16), P. 3970 - 3970

Published: Aug. 17, 2022

For decades, glioblastoma multiforme (GBM), a type of the most lethal brain tumor, has remained formidable challenge in terms its treatment. Recently, many novel discoveries have underlined regulatory roles neurotransmitters microenvironment both physiologically and pathologically. By targeting receptors synaptically or non-synaptically, activate multiple signaling pathways. Significantly, ligands acting on neurotransmitter shown great potential for inhibiting GBM growth development, requiring further research. Here, we provide an overview advances concerning role normal neural microenvironments, discuss targeted drugs used

Language: Английский

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