Search Results (608)

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, necessitating novel therapeutic approaches. Oncolytic treatments, particularly oncolytic viruses (OVs), have emerged as promising candidates by selectively infecting and lysing tumor cells while stimulating anti-tumor immunity. Various virus-based therapies are under investigation, including genetically engineered herpes simplex virus (HSV), adenovirus, poliovirus, reovirus, vaccinia virus, measles virus, and Newcastle disease virus, each exploiting unique tumor-selective mechanisms. While some, such as HSV-based therapies including G207 and Delytact^TM, have demonstrated clinical progress, significant challenges persist, including immune evasion, heterogeneity in patient response, and delivery barriers due to the blood–brain barrier. Moreover, combination strategies integrating OVs with immune checkpoint inhibitors, chemotherapy, and radiation are promising but require further clinical validation. Non-viral oncolytic approaches, such as tumor-targeting bacteria and synthetic peptides, remain underexplored. This review highlights current advancements while addressing critical gaps in the literature, including the need for optimized delivery methods, better biomarker-based patient stratification, and a deeper understanding of GBM’s immunosuppressive microenvironment. Future research should focus on enhancing OV specificity, engineering viruses to deliver therapeutic genes, and integrating OVs with precision medicine strategies. By identifying these gaps, this review provides a framework for advancing oncolytic therapies in GBM treatment. Full article

The incorporation of nucleoside analogs into DNA by polymerases, followed by their removal through base excision repair (BER), represents a promising strategy for cancer chemotherapy. In this study, we investigated the incorporation and cytotoxic effects of several nucleoside analogs—some of which are epigenetic reprogramming intermediates—in the U87 glioblastoma cell line. We found that two analogs, 5-hydroxymethyl-2′-deoxyuridine (5HmdU) and trifluorothymidine (TFT), are both cytotoxic and are efficiently incorporated into genomic DNA. In contrast, the 5-carboxy analogs—5-carboxy-2′-deoxyuridine (5CadU) and 5-carboxycytidine (5CadC)—showed no cytotoxicity and were not incorporated into DNA. Interestingly, 5-hydroxymethyl-2′-deoxycytidine (5HmdC) was cytotoxic but was not directly incorporated into DNA. Instead, it was deaminated into 5HmdU, which was then incorporated and likely responsible for the observed toxicity. 5HmdU is actively removed from DNA through the BER pathways. In contrast, TFT remains stably incorporated and is neither excised by BER nor does it hydrolyze into 5CadU—a known substrate for the DNA glycosylase SMUG1. We also found that N⁶-benzyladenosine (BzAdo), an inhibitor of the enzyme 2′-deoxynucleoside 5′-phosphate N-hydrolase (DNPH1), enhances the cytotoxicity of 5HmdU. However, the thymidine phosphorylase inhibitor tipiracil hydrochloride (TPI) does not increase the cytotoxic effect of TFT in U87 cells. Together, these findings highlight 5HmdU and TFT as promising chemotherapeutic agents for glioblastoma, each with distinct mechanisms of action and cellular processing. Full article

Background/Objectives: Temozolomide is an important drug used for the treatment of glioblastoma multiforme. Covalent conjugation of temozolomide to triplex-forming oligonucleotides could facilitate better sequence discrimination when targeted to DNA to lessen off-target effects and potentially reduce side-effects associated with conventional chemotherapy. The base sensitivity of temozolomide precludes use of basic deprotection conditions that typify the solid-supported synthesis of oligonucleotides. Methods: A novel di-iso-propylsilylene-linked solid support was developed and used in solid-supported synthesis of oligonucleotide conjugates. Results: Conditions were established whereby fully deprotected, solid-supported oligonucleotides could be prepared for derivatisation. Cleavage of the di-iso-propylsilylene linker was possible using mild, acidic conditions. Conclusions: The di-iso-propylsilylene-linked solid support was developed and shown to be compatible with base-sensitive oligonucleotide conjugate formation. The DNA triplex formation exhibited by a temozolomide oligonucleotide conjugate was equal in stability to the unconjugated control, opening new possibilities for sequence selective delivery of temozolomide to targeted DNA. Full article

Glioblastoma is the most common and aggressive malignant primary brain tumour. Patients with glioblastoma have a median survival of only around 14.6 months after diagnosis, despite the availability of various conventional multimodal treatments including chemotherapy, radiation therapy, and surgery. Therefore, photodynamic therapy (PDT) has emerged as an advanced, selective and more controlled therapeutic approach, which has minimal systemic toxicity and fewer side effects. PDT is a less invasive therapy that targets all cells or tissues that possess the photosensitizer (PS) itself, without affecting the surrounding healthy tissues. Polymeric NPs (PNPs) as carriers can improve the targeting ability and stability of PSs and co-deliver various anticancer agents to achieve combined cancer therapy. Because of their versatile tuneable features, these PNPs have the capacity to open tight junctions of the blood–brain barrier (BBB), easily transport drugs across the BBB, protect against enzymatic degradation, prolong the systemic circulation, and sustainably release the drug. Conjugated polymer NPs, poly(lactic-co-glycolic acid)-based NPs, lipid–polymer hybrid NPs, and polyethylene-glycolated PNPs have demonstrated great potential in PDT owing to their unique biocompatibility and optical properties. Although the combination of PDT and PNPs has great potential and can provide several benefits over conventional cancer therapies, there are several limitations that are hindering its translation into clinical use. This review aims to summarize the recent advances in the combined use of PNPs and PDT in the case of glioblastoma treatment. By evaluating various types of PDT and PNPs, this review emphasizes how these innovative approaches can play an important role in overcoming glioblastoma-associated critical challenges, including BBB and tumour heterogeneity. Furthermore, this review also discusses the challenges and future directions for PNPs and PDT, which provides insight into the potential solutions to various problems that are hindering their clinical translation in glioblastoma treatment. Full article

To date, there is no effective treatment for glioblastoma (GBM). This study aimed to compare the effectiveness of sodium dichloroacetate (NaDCA), a valproic acid and NaDCA combination (VPA–NaDCA), or temozolomide (TMZ) on U87 and T98G cell tumors on the chick embryo chorioallantoic membrane (CAM), and on the expression of proliferating cell nuclear antigen (PCNA), polycomb inhibitory complex catalytic subunit 2 (EZH2), and TP53 gene-encoded p53 protein (p53) in tumors on the CAM, and SLC12A2 (gene encoding Na⁺-K⁺-2Cl⁻ (NKCC1) co-tarnsporter), SLC12A5 (gene encoding K⁺-Cl⁻ (KCC2) co-transporter), SLC5A8 (gene encoding Na⁺-dependent monocarboxylate transporter) and CDH1 (gene encoding the E-cadherin protein) and CDH2 (gene encoding the N-cadherin protein) in cells. VPA–NaDCA and TMZ reduced the invasion of U87 and T98G tumors, as well as the expression of PCNA and EZH2 in the tumor. TMZ reduced p53 expression in tumors from both cell lines, whereas VPA–NaDCA did not affect the expression of this marker. VPA–NaDCA, but not TMZ, reduced SLC12A2 expression in T98G cells. However, VPA–NaDCA and TMZ did not affect SLC12A2 expression in U87 cells. VPA–NaDCA increased SLC5A8 expression only in U87 cells, and TMZ did not affect gene expression in either cell line. Only VPA–NaDCA increased CDH1 expression and decreased CDH2 expression in T98G cells, whereas TMZ had no effect on gene expression in the study cells. This study demonstrated that VPA–NaDCA exhibits a more effective anticancer effect than NaDCA. The data suggest that VPA–NaDCA has a more effective impact than TMZ; however, the effect of investigational medicines on carcinogenesis varies depending on the cell line. The study of the efficacy of drugs used to treat tumors on the CAM and cells demonstrates that it is essential to assess the effectiveness of treatment, which should be personalized, before administering chemotherapy. Full article

Glioblastoma multiforme (GBM), the most aggressive and therapy-resistant glioma subtype, remains an urgent clinical challenge due to its invasive nature, molecular heterogeneity, and the protective constraints of the blood–brain barrier (BBB). Liposomes and extracellular vesicles (EVs) have emerged as two of the most promising nanocarrier systems capable of overcoming these limitations through improved drug delivery and cellular targeting. Their applications in glioma therapy span chemotherapy, immunotherapy, and gene therapy, each presenting distinct advantages and mechanisms of action. Liposomes offer structural flexibility, controlled release, and a well-established clinical framework, while EVs provide innate biocompatibility, low immunogenicity, and the ability to mimic natural intercellular communication. Both systems demonstrate the capacity to traverse the BBB and selectively accumulate in tumor tissue, yet they differ in scalability, cargo loading efficiency, and translational readiness. Comparative evaluation of their functions across therapeutic modalities reveals complementary strengths that may be leveraged in the development of more effective, targeted strategies for glioma treatment. Full article

Background: Sex differences play a significant role in the epidemiology, biology, and outcomes of many cancers, including glioblastoma (GB), the most common and aggressive primary brain tumor. GB is more frequent in males, while females tend to have longer survival, though the underlying reasons for these differences remain poorly understood. Potential contributors include hormonal influences, sex-specific risk factors, and treatment disparities. Understanding these differences is critical for optimizing personalized treatment strategies. Methods: We conducted a retrospective analysis of patients with gliomas from a neuro-oncological database, with a primary focus on GB cases. Variables collected included sex, age, tumor type, molecular biomarker, and treatment modalities. The primary objective was to assess sex-based differences in tumor characteristics and outcomes, while the secondary objective was to identify predictors of time to progression and mortality. Results: The cohort comprised 125 GB, 48 astrocytomas, and 16 oligodendrogliomas, with no significant sex-based differences in age or tumor type distribution. Among GB patients, multifocality was more prevalent in females (14% vs. 8%; p = 0.01); also, EGFR amplification was more frequent in females (25.5% vs. 52.5%; p = 0.007). Males received chemotherapy (80% vs. 63%; p = 0.04) and radiotherapy (84% vs. 67%; p = 0.03) more frequently than females. Survival was positively associated with MGMT methylation (p = 0.002) and negatively associated with TERT mutation (p = 0.01). Multivariable analysis identified TERT mutation as a predictor of increased mortality (HR = 4.1; 95% CI: 1.2–14; p = 0.025), while multifocality predicted both mortality (HR = 2.3; 95% CI: 1.3–3.9; p = 0.003) and reduced time to progression (HR = 3.3; 95% CI: 1.02–10.6; p = 0.04). Conclusions: This study underscores the importance of sex and molecular profiling in GB management, revealing distinct patterns in tumor characteristics and treatment administration between males and females. Our findings advocate for the integration of sex-specific considerations and molecular profiling into clinical decision-making to improve outcomes for GB patients. Full article

Being one of the most aggressive primary brain tumors, glioblastoma multiforme (GBM) is known from the median survivals of just 15 months following diagnosis. Conventional treatments, including surgical resection, radiotherapy, and chemotherapy, have limited efficiency due to the invasive nature of glioma cells and the presence of a blood–brain barrier. Therefore, adjuvant therapy in the form of a localized delivery of chemotherapeutic agents is indispensable to increase the chances of patients. Among a variety of advanced drug carriers, collagen has recently emerged as an excellent choice for regional chemotherapy, mainly due to its biocompatibility, biodegradability, weak antigenicity, biomimetics, and well-known safety profile, as well as its native presence in the extracellular matrix of the central nervous system. The aim of this paper is to highlight the most recent studies describing the application of collagen as a drug carrier able to provide an extended delivery of chemotherapeutic agents directly to the GBM site, and to provide exciting opportunities for its future applications. Full article

Glioblastoma (GB) is the most common malignant primary CNS tumor with a fast-growing and invasive profile. As a result of the poor prognosis and limited therapy available, glioblastoma shows a high mortality rate. Given the scarcity of effective chemotherapy options, multiple studies have explored the potential of tyrosine kinase inhibitors. To mitigate resistance and improve potency and selectivity, we proposed the combination of a potent irreversible epidermal growth factor receptor inhibitor—LASSBio-1971—and a potent phosphatidylinositol-3-kinase/mammalian target of rapamycin dual inhibitor—Gedatolisib—through an in vitro phenotypic study using five human GB lines. Here, we aimed to establish the cytotoxic potency, selectivity, and effect on proliferation, apoptosis, migration, and the cell cycle. Our data showed the cytotoxic potency of Gedatolisib and LASSBio-1971 and improved selectivity in the GB cell lines. They highlighted the synergistic response from their combination and its impact on migration reduction, G0/G1 cell cycle arrest, GB cytotoxicity, and apoptosis-inducing effects for different GB cell lines. The drug combination studies in phenotypic in vitro models made it possible to suggest a new potential treatment for glioblastoma that justifies further safety in in vivo phases of preclinical trials with the combination. Full article

Isoforms of prostate transmembrane protein, androgen induced 1 (PMEPA1), are regulated either by TGF-beta or AR activation and provide negative loop-regulation of these signaling pathways. High levels of PMEPA1 protein have been observed in various tumor types, including prostate, bladder, colorectal cancers, and glioblastoma. Direct oncogenic role of PMEPA1 in hepatocellular carcinoma has been recently shown on an animal model. New studies also indicate an upregulation of PMEPA1 in tumor-associated immune and stromal cells; however, its specific role in tumor stromal cells remains largely unexplored. In our previous research, we developed a cancer-stroma sphere (CSS) model that integrates tumor cells with mesenchymal stem cells (MSCs). Evaluations of chemotherapy and CAR-T therapies on CSSs have demonstrated that this model closely mimics in vivo data regarding cytotoxicity and adverse effects of therapy. In the present study, we reveal that PMEPA1 is significantly overexpressed in MSCs within the CSS. Moreover, this overexpression has been induced under short-term co-culture conditions. Among the five isoforms of PMEPA1, PMEPA1a and PMEPA1b isoforms have been detected in MSCs. These findings underscore the potential role of PMEPA1 in the tumor microenvironment modulation by MSCs. Full article

Background: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are enzymes that catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), which is essential for many metabolic processes, including some steps in DNA repair. In tumors, notably in gliomas, IDH1 and IDH2 are frequently mutated. The mutation found in different cancers is functionally active, causing, instead of α-KG, the formation of 2-hydroxyglutarate (2-HG), which inhibits α-KG-dependent enzymes. Gliomas harboring mutated IDH1/2 show a better prognosis than IDH1 wild-type (wt) tumors of the same grade, which might result from the inhibition of DNA repair functions. A DNA repair enzyme dependent on α-KG is alkB homolog 2 (ALKBH2), which removes several lesions from DNA. These findings prompted us to investigate the response of glioma cells to artesunate (ART), a plant ingredient with genotoxic and anticancer activity currently used in several trials. Materials and Methods: We used isogenic glioblastoma cell lines that express IDH1 wild-type or, based on a TET-inducible system, the IDH1 mutant (mt) protein, and treated them with increasing doses of artesunate. We also treated glioblastoma cells with 2-HG, generated ALKBH2 knockout cells, and checked their sensitivity to the cytotoxic effects of artesunate. Results: We show that the cell-killing effect of ART is enhanced if the IDH1 mutant (R132H) is expressed in glioblastoma cells. Further, we show that 2-HG imitates the effect of IDH1mt as 2-HG ameliorates the cytotoxicity of ART. Finally, we demonstrate that the knockout of ALKBH2 causes the sensitization of glioblastoma cells to ART. Conclusions: The data indicate that ALKBH2 protects against the anticancer effect of ART, and the mutation of IDH1/2 commonly occurring in low-grade gliomas sensitizes to ART via an ALKBH2-dependent mechanism. The data support the use of ART in the therapy of IDH1/2-mutated cancers both in combination with chemotherapy and adjuvant treatment. Full article

Primary brain tumors represent a significant focus of contemporary research. With advancements in technology and the increasing detection of cases through novel diagnostic methods, innovative therapies and approaches to chemotherapy continue to emerge. The paper explores recent advancements in chemotherapy for glioblastoma, highlighting innovative approaches that provide valuable mechanistic insights. It delves into the mechanisms of action, molecular targets, and the future potential of emerging therapies for gliomas. Additionally, this paper offers an overview investigating a range of therapies, including various chemotherapeutic agents, CAR-T cell therapies, drugs targeting cellular respiration, and other approaches. Furthermore, the paper addresses chemotherapy-related challenges, including the blood–brain barrier, drug resistance, and immunosuppression, while proposing potential solutions to overcome these obstacles. Full article

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

Background: Disparities in neuro-oncological care between high-income and low- and middle-income countries (LMICs) are well documented, yet region-specific data from Latin America remain limited. This review evaluates epidemiologic trends, access to care, and systemic challenges in brain tumor management across Latin American LMICs, using Argentina as a case study. Methods: A systematic review of peer-reviewed literature was conducted focusing on brain tumor incidence, mortality, risk factors, and availability of diagnostics and treatments in Latin America. Socioeconomic, cultural, and systemic barriers were also analyzed. Results: Latin America exhibits some of the highest global brain tumor mortality rates, with Brazil reporting age-standardized rates exceeding 4.5 per 100,000. Glioblastomas are frequently diagnosed at younger ages, often in the fifth decade of life, compared to the global average. Meningioma incidence has increased by 15–20% over the last decade, yet region-wide data remain fragmented. Access to neuroimaging, neurosurgery, radiotherapy, and chemotherapy is limited, with up to 60% of patients relying solely on under-resourced public health systems. Less than 30% of hospitals in rural areas have MRI availability, and continuous professional training is infrequent. Innovative adaptations, such as awake craniotomy, are used in some LMIC centers in response to equipment scarcity. Conclusions: Brain tumor care in Latin America is hindered by limited epidemiological data, restricted access to diagnostics and treatment, and insufficient workforce training. Targeted investments in healthcare infrastructure, international educational collaborations, and policy-level reforms are critical to reducing disparities and improving outcomes in neuro-oncology across the region. Full article

Glioblastoma, a highly malignant tumor, has a poor prognosis, necessitating the development of effective therapeutic strategies due to the low success rates of existing treatments. Graphene quantum dots (GQDs) have garnered attention for their unique physicochemical, electronic, and optical properties, along with biocompatibility and the ability to cross the blood–brain barrier. This systematic review evaluates the current applications of GQDs in glioblastoma management. A search across databases such as PubMed, Science Direct, and Web of Science identified 658 papers, with 10 selected for this review based on the eligibility criteria. Most of the selected studies explored GQDs as pretreatment agents for therapies like chemotherapy and photothermal therapy, alongside their roles in biosensing, bioimaging, and drug delivery. Although research is still limited, this review highlights the significant potential of GQDs as multifunctional platforms in glioblastoma therapy. Further studies are essential to optimize these nanostructures for clinical applications, aiming to improve the precision and effectiveness of treatments while reducing systemic side effects. Full article