Search Results (98)

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with a dismal prognosis despite advances in multimodal treatment. Conventional therapies fail to achieve durable responses due to GBM’s molecular heterogeneity and capacity to evade therapeutic pressures. Epigenetic alterations have emerged as critical contributors to GBM pathobiology, including aberrant DNA methylation, histone modifications, and non-coding RNA (ncRNA) dysregulation. These mechanisms drive oncogenesis, therapy resistance, and immune evasion. This scoping review evaluates the current state of knowledge on epigenetic modifications in GBM, synthesizing findings from original articles and preclinical and clinical trials published over the last decade. Particular attention is given to MGMT promoter hypermethylation status as a biomarker for temozolomide (TMZ) sensitivity, histone deacetylation and methylation as modulators of chromatin structure, and microRNAs as regulators of pathways such as apoptosis and angiogenesis. Therapeutically, epigenetic drugs, like DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis), appear as promising approaches in preclinical models and early trials. Emerging RNA-based therapies targeting dysregulated ncRNAs represent a novel approach to reprogram the tumor epigenome. Combination therapies, pairing epigenetic agents with immune checkpoint inhibitors or chemotherapy, are explored for their potential to enhance treatment response. Despite these advancements, challenges such as tumor heterogeneity, the blood–brain barrier (BBB), and off-target effects remain significant. Future directions emphasize integrative omics approaches to identify patient-specific targets and refine therapies. This article thus highlights the potential of epigenetics in reshaping GBM treatment paradigms. Full article

Glioblastoma (GBM) is an exceedingly aggressive primary brain tumor defined by rapid growth, extensive infiltration, and resistance to standard therapies. A central factor driving these malignancies is the subpopulation of glioblastoma stem cells (GSCs), which possess self-renewal capacity, multipotency, and the ability to regenerate tumor heterogeneity. GSCs contribute to key hallmarks of GBM pathobiology, including relentless progression, resistance to chemotherapy and radiotherapy, and inevitable recurrence. GSCs exhibit distinct molecular signatures, enhanced DNA repair, and metabolic adaptations that protect them against conventional treatments. Moreover, they reside within specialized niches—such as perivascular or hypoxic microenvironments—that sustain stemness, promote immunosuppression, and facilitate angiogenesis. Recent discoveries highlight signaling pathways like Notch, Wnt/β-catenin, Hedgehog, STAT3-PARN, and factors such as TFPI2 and HML-2 as critical regulators of GSC maintenance, plasticity, and immune evasion. These findings underscore the complexity of GSC biology and their pivotal role in driving GBM heterogeneity and therapeutic failure. Emerging therapeutic strategies aim to target GSCs through multiple avenues, including surface markers, immunotherapeutics (e.g., CAR T cells), metabolic vulnerabilities, and combination regimens. Advances in patient-derived organoids, single-cell omics, and 3D co-culture models enable more accurate representation of the tumor ecosystem and personalized therapeutic approaches. Ultimately, improved understanding of GSC-specific targets and the tumor microenvironment promises more effective interventions, paving the way toward better clinical outcomes for GBM patients. Full article

Glioblastoma (GBM) is an aggressive brain tumor characterized by molecular complexity and resistance to conventional treatments, including surgery, radiation, and chemotherapy. Despite these challenges, advancements in receptor tyrosine kinase (RTK) research, combined with multi-omics approaches, hold promise for improving patient outcomes and survivability. RTKs are central to GBM progression, influencing cell proliferation, survival, and angiogenesis. However, the complexity of RTK signaling necessitates a broader, integrative perspective, which has been enabled by the emergence of -omics sciences. Multi-omics technologies—including genomics, transcriptomics, proteomics, and metabolomics—offer unprecedented insights into the molecular landscape of GBM and its RTK-driven pathways. Genomic studies have revealed mutations and amplifications in RTK-related genes, while transcriptomics has uncovered alterations in gene expression patterns, providing a clearer picture of how these aberrations drive tumor behavior. Proteomics has further delineated changes in protein expression and post-translational modifications linked to RTK signaling, highlighting novel therapeutic targets. Metabolomics complements these findings by identifying RTK-associated metabolic reprogramming, such as shifts in glycolysis and lipid metabolism, which sustain tumor growth and therapy resistance. The integration of these multi-omics layers enables a comprehensive understanding of RTK biology in GBM. For example, studies have linked metabolic alterations with RTK activity, offering new biomarkers for tumor classification and therapeutic targeting. Additionally, single-cell transcriptomics has unveiled intratumoral heterogeneity, a critical factor in therapy resistance. This article highlights the transformative potential of multi-omics in unraveling the complexity of RTK signaling in GBM. By combining these approaches, researchers are paving the way for precision medicine strategies that may significantly enhance diagnostic accuracy and treatment efficacy, providing new hope for patients facing this devastating disease. Full article

Glioblastoma (GBM) is a highly aggressive and malignant brain tumor, characterized by hypoxia in its microenvironment, which drives its growth and resistance to treatments. Hypoxia-inducible factor 1 (HIF-1) plays a central role in GBM progression by regulating cellular adaptation to low oxygen availability, promoting processes such as angiogenesis and cell invasion. However, studying and modeling GBM under hypoxic conditions is complex, especially due to the limitations of animal models. In this study, we developed a glioma spheroid model using an alginate–gelatin hydrogel scaffold, which enabled the simulation of hypoxic conditions within the tumor. The scaffold-based model demonstrated high reproducibility, facilitating the analysis of HIF-1α expression, a key protein in the hypoxic response of GBM. Furthermore, cell viability, the microstructural features of the encapsulated spheroids, and the water absorption rate of the hydrogel were assessed. Our findings validate the three-dimensional (3D) glioblastoma spheroids model as a valuable platform for studying hypoxia in GBM and evaluating new therapies. This approach could offer a more accessible and specific alternative for studying the tumor microenvironment and therapeutic resistance in GBM. Full article

Growth differentiation factor 6 (GDF6), a member of the TGF-β superfamily, plays multifaceted roles in tumorigenesis, yet its molecular mechanisms and cancer-type-specific regulatory networks remain poorly defined. This study investigates GDF6’s context-dependent functions through pan-cancer multi-omics integration and functional validation. Transcriptomic data from TCGA (33 cancers, n = 10,535) and GTEx were analyzed to assess GDF6 dysregulation. Co-expression networks, pathway enrichment (KEGG/GO), and epigenetic interactions (m6A, m5C, m1A) were explored. Functional assays included siRNA knockdown, wound healing, and validation in immunotherapy cohorts. GDF6 exhibited bidirectional expression patterns, with downregulation in 23 cancers (e.g., GBM, BRCA) and upregulation in 7 malignancies (e.g., KIRC, PAAD). Mechanistically, GDF6 activated the PI3K-Akt/VEGF pathways, thereby promoting angiogenesis and metastasis. It modulated epigenetic regulation through interactions with m6A readers and erasers. Additionally, GDF6 reshaped the immune microenvironment by recruiting myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts. Notably, GDF6’s dual role extended to immunotherapy: it suppressed anti-PD1 efficacy but enhanced anti-PD-L1 sensitivity, linked to differential MHC-II and hypoxia-response regulation. This study deciphers GDF6’s context-dependent molecular networks, revealing its dual roles in metastasis and immune evasion. These findings highlight GDF6 as a central node in TGF-β-mediated oncogenic signaling and a potential therapeutic target for precision intervention. Full article

Glioblastomas (GBMs), among the most aggressive and resilient brain tumors, characteristically exhibit high angiogenic potential, leading to the formation of a dense yet aberrant vasculature, both morphologically and functionally. With these premises, numerous expectations were initially placed on anti-angiogenic therapies, soon dashed by their limited efficacy in concretely improving patient outcomes. Neovascularization in GBM soon emerged as a complex, dynamic, and heterogeneous process, hard to manage with the classical standard of care. Growing evidence has revealed the existence of numerous non-canonical strategies of angiogenesis, variously exploited by GBM to meet its ever-increasing metabolic demand and differently involved in tumor progression, recurrence, and escape from treatments. In this review, we provide an accurate description of each neovascularization mode encountered in GBM tumors to date, highlighting the molecular players and signaling cascades primarily involved. We also detail the key architectural and functional aspects characteristic of the GBM vascular compartment because of an intricate crosstalk between the different angiogenic networks. Additionally, we explore the repertoire of emerging therapies against GBM that are currently under study, concluding with a question: faced with such a challenging scenario, could combined therapies, tailored to the patient’s genetic signatures, represent an effective game changer? Full article

Glioblastoma, the most common primary malignant brain tumor in adults, carries a poor prognosis, with a median survival of just 15 months, significantly impacting patients’ quality of life. The aggressive growth of these highly vascularized tumors relies heavily on angiogenesis, driven primarily by vascular endothelial growth factor-A. Therefore, VEGF signaling pathway has become a prime therapeutic target in GBM treatment over the past decade. While anti-angiogenic treatment showed promise, agents like bevacizumab have ultimately failed to improve overall survival. This highlights the presence of compensatory angiogenic mechanisms that bypass VEGF inhibition, necessitating further investigation into resistance mechanisms and the development of more effective therapeutic strategies. This review examined the current landscape of anti-angiogenic agents for GBM, analyzed the mechanisms driving resistance to these therapies, and explored potential strategies for enhancing their effectiveness. Full article

Despite multimodal therapies, the treatment of glioblastoma remains challenging. In addition to the very complex mechanisms of cancer cells, including specialized phenotypes that enable them to proliferate, invade tissues, and evade immunosurveillance, they exhibit a pronounced resistance to chemo- and radiotherapy. More advanced tumors create a hypoxic environment that supports their proliferation and survival, while robust angiogenesis ensures a constant supply of nutrients. In GBM, these structures are very pronounced and contribute to the creation and maintenance of a highly immunosuppressive microenvironment that promotes tumor growth and immune escape. In addition, the high accumulation of immunosuppressive tumor-infiltrating leukocytes and other cells, the pronounced expression of immune checkpoint molecules, and the low mutational burden, i.e., the low number of neoantigens, are hallmarks of GBM and contribute to the challenge of therapeutic approaches. Here, we review a number of mechanisms that GBM exploits to support tumor growth and potential treatments. These include new chemotherapeutics, tumor treating fields, and small molecules, including compounds targeting angiogenesis or blockers of tyrosine kinases that inhibit tumor cell proliferation and survival. In addition, we focus on immunotherapies such as immune checkpoint blockade or cell therapies, in particular vaccination with dendritic cells and CAR-T cells, which can either kill GBM cells directly or bypass immunosuppression by modulating the tumor microenvironment or boosting the patient’s own immune response. Full article

Background: Angiogenesis is a key factor necessary for tissue growth but becomes often dysregulated in cancer, driving tumour progression. Glioblastoma multiforme (GBM) induces abnormal vascular remodelling via Hypoxia-activated VEGF, FGF and PDGF. Despite increased vascularization, hypoxia persists, worsening malignancy. Additionally, emerging evidence highlights extracellular vesicles (EVs) as key mediators of angiogenesis as conduits transferring bioactive cargo modulating cellular signaling. By promoting neovascularization, EVs can facilitate tumour growth, hinder drug delivery, and contribute to therapeutic resistance, making them potential therapeutic targets. Objective: This study explores the role of GBM-derived EVs in promoting aberrant angiogenesis by modulating VEGF and MMP signalling and correlating them with EV biogenesis to better understand tumour vascularisation and therapeutic paucities. Methods: This study investigates the role of GBM-derived EVs in angiogenesis dysregulation, via in silico and in vitro approaches, making use of available databases to study the enrichment profiles of key angiogenic drivers enriched in GBM and EVs followed by validation studies using 2D cell culture of HUVEC and U87MG cells on treatment with EV inhibitor. Results: We observed that GBM-derived EVs can be key collaborators of promoting angiogenesis by upregulating key pro-angiogenic genes (VEGFA, NRP1, MMP9) and EV biogenesis markers (CD9, CD81, TSG101), facilitating endothelial cell migration and vascular remodelling. Functional assays further confirmed that EVs act as vectors for pro-angiogenic signals, while their inhibition with GW4869 significantly reduced angiogenic activity, highlighting their role in tumour vascularization. Conclusions: Targeting EV-mediated angiogenesis presents a promising therapeutic strategy for GBM, warranting further validation in preclinical and clinical models. Full article

We explored the rationale for treating glioblastoma (GBM) with regorafenib. In 103 newly diagnosed GBM patients, we assessed mutations, copy number variants (CNVs), fusions, and overexpression in 46 genes encoding protein kinases (PKs) potentially targeted by regorafenib or its metabolites and performed a functional enrichment analysis to assess their implications in angiogenesis. We analyzed regorafenib’s binding inhibitory activity and target affinity for these 46 PKs and focused on a subset of 18 genes inhibited by regorafenib at clinically achievable concentrations and on 19 genes involved in angiogenesis. Putative oncogenic alterations were defined as oncogenic/likely oncogenic mutations, oncogenic fusions, CNVs > 5, and/or gene overexpression. Regorafenib did not target all 46 PKs. For the 46-gene set, 40 genes (86.9%) and 73 patients (70.8%) harbored at least one alteration in genes encoding targetable PKs, but putative oncogenic alterations were present in only 34 patients (33%). In the 18-gene set, 18 genes (100%) and 48 patients (46.6%) harbored alterations, but putative oncogenic alterations were detected in only 26 patients (25.2%). Thirty patients (29.1%) had oncogenic alterations in the 18-gene set and/or in angiogenesis-related genes. Around 33% of patients had oncogenic alterations in any of the 46 potential targets. Additionally, the suboptimal dosing of regorafenib, due to its poor penetration of the blood–brain barrier, may reduce the likelihood of effectively targeting certain PKs. Future use of multi-target drugs must be guided by a thorough understanding of target presence, effective inhibition, and the drug’s ability to reach brain tumors at adequate concentrations. Full article

Glioblastoma (GBM) is the most common and lethal intracranial tumor in adults. Despite advances in the understanding of the molecular events responsible for disease development and progression, survival rates and mortality statistics for GBM patients have been virtually unchanged for decades and chemotherapeutic drugs used to treat GBM are limited. Arsenic derivatives, known as highly effective anticancer agents for leukemia therapy, has been demonstrated to exhibit cytocidal effects toward GBM cells by inducing cell death, cell cycle arrest, inhibition of migration/invasion, and angiogenesis. Differentiation induction of glioma stem-like cells (GSCs) and inhibition of neurosphere formation have also been attributed to the cytotoxicity of arsenic derivatives. Intriguingly, similar cytotoxic effects against GBM cells and GSCs have also been observed in natural agents such as anthocyanidins, tetrandrine, and bufadienolides. In the current review, we highlight the available data on the molecular mechanisms underlying the multifaceted anticancer activity of arsenic compounds and natural agents against cancer cells, especially focusing on GBM cells and GCSs. We also outline possible strategies for developing anticancer therapy by combining natural agents and arsenic compounds, as well as temozolomide, an alkylating agent used to treat GBM, in terms of improvement of chemotherapy sensitivity and minimization of side effects. Full article

Odorant receptors (ORs), which constitute approximately 50% of all human G protein-coupled receptors, are increasingly recognized for their diverse roles beyond odor perception, including functions in various pathological conditions like brain diseases and cancers. However, the roles of ORs in glioblastoma (GBM), the most aggressive primary brain tumor with a median survival of only 15 months, remain largely unexplored. Here, we performed an integrated transcriptomic analysis combining The Cancer Genome Atlas RNA-seq and single-cell RNA sequencing data from GBM patients to uncover cell-type-specific roles of ORs within the tumor and its microenvironment. Our findings reveal that ORs display distinct expression patterns, with OR51E1 enriched in pericytes linked to vascular remodeling and angiogenesis, OR2B11 associated with tumor-associated macrophages supporting immunosuppressive phenotypes, and OR2L13 correlated with synaptic activity in recurrent tumors, potentially mediating treatment-induced neuronal adaptations. These results highlight ORs as potential therapeutic targets, offering new insights into their regulatory roles in GBM progression, immune modulation, and treatment resistance. Full article

Background: Targeted therapies have been largely ineffective against glioblastoma (GBM) owing to the tumor’s heterogeneity and intrinsic and adaptive treatment resistance. Targeting multiple pro-survival pathways simultaneously may overcome these limitations and yield effective treatments. Heat shock protein 90 (HSP90), an essential component of the epichaperome complex, is critical for the proper folding and activation of several pro-survival oncogenic proteins that drive GBM biology. Methods: Using a panel of biochemical and biological assays, we assessed the expression of HSP90 and its downstream targets and the effects of PU-H71, a highly specific and potent HSP90 inhibitor, on target modulation, downstream biochemical alterations, cell cycle progression, proliferation, migration, and apoptosis in patient-derived glioma stem-like cells (GSCs) with molecular profiles characteristic of GBM, as well as commercial glioma cell lines and normal human astrocytes (NHAs). Results: HSP90 inhibition by PU-H71 in GSCs significantly reduced cell proliferation, colony formation, wound healing, migration, and angiogenesis. In glioma cells, but not NHAs, potent PU-H71-mediated HSP90 inhibition resulted in the downregulation of pro-survival client proteins such as EGFR, MAPK, AKT, and S6. This reduction in pro-survival signals increased glioma cells’ sensitivity to temozolomide, a monofunctional alkylator, and the combination of PU-H71 and temozolomide had greater anticancer efficacy than either agent alone. Conclusions: These results confirm that HSP90 is a strong pro-survival factor in molecularly heterogeneous gliomas and suggest that epichaperome inhibition with HSP90 inhibitors warrants further investigation for the treatment of gliomas. Full article

Glioblastoma Multiforme (GBM) is the most aggressive primary tumor of the Central Nervous System (CNS) with a low survival rate. The malignancy of GBM is sustained by a bidirectional crosstalk between tumor cells and the Tumor Microenvironment (TME). This mechanism of intercellular communication is mediated, at least in part, by the release of exosomes. Glioma-Derived Exosomes (GDEs) work, indeed, as potent signaling particles promoting the progression of brain tumors by inducing tumor proliferation, invasion, migration, angiogenesis and resistance to chemotherapy or radiation. Given their nanoscale size, exosomes can cross the blood–brain barrier (BBB), thus becoming not only a promising biomarker to predict diagnosis and prognosis but also a therapeutic target to treat GBM. In this review, we describe the structural and functional characteristics of exosomes and their involvement in GBM development, diagnosis, prognosis and treatment. In addition, we discuss how exosomes can be modified to be used as a therapeutic target/drug delivery system for clinical applications. Full article

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years in the median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic treatments) or destroying formed tumor vasculature (vascular disrupting agents) show promise. This study summarizes the existing knowledge regarding the processes by which glioblastoma (GBM) tumors acquire resistance to antiangiogenic treatments. The discussion encompasses the activation of redundant proangiogenic pathways, heightened tumor cell invasion and metastasis, resistance induced by hypoxia, creation of vascular mimicry channels, and regulation of the tumor immune microenvironment. Subsequently, we explore potential strategies to overcome this resistance, such as combining antiangiogenic therapies with other treatment methods, personalizing treatments for each patient, focusing on new therapeutic targets, incorporating immunotherapy, and utilizing drug delivery systems based on nanoparticles. Additionally, we would like to discuss the limitations of existing methods and potential future directions to enhance the beneficial effects of antiangiogenic treatments for patients with GBM. Therefore, this review aims to enhance the research outcome for GBM and provide a more promising opportunity by thoroughly exploring the mechanisms of resistance and investigating novel therapeutic strategies. Full article