RESUMEN
Glioblastoma (GBM) is a highly prevalent and deadly brain tumor with high mortality rates, especially among adults. Despite extensive research, the underlying mechanisms driving its progression remain poorly understood. Computational analysis offers a powerful approach to explore potential prognostic biomarkers, drug targets, and therapeutic agents for GBM. In this study, we utilized three gene expression datasets from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) associated with GBM progression. Our goal was to uncover key molecular players implicated in GBM pathogenesis and potential avenues for targeted therapy. Analysis of the gene expression datasets revealed a total of 78 common DEGs that are potentially involved in GBM progression. Through further investigation, we identified nine hub DEGs that are highly interconnected in protein-protein interaction (PPI) networks, indicating their central role in GBM biology. Gene Ontology (GO) and pathway enrichment analyses provided insights into the biological processes and immunological pathways influenced by these DEGs. Among the nine identified DEGs, survival analysis demonstrated that increased expression of GMFG correlated with decreased patient survival rates in GBM, suggesting its potential as a prognostic biomarker and preventive target for GBM. Furthermore, molecular docking and ADMET analysis identified two compounds from the NIH clinical collection that showed promising interactions with the GMFG protein. Besides, a 100 nanosecond molecular dynamics (MD) simulation evaluated the conformational changes and the binding strength. Our study highlights the potential of GMFG as both a prognostic biomarker and a therapeutic target for GBM. The identification of GMFG and its associated pathways provides valuable insights into the molecular mechanisms driving GBM progression. Moreover, the identification of candidate compounds with potential interactions with GMFG offers exciting possibilities for targeted therapy development. However, further laboratory experiments are required to validate the role of GMFG in GBM pathogenesis and to assess the efficacy of potential therapeutic agents targeting this molecule.
Asunto(s)
Biomarcadores de Tumor , Neoplasias Encefálicas , Regulación Neoplásica de la Expresión Génica , Glioblastoma , Mapas de Interacción de Proteínas , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/tratamiento farmacológico , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Mapas de Interacción de Proteínas/genética , Perfilación de la Expresión Génica/métodos , Simulación del Acoplamiento Molecular , Transcriptoma/genética , Bases de Datos Genéticas , Ontología de Genes , Biología Computacional/métodosRESUMEN
Melanoma brain metastases present a major challenge in cancer treatment and reduce overall survival despite advances in managing primary melanoma. Immune checkpoint inhibitors (ICIs) that target PD-1/PD-L1 pathways have shown promise in treating advanced melanoma, but their efficacy for melanoma brain metastases is debated. This systematic review and meta-analysis summarize evidence on anti-PD-1/PD-L1 inhibitors for melanoma brain metastases. This systematic review and meta-analysis followed PRISMA guidelines. PICO criteria targeted melanoma brain metastasis patients treated with PD-1/PD-L1 inhibitors, assessing overall survival, progression-free survival, and complications. Inclusion criteria were English studies on humans using PD-1/PD-L1 inhibitors for melanoma brain metastases with > 10 patients. A total of 22 trials involving 1523 melanoma brain metastase patients treated with anti-PD-1/PD-L1 inhibitors were thoroughly analyzed. Our findings show the 6-month OS rate of 0.75 [95%CI:0.67-0.84], the 6-months PFS rate of 0.42 [95%CI:0.31-0.52], the 1-year OS rate of 0.63 [95%CI:0.52-0.74], the 1-year PFS rate was 0.45 [95%CI:0.32-0.58], the 18-months OS rate of 0.52 [95%CI:0.37-0.67], the 2-year OS rate of 50% [95% CI: (34%-65%)], the 2 year PFS rate of 0.36 (95%CI:0.23-0.50), the 3-year OS rate of 0.42 (95%CI:0.17-0.67), the 4-year PFS rate of 0.35 [95%CI:0.08-0.61], the 4-year OS rate of 0.29 [95%CI:0.01-0.56], the 5-year OS rate of 0.29 (95%CI:0.09-0.50), and the 5-year PFS rate of 0.11 (95%CI:0.03-0.19). The combined disease stability rate was 0.13 [95%CI:0.05-0.20], the progressive disease rate was 0.49 [95%CI:0.37-0.62], the partial response rate was 0.14 [95%CI:0.07-0.20], the object response rate was 0.35 [95%CI:0.24-0.46], and the complete response rate was 0.22 [95%CI:0.12-0.32]. In conclusion, our meta-analysis provides compelling evidence supporting the efficacy of PD-1/PD-L1 inhibitors in patients with melanoma brain tumors, as evidenced by favorable survival outcomes and disease control rates.
Asunto(s)
Antígeno B7-H1 , Neoplasias Encefálicas , Inhibidores de Puntos de Control Inmunológico , Melanoma , Receptor de Muerte Celular Programada 1 , Humanos , Melanoma/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antígeno B7-H1/antagonistas & inhibidoresRESUMEN
Vasculogenic mimicry (VM) serves as a vascular-like channel that provides important substances for tumor growth and is a primary factor in glioblastoma (GBM) drug resistance. Human Antigen R (HuR)-an mRNA-binding protein-is highly expressed in GBM, closely related to tumor progression, and deemed a potential drug target. Although some small-molecule compounds have been identified to disrupt HuR binding to target mRNA, they remain in the preclinical research stage, suggesting the need for further validation and development of HuR inhibitors. In our study, we aim to screen for potential HuR inhibitors and investigate their efficacy and molecular mechanisms in GBM. We employed the fluorescence polarization method to identify HuR inhibitors from a natural compound library, confirming the efficacy of juglone in effectively inhibiting the binding of HuR to AREVegf-a. Further validation of the binding of juglone to HuR at the protein level was conducted through electrophoretic mobility shift analysis, surface plasmon resonance, and molecular docking. Furthermore, juglone demonstrated inhibitory effects on glioma growth and VM formation in vitro and in vivo. Moreover, it was observed that juglone reversed epithelial-mesenchymal transition by inhibiting the VEGF-A/VEGFR2/AKT/SNAIL signaling pathway. Finally, we established the capability of juglone to target HuR in U251 cells through HuR knockdown, mRNA stability, and cell thermal shift assays. Therefore, this study identifies juglone as a novel HuR inhibitor, potentially offering promise as a lead compound for anti-VM therapy in GBM by targeting HuR. Abbreviations: AKT, protein kinase B; ARE, adenine-and uridine-rich elements; CETSA, cellular thermal shift assay; DMEM, Dulbecco's modified Eagle's medium; ELISA, enzyme linked immune sorbent assay; EMSA, electrophoretic mobility shift assay; EMT, epithelial mesenchymal transition; FP, fluorescence polarization; GBM, glioblastoma; HTS, high-throughput screening; HuR, human antigen R; IF, Immunofluorescence; PAS, periodic acid-Schiff; PI3K, phosphoinositide-3 kinase; qRT-PCR, quantitative real-time PCR; RRMs, RNA recognition motifs; SPR, surface plasmon resonance. TMZ, temozolomide; VM, vasculogenic mimicry; VEGF-A, Vascular endothelial growth factor-A; VEGFR2, Vascular endothelial growth factor receptor-2.
Asunto(s)
Proteína 1 Similar a ELAV , Naftoquinonas , Factor A de Crecimiento Endotelial Vascular , Humanos , Proteína 1 Similar a ELAV/metabolismo , Proteína 1 Similar a ELAV/genética , Proteína 1 Similar a ELAV/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Naftoquinonas/farmacología , Animales , Ratones , Línea Celular Tumoral , Ratones Desnudos , Glioma/metabolismo , Glioma/tratamiento farmacológico , Glioma/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Smac mimetic compounds (SMCs) are small molecule drugs that sensitize cancer cells to TNF-α-induced cell death and have multiple immunostimulatory effects through alterations in NF-κB signaling. The combination of SMCs with immunotherapies has been reported to result in durable cures of up to 40% in syngeneic, orthotopic murine glioblastoma (GBM) models. Herein, we find that SMC resistance is not due to a cell-intrinsic mechanism of resistance. We thus evaluated the contribution of GBM and brain stromal components to identify parameters leading to SMC efficacy and resistance. The common physiological features of GBM tumors, such as hypoxia, hyaluronic acid, and glucose deprivation were found not to play a significant role in SMC efficacy. SMCs induced the death of microglia and macrophages, which are the major immune infiltrates in the tumor microenvironment. This death of microglia and macrophages then enhances the ability of SMCs to induce GBM cell death. Conversely, astrocytes promoted GBM cell growth and abrogated the ability of SMCs to induce death of GBM cells. The astrocyte-mediated resistance can be overcome in the presence of exogenous TNF-α. Overall, our results highlight that SMCs can induce death of microglia and macrophages, which then provides a source of death ligands for GBM cells, and that the targeting of astrocytes is a potential mechanism for overcoming SMC resistance for the treatment of GBM.
Asunto(s)
Astrocitos , Glioblastoma , Microambiente Tumoral , Glioblastoma/patología , Glioblastoma/tratamiento farmacológico , Glioblastoma/inmunología , Microambiente Tumoral/efectos de los fármacos , Animales , Humanos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Línea Celular Tumoral , Ratones , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Inflamación/patología , Inflamación/tratamiento farmacológico , Proteínas Mitocondriales/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones Endogámicos C57BLRESUMEN
The recurrent nature of glioblastoma negatively impacts conventional treatment strategies leading to a growing need for nanomedicine. Nanotherapeutics, an approach designed to deliver drugs to specific sites, is experiencing rapid growth and gaining immense popularity. Having potential in reaching the hard-to-reach disease sites, this field has the potential to show high efficacy in combatting glioblastoma progression. The presence of glioblastoma stem cells (GSCs) is a major factor behind the poor prognosis of glioblastoma multiforme (GBM). Stemness potential, heterogeneity, and self-renewal capacity, are some of the properties that make GSCs invade across the distant regions of the brain. Despite advances in medical technology and MRI-guided maximal surgical resection, not all GSCs residing in the brain can be removed, leading to recurrent disease. The aggressiveness of GBM is often correlated with immune suppression, where the T-cells are unable to infiltrate the cancer initiating GSCs. Standard of care therapies, including surgery and chemotherapy in combination with radiation therapy, have failed to tackle all the challenges of the GSCs, making it increasingly important for researchers to develop strategies to tackle their growth and proliferation and reduce the recurrence of GBM. Here, we will focus on the advancements in the field of nanomedicine that has the potential to show positive impact in managing glioblastoma tumor microenvironment. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Nanomedicina , Células Madre Neoplásicas , Glioblastoma/terapia , Glioblastoma/diagnóstico por imagen , Glioblastoma/tratamiento farmacológico , Humanos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamiento farmacológico , Animales , Recurrencia Local de Neoplasia , Terapia de Inmunosupresión , Invasividad Neoplásica , RatonesRESUMEN
INTRODUCTION: Glioblastoma (GBM) poses a significant challenge in oncology, with median survival times barely extending beyond a year due to resistance to standard therapies like temozolomide (TMZ). This study introduces a novel therapeutic strategy combining progesterone (Prog) and abiraterone (Abi) aimed at enhancing GBM treatment efficacy by modulating the tumor microenvironment and augmenting NK cell-mediated immunity. METHODS: We employed in vitro and in vivo GBM models to assess the effects of Prog and Abi on cell viability, proliferation, apoptosis, and the immune microenvironment. Techniques included cell viability assays, Glo-caspase 3/7 apoptosis assays, RNA-seq and qPCR for gene expression, Seahorse analysis for mitochondrial function, HPLC-MS for metabolomics analysis, and immune analysis by flow cytometry to quantify NK cell infiltration. RESULTS: Prog significantly reduced the IC50 of Abi in TMZ-resistant GBM cell, suggesting the enhanced cytotoxicity. Treatment induced greater apoptosis than either agent alone, suppressed tumor growth, and prolonged survival in mouse models. Notably, there was an increase in CD3-/CD19-/CD56+/NK1.1+ NK cell infiltration in treated tumors, indicating a shift towards an anti-tumor immune microenvironment. The combination therapy also resulted in a reduction of MGMT expression and a suppression of mitochondrial respiration and glycolysis in GBM cells. CONCLUSION: The combination of Prog and Abi represents a promising therapeutic approach for GBM, showing potential in suppressing tumor growth, extending survival, and modulating the immune microenvironment. These findings warrant further exploration into the clinical applicability of this strategy to improve outcomes for GBM patients.
Asunto(s)
Glioblastoma , Células Asesinas Naturales , Progesterona , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/metabolismo , Glioblastoma/inmunología , Humanos , Ratones , Animales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Progesterona/farmacología , Androstenos/farmacología , Androstenos/uso terapéutico , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Apoptosis/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Modelos Animales de EnfermedadRESUMEN
Epithelioid glioblastoma (eGB), a very aggressive and rare brain tumour, is associated with a dismal median overall survival. Effective therapies for patients with eGB, particularly with leptomeningeal dissemination, are still lacking. Here, we describe a case of a 25-year-old male diagnosed with an intramedullary cervical tumour with subsequent leptomeningeal disease. Histopathology identified a highly necrotising, epithelioid-type tumour with high cell density, most compatible with the diagnosis of an eGB. DNA analysis revealed an unprecedented B-Raf protooncogene, serine/threonine kinase (BRAF) gene variant in exon 15 (ENST00000288602.6, c.1799_1810delinsATG, p.(V600_W604delinsDG)), triggering activation of the mitogen-activated protein kinase (MAPK) pathway. Consequently, we initiated MAPK inhibitor (MAPKi) therapy, utilizing a combination of BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. Liquid chromatography-tandem mass spectrometry analysis confirmed the drugs' presence in the patient's cerebrospinal fluid, indicating their capacity to cross the blood-brain barrier. Remarkably, the patient responded very well to therapy and transitioned from a near-comatose state to significantly improved health, sustained for over three months. This study highlights that MAPKi, particularly targeted towards novel BRAFV600 mutations, might offer promising advancements in eGB treatment strategies.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Mutación , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Masculino , Adulto , Glioblastoma/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/genéticaRESUMEN
Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter's tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.
Asunto(s)
Glioblastoma , Proteínas de Unión a Hormona Tiroide , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X , Glioblastoma/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , Animales , Línea Celular Tumoral , Ratones , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/metabolismo , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones Desnudos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Proteínas de la Membrana/metabolismo , Proteínas Portadoras/metabolismo , Hormonas Tiroideas/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Aldehído Oxidorreductasas , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NHRESUMEN
OBJECTIVE: Most recurrent glioblastoma (rGBM) patients do not benefit from immune checkpoint inhibition, emphasizing the necessity for response biomarkers. This study evaluates whether tumor in situ fluid (TISF) circulating tumor DNA (ctDNA) could serve as a biomarker for response to low-dose bevacizumab (Bev) plus anti-PD-1 therapy in rGBM patients, aiming to enhance systemic responses to immunotherapy. METHODS: In this phase II trial, 32 GBM patients with first recurrence after standard therapy were enrolled and then received tislelizumab plus low-dose Bev each cycle. TISF samples were analyzed for ctDNA using a 551-gene panel before each treatment. RESULTS: The median progression-free survival (mPFS) and overall survival (mOS) were 8.2 months (95% CI, 5.2-11.1) and 14.3 months (95% CI, 6.5-22.1), respectively. The 12-month OS was 43.8%, and the objective response rate was 56.3%. Patients with more than 20% reduction in the mutant allele fraction and tumor mutational burden after treatment were significantly associated with better prognosis compared to baseline TISF-ctDNA. Among detectable gene mutations, patients with MUC16 mutation, EGFR mutation & amplification, SRSF2 amplification, and H3F3B amplification were significantly associated with worse prognosis. CONCLUSIONS: Low-dose Bev plus anti-PD-1 therapy significantly improves OS in rGBM patients, offering guiding significance for future individualized treatment strategies. TISF-ctDNA can monitor rGBM patients' response to combination therapy and guide treatment. CLINICAL TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT05540275.
Asunto(s)
Bevacizumab , Neoplasias Encefálicas , ADN Tumoral Circulante , Glioblastoma , Inhibidores de Puntos de Control Inmunológico , Recurrencia Local de Neoplasia , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Anciano , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , PronósticoRESUMEN
Glioblastoma (GBM) is a severe form of brain tumor that has a high fatality rate. It grows aggressively and most of the time results in resistance to traditional treatments like chemo- and radiotherapy and surgery. Biodiversity, beyond representing a big resource for human well-being, provides several natural compounds that have shown great potential as anticancer drugs. Many of them are being extensively researched and significantly slow GBM progression by reducing the proliferation rate, migration, and inflammation and also by modulating oxidative stress. Here, the use of some natural compounds, such as Allium lusitanicum, Succisa pratensis, and Dianthus superbus, was explored to tackle GBM; they showed their impact on cell number reduction, which was partially given by cell cycle quiescence. Furthermore, a reduced cell migration ability was reported, accomplished by morphological cytoskeleton changes, which even highlighted a mesenchymal-epithelial transition. Furthermore, metabolic studies showed an induced cell oxidative stress modulation and a massive metabolic rearrangement. Therefore, a new therapeutic option was suggested to overcome the limitations of conventional treatments and thereby improve patient outcomes.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Estrés Oxidativo/efectos de los fármacos , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Antineoplásicos/farmacologíaRESUMEN
Glioblastoma (GBM) is one of the most aggressive cancers, characterized by a decrease in antioxidant levels. Evidence has demonstrated that ferulic acid (FA), a natural antioxidant particularly abundant in vegetables and fruits, could be a promising candidate for GBM treatment. Since FA shows a high instability that compromises its therapeutic application, it has been encapsulated into Nanostructured Lipid Carriers (NLCs) to improve its bioavailability in the brain. It has been demonstrated that tissue transglutaminase (TG2) is a multi-functional protein implicated in many physiological and pathological processes, including cancer. TG2 is also involved in GBM correlated with metastasis formation and drug resistance. Therefore, the evaluation of TG2 expression levels and its cellular localization are important to assess the anti-cancer effect of FA against GBM cancer. Our results have demonstrated that treatment with free FA and FA-NLCs in the U87-MG cancer cell line differently modified TG2 localization and expression levels. In the cells treated with free FA, TG2 appeared expressed both in the cytosol and in the nucleus, while the treatment with FA-NLCs showed that the protein is exclusively localized in the cytosol, exerting its pro-apoptotic effect. Therefore, our data suggest that FA loaded in NLCs could represent a promising natural agent for supplementing the current anti-cancer drugs used for the treatment of GBM.
Asunto(s)
Ácidos Cumáricos , Proteínas de Unión al GTP , Glioblastoma , Nanopartículas , Proteína Glutamina Gamma Glutamiltransferasa 2 , Transglutaminasas , Ácidos Cumáricos/farmacología , Humanos , Transglutaminasas/metabolismo , Transglutaminasas/genética , Glioblastoma/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Proteína Glutamina Gamma Glutamiltransferasa 2/metabolismo , Línea Celular Tumoral , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/genética , Nanopartículas/química , Portadores de Fármacos/química , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
Glioblastoma (GBM) is associated with a median survival rate of less than 15 months, necessitating innovative treatment approaches. This study investigates the safety and efficacy of the low-frequency magnetic field (LFMF) OM-100 instrument in GBM therapy. In vitro experiments utilized normal astrocyte and GBM cell lines, determining that OM-100 at 100 kHz for 72 h selectively targeted GBM cells without harming normal cells. Subsequent analyses revealed OM-100's impact on cell viability, apoptosis, migration, invasion, reactive oxide species levels, and PD-L1 expression. In vivo studies on mice with U87-induced GBM demonstrated OM-100's synergy with anti-PD-1 therapy, leading to significant tumor volume reduction and increased apoptosis. Notably, OM-100 exhibited safety in healthy mice. Overall, OM-100 could enhance anti-PD-1 immunotherapy effectiveness probably by directly inhibiting tumor proliferation and migration as well as promoting PD-L1 expression, offering a promising therapeutic strategy for GBM treatment.
Asunto(s)
Proliferación Celular , Glioblastoma , Inmunoterapia , Receptor de Muerte Celular Programada 1 , Glioblastoma/terapia , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/metabolismo , Animales , Ratones , Humanos , Línea Celular Tumoral , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Inmunoterapia/métodos , Proliferación Celular/efectos de los fármacos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Magnetoterapia/métodos , Supervivencia Celular/efectos de los fármacosRESUMEN
The main reasons for the difficulty in curing and high recurrence rate of glioblastoma multiforme (GBM) include: 1. The difficulty of chemotherapy drugs in penetrating the blood-brain barrier (BBB) to target tumor cells; 2. The presence of glioma stem cells (GSCs) leading to chemotherapy resistance. Therefore, breaking through the limitations of the BBB and overcoming the drug resistance caused by GSCs are the main strategies to address this problem. This study presents our results on the development of lactoferrin (Lf)/CD133 antibody conjugated nanostructured lipid carriers (Lf/CD133-NLCS) for simultaneously targeting BBB and GSCs. Temozolomide (TMZ) loaded Lf/CD133-NLCS (Lf/CD133-NLCS-TMZ) exhibited high-efficiencyin vitroanti-tumor effects toward malignant glioma cells (U87-MG) and GSCs, while demonstrating no significant toxicity to normal cells at concentrations lower than 200 µg ml-1. The results of thein vitrotargeting GBM study revealed a notably higher cellular uptake of Lf/CD133-NLCS-TMZ in U87-MG cells and GSCs in comparison to Lf/CD133 unconjugated counterpart (NLCS-TMZ). In addition, increased BBB permeability were confirmed for Lf/CD133-NLCS-TMZ compared to NLCS-TMZ bothin vitroandin vivo. Taking together, Lf/CD133-NLCS-TMZ show great potential for dual targeting of BBB and GSCs, as well as GBM therapy based on this strategy.
Asunto(s)
Antígeno AC133 , Barrera Hematoencefálica , Neoplasias Encefálicas , Portadores de Fármacos , Glioblastoma , Lactoferrina , Lípidos , Nanoestructuras , Células Madre Neoplásicas , Temozolomida , Barrera Hematoencefálica/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Lactoferrina/química , Antígeno AC133/metabolismo , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Temozolomida/farmacología , Línea Celular Tumoral , Nanoestructuras/química , Portadores de Fármacos/química , Animales , Lípidos/química , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Ratones , Sistemas de Liberación de Medicamentos , Anticuerpos/químicaRESUMEN
BACKGROUND AND PURPOSE: The poor delivery of drugs to infiltrating tumor cells contributes to therapeutic failure in glioblastoma. During the early phase of an anti-angiogenic treatment, a remodeling of the tumor vasculature could occur, leading to a more functional vessel network that could enhance drug delivery. However, the restructuration of blood vessels could increase the proportion of normal endothelial cells that could be a barrier for the free diffusion of drugs. The net balance, in favor or not, of a better delivery of compounds during the course of an antiangiogenic treatment remains to be established. This study explored whether cediranib and thalidomide could modulate perfusion and vessel permeability in the brain U87 tumor mouse model. METHODS: The dynamic evolution of the diffusion of agents outside the tumor core using the fluorescent dye Evans Blue in histology and Gd-DOTA using dynamic contrast-enhanced (DCE)-MRI. CD31 labelling of endothelial cells was used to measure the vascular density. RESULTS AND INTERPRETATION: Cediranib and thalidomide effectively reduced tumor size over time. The accessibility of Evans Blue outside the tumor core continuously decreased over time. The vascular density was significantly decreased after treatment while the proportion of normal vessels remained unchanged over time. In contrast to histological studies, DCE-MRI did not tackle any significant change in hemodynamic parameters, in the core or margins of the tumor, whatever the parameter used or the pharmacokinetic model used. While cediranib and thalidomide were effective in decreasing the tumor size, they were ineffective in transiently increasing the delivery of agents in the core and the margins of the tumor.
Asunto(s)
Inhibidores de la Angiogénesis , Neoplasias Encefálicas , Glioblastoma , Quinazolinas , Talidomida , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/irrigación sanguínea , Talidomida/farmacología , Talidomida/uso terapéutico , Animales , Inhibidores de la Angiogénesis/farmacología , Ratones , Quinazolinas/farmacología , Quinazolinas/farmacocinética , Quinazolinas/uso terapéutico , Humanos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Imagen por Resonancia Magnética , Ensayos Antitumor por Modelo de Xenoinjerto , Permeabilidad Capilar/efectos de los fármacos , Ratones Desnudos , Línea Celular Tumoral , IndolesRESUMEN
BACKGROUND: Brain metastasis (BrM) is prevalent among patients with NSCLC, and surgical resection of BrM constitutes a promising treatment strategy for local management and histopathological diagnosis, although it is offered for a select group of patients. Limited information exists concerning the improvement in performance status (PS) following BrM resection or the outcomes stratified by subsequent systemic therapy. METHODS: We conducted a retrospective single-center cohort study including NSCLC patients with surgically resected BrM and focused on the improvement in PS and subsequent therapy after BrM resection. RESULTS: 71 patients were included, and the median overall survival was 18.3 months (95% confidence interval [95% CI]: 8.7, not reached). Patients with NSCLC who underwent surgical resection of BrM showed significant improvement in PS (18% and 39% showed ECOG PS of 0-1, before and after BrM resection, respectively [p = 0.006]), and patients with PS improvement were younger than those with PS unimprovement (median, 62 years versus 66 years; p = 0.041). Regarding subsequent systemic therapy after BrM resection, 21 patients (30%) received cytotoxic chemotherapy, 14 patients (20%) received tyrosine kinase inhibitors (TKIs), 3 patients (4%) received immune checkpoint inhibitors (ICIs), and 21 patients (30%) received no subsequent therapy. The survival outcomes of patients stratified by subsequent systemic treatments suggested the tendency that those who received TKI or ICI showed better survival outcomes, although a small number of patients hindered statistical comparisons. CONCLUSIONS: We describe the outcomes of patients with NSCLC who underwent surgical resection of BrM, revealing that younger patients were more likely to anticipate improvement in PS, and patients who received TKI or ICI after BrM resection tended to exhibit a more preferable prognosis.
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Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Masculino , Femenino , Estudios Retrospectivos , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Terapia CombinadaRESUMEN
This study aimed to evaluate the effects of dabrafenib and/or trametinib therapy in BRAF v600-mutant glioma treatment. PubMed, the Cochrane Library, EMBASE and Web of Science were searched from inception to Sep 2023. Inclusion criteria were designed based on the PICO principle to select relevant articles. Search keywords included 'dabrafenib', 'trametinib', 'glioma' and other related keywords. Outcomes included overall survival (OS), progression-free survival (PFS), adverse events (AEs), and death events. Methodological index for non-randomized studies (MINORS) was used to assess the methodological quality. Stata 14.0 was selected to perform the Cochrane Q and I2 statistics to test the heterogeneity among all studies. As for publication bias assessment and sensitivity analysis, the funnel plot, Egger regression test, Begg test, and trim and fill method were selected. Including 8 studies for meta-analysis. The pooled results of the single-arm trials showed that the median PFS and median OS after treatment were 6.10 months and 22.73 months, respectively. Notably, this study found a high incidence of AEs and death events of 50% and 43% after treatment. All the above findings were statistically significant. Also, this study statistically supported the advantage of disease response improvement after the combination therapy in BRAF v600-mutant glioma patients, which were shown as a pooled rate of PR (30%), a pooled rate of CR (18%), and a pooled rate of ORR (39%). And the AE rate was lower in the monotherapy group (AE: 25%) than in the combination treatment group (AE: 60%). Sensitivity analysis indicated that all the results were robust. Based on current literature outcomes, dabrafenib and/or trametinib may lead to the median PFS of 6.10 months and median OS as 22.73 months for BRAF v600-mutant glioma patients, and the safety of monotherapy is better than that of combination therapy. This conclusion needs to be treated with caution and further verified.
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Neoplasias Encefálicas , Glioma , Imidazoles , Mutación , Oximas , Proteínas Proto-Oncogénicas B-raf , Piridonas , Pirimidinonas , Humanos , Oximas/uso terapéutico , Pirimidinonas/uso terapéutico , Piridonas/uso terapéutico , Imidazoles/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
The effect of chemotherapy for anti-glioblastoma is limited due to insufficient drug delivery across the blood-brain-barrier. Poloxamer 188-coated nanoparticles can enhance the delivery of nanoparticles across the blood-brain-barrier. This study presents the design, preparation, and evaluation of a combination of PLGA nanoparticles (PLGA NPs) loaded with methotrexate (P-MTX NPs) and PLGA nanoparticles loaded with paclitaxel (P-PTX NPs), both of which were surface-modified with poloxamer188. Cranial tumors were induced by implanting C6 cells in a rat model and MRI demonstrated that the tumors were indistinguishable in the two rats with P-MTX NPs + P-PTX NPs treated groups. Brain PET scans exhibited a decreased brain-to-background ratio which could be attributed to the diminished metabolic tumor volume. The expression of Ki-67 as a poor prognosis factor, was significantly lower in P-MTX NPs + P-PTX NPs compared to the control. Furthermore, the biodistribution of PLGA NPs was determined by carbon quantum dots loaded into PLGA NPs (P-CQD NPs), and quantitative analysis of ex-vivo imaging of the dissected organs demonstrated that 17.2 ± 0.6% of the NPs were concentrated in the brain after 48 h. The findings highlight the efficacy of combination nanochemotherapy in glioblastoma treatment, indicating the need for further preclinical studies.
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Barrera Hematoencefálica , Neoplasias Encefálicas , Glioblastoma , Metotrexato , Nanopartículas , Poloxámero , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Animales , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/metabolismo , Glioblastoma/diagnóstico por imagen , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Nanopartículas/química , Ratas , Poloxámero/química , Metotrexato/química , Metotrexato/administración & dosificación , Metotrexato/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Distribución Tisular , Portadores de Fármacos/química , Masculino , Sistemas de Liberación de Medicamentos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , HumanosRESUMEN
BACKGROUND: The Hippo pathway is a conserved tumour suppressor signalling pathway, and its dysregulation is often associated with abnormal cell growth and tumorigenesis. We previously revealed that the transcriptional coactivator Yes-associated protein (YAP), the key effector of the Hippo pathway, is a molecular target for glioblastoma (GBM), the most common malignant brain tumour. Inhibiting YAP with small interfering RNA (siYAP) or the specific inhibitor verteporfin (VP) can diminish GBM growth to a certain degree. RESULTS: In this study, to enhance the anti-GBM effect of siYAP and VP, we designed stepwise-targeting and hypoxia-responsive liposomes (AMVY@NPs), which encapsulate hypoxia-responsive polymetronidazole-coated VP and DOTAP adsorbed siYAP, with angiopep-2 (A2) modification on the surface. AMVY@NPs exhibited excellent bloodâbrain barrier crossing, GBM targeting, and hypoxia-responsive and efficient siYAP and VP release properties. By inhibiting the expression and function of YAP, AMVY@NPs synergistically inhibited both the growth and stemness of GBM in vitro. Moreover, AMVY@NPs strongly inhibited the growth of orthotopic U87 xenografts and improved the survival of tumour-bearing mice without adverse effects. CONCLUSION: Specific targeting of YAP with stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and VP efficiently inhibited GBM progression. This study provides a valuable drug delivery platform and creative insights for molecular targeted treatment of GBM in the future.
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Neoplasias Encefálicas , Glioblastoma , Liposomas , Ratones Desnudos , ARN Interferente Pequeño , Verteporfina , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Liposomas/química , Verteporfina/farmacología , Verteporfina/uso terapéutico , Animales , Humanos , Línea Celular Tumoral , Ratones , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Proteínas Señalizadoras YAP , Nanopartículas/química , Ratones Endogámicos BALB C , Factores de Transcripción/metabolismo , Angiomotinas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , PéptidosRESUMEN
INTRODUCTION: Glioma is one of the most commonly tumours which occurs in the central nervous system and accounts for nearly 80% of brain tumours, with a significantly high mortality and morbidity. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as EGFR targeted therapy in various types of solid tumours; however, effective treatment for glioma is still limited. Osimertinib is an irreversible, oral third-generation TKI that targets the mutation at T790M, which causes cancer cells to acquire resistance to drugs. Osimertinib could be effective in the treatment of EGFR mutations with minimal effects on the activity of wild-type EGFR. Absent in melanoma 2 (AIM2) is highly expressed in glioma cells, promoting the maturation of pro-cancer cytokines and contributing to progression of glioma. However, the secretion of pro-cancer cytokines of tumour cells has been regarded as the resistance mechanism to EGFR-TKIs, including osimertinib. A high level of these cytokines also indicates a shorter progression-free survival (PFS). As AIM2 regulates the secretion of pro-cancer cytokines, we thought inhibition of AIM2 may contribute to the therapeutic effect of EGFR-TKIs. MATERIAL AND METHODS: We first established AIM2 inhibition and overexpression in cells. Then, the viability rate of cells was calculated by cell counting kit-8 (CCK-8) method, and apoptotic ratio of cells were measured by flow cytometry. The expression of inflammatory-related genes was detected using quantitative polymerase chain reaction (qPCR), concentrations of inflammatory-related factors were measured using enzyme-linked immunosorbent assay (ELISA). The expression of Wnt/b-catenin and EGFR/Ras/Mitogen-activated protein kinase kinase 1 (MEK) signalling pathway components was detected using western blotting. RESULTS: We found that inhibition of AIM2 enlarged the effect of osimertinib on the upregulation of inflammatory gene expression and secretion of these genes, increasing apoptosis. In addition, we also found that AIM2 could enhance the effect of osimertinib on reducing the expression of the Wnt/b-catenin and EGFR/Ras/MEK signalling pathways, resulting in the inhibition of cellular proliferation, and exerting an anti-tumour effect. These effects were also observed using in vivo experiments. CONCLUSIONS: AIM2 presents a potential therapeutic target in treatment of glioma.