From signalling pathways to targeted therapies: unravelling glioblastoma’s secrets and harnessing two decades of progress

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Oct. 20, 2023

Glioblastoma, a rare, and highly lethal form of brain cancer, poses significant challenges in terms therapeutic resistance, poor survival rates for both adult paediatric patients alike. Despite advancements cancer research driven by technological revolution, translating our understanding glioblastoma pathogenesis into improved clinical outcomes remains critical unmet need. This review emphasises the intricate role receptor tyrosine kinase signalling pathways, epigenetic mechanisms, metabolic functions tumourigenesis resistance. We also discuss extensive efforts over past two decades that have explored targeted therapies against these pathways. Emerging approaches, such as antibody-toxin conjugates or CAR T cell therapies, offer potential specifically targeting proteins on surface. Combination strategies incorporating protein-targeted therapy immune-based demonstrate great promise future research. Moreover, gaining insights cell-of-origin treatment response holds to advance precision medicine approaches. Addressing is crucial improving moving towards more effective therapies.

Language: Английский

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Introducing HDAC-Targeting Radiopharmaceuticals for Glioblastoma Imaging and Therapy

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(2), P. 227 - 227

Published: Feb. 1, 2023

Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, radiotherapy, chemotherapy and targeted therapy, the overall prognosis remains poor. One of interesting targets GB is histone deacetylase family (HDAC). Due to their pleiotropic effects on, e.g., DNA repair, cell proliferation, differentiation, apoptosis cycle, HDAC inhibitors have gained a lot attention last decade as anti-cancer agents. known underlying mechanism, therapeutic activity not well-defined. In this review, an extensive overview given current status followed by HDAC-targeting radiopharmaceuticals. Imaging expression or could provide key insights regarding role enzymes gliomagenesis, thus identifying patients likely benefit from HDACi-targeted therapy.

Language: Английский

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Valproate and lithium: Old drugs for new pharmacological approaches in brain tumors?

Cancer Letters, Journal Year: 2023, Volume and Issue: 560, P. 216125 - 216125

Published: March 12, 2023

Beyond its use as an antiepileptic drug, over time valproate has been increasingly used for several other therapeutic applications. Among these, the antineoplastic effects of have assessed in vitro and vivo preclinical studies, suggesting that this agent significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. During last years various clinical trials tried to find out if co-administration could enhance activity chemotherapy glioblastoma patients suffering from brain metastases, demonstrating inclusion schedule causes improved median overall survival some but not others. Thus, concomitant are still controversial. Similarly, lithium tested anticancer drug studies mainly using unregistered formulation chloride salts. Although, there no data showing superimposable registered carbonate, shown hepatocellular cancers. However, few interesting performed with carbonate on a very small number patients. Based published data, represent potential complementary approach standard chemotherapy. Same advantageous characteristics less convincing carbonate. Therefore, planning specific phase III is necessary validate repositioning these drugs present future oncological research.

Language: Английский

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Elucidating the Dual Mechanistic Action and Synergism of Platinum Complexes bearing Valproic Acid as Leaving Ligand on NF-κB and Inflammatory Pathways in Glioma

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 290, P. 117522 - 117522

Published: March 19, 2025

Language: Английский

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Effects of valproic acid on rat C6 glioma cells proliferation and animals survival in the experiment

Ukrainian Neurosurgical Journal, Journal Year: 2025, Volume and Issue: 31(1), P. 16 - 22

Published: March 31, 2025

Лікування гліобластоми є актуальною проблемою нейроонкології, оскільки навіть сучасні медичні та технологічні розробки не дали змоги досягти значного прогресу в її вирішенні. Вальпроєва кислота протиепілептичним препаратом із доведеною ефективністю. Також вивчають потенційні онкостатичні ефекти при лікуванні пухлин головного мозку. Мета: вивчити вплив вальпроєвої кислоти на ріст гліоми C6 щурів in vivo. Матеріали і методи. Після експериментального моделювання проводили ін’єкції внутрішньоочеревинно. Виживаність аналізували за допомогою кривої Каплана‒Мейєра. Гістологічно досліджували пухлини. Висновки про проліферативну активність робили підставі визначення концентрації Ki67-позитивних клітин. Результати. статистично значуще підвищувала медіану (Ме) виживаності гліомами від 11 до 13 діб (р=0,05) значно знижувала клітин (3,53±0,96, Ме ‒3,08 2,17±0,38, ‒ 2,11, р=0,05). Висновки. Отримані результати свідчать те, що вальпроєва пригнічує vivo, тому можна розглядати як перспективний засіб у комплексній терапії гліом клінічній практиці, потребує подальших досліджень.

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The tumor-associated fibrotic reactions in microenvironment aggravate glioma chemoresistance

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: May 28, 2024

Malignant gliomas are one of the most common and lethal brain tumors with poor prognosis. Most patients glioblastoma (GBM) die within 2 years diagnosis, even after receiving standard treatments including surgery combined concomitant radiotherapy chemotherapy. Temozolomide (TMZ) is first-line chemotherapeutic agent for gliomas, but frequent acquisition chemoresistance generally leads to its treatment failure. Thus, it’s urgent investigate strategies overcoming glioma chemoresistance. Currently, many studies have elucidated that cancer not only associated high expression drug-resistance genes in cells also can be induced by alterations tumor microenvironment (TME). Numerous explored use antifibrosis drugs sensitize chemotherapy solid tumors, surprisingly, these preclinical clinical attempts exhibited promising efficacy treating certain types cancer. However, it remains unclear how tumor-associated fibrotic (GME) mediate Furthermore, possible mechanisms behind this phenomenon yet determined. In review, we summarized molecular which reactions drive transformation from a chemosensitive chemoresistant state. Additionally, outlined antitumor functions, suggesting may effective through TME normalization.

Language: Английский

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Hippo Pathway in Regulating Drug Resistance of Glioblastoma

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(24), P. 13431 - 13431

Published: Dec. 14, 2021

Glioblastoma (GBM) represents the most common and malignant tumor of Central Nervous System (CNS), affecting both children adults. GBM is one deadliest types it shows a strong multidrug resistance (MDR) an immunosuppressive microenvironment which remain great challenge to therapy. Due high recurrence after treatment, understanding chemoresistance phenomenon how stimulate antitumor immune response in this pathology crucial. The deregulation Hippo pathway involved genesis, nature GBM. This evolutionarily conserved signaling with kinase cascade core, controls translocation YAP (Yes-Associated Protein)/TAZ (Transcriptional Co-activator PDZ-binding Motif) into nucleus, leading regulation organ size growth. With review, we want highlight immunosuppression work has key role them. We linger on evaluating effect its de-regulation among different human cancers. Moreover, consider pathways are cross-linked genesis hypothetical mechanisms responsible for activation Furthermore, describe various drugs targeting pathway. In conclusion, all evidence described largely support involvement gliomas progression, development microenvironment. Therefore, promising target treatment grade particular

Language: Английский

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Current Opportunities for Targeting Dysregulated Neurodevelopmental Signaling Pathways in Glioblastoma

Cells, Journal Year: 2022, Volume and Issue: 11(16), P. 2530 - 2530

Published: Aug. 15, 2022

Glioblastoma (GBM) is the most common and highly lethal type of brain tumor, with poor survival despite advances in understanding its complexity. After current standard therapeutic treatment, including tumor resection, radiotherapy concomitant chemotherapy temozolomide, median overall patients this less than 15 months. Thus, there an urgent need for new insights into GBM molecular characteristics progress targeted therapy order to improve clinical outcomes. The literature data revealed that a number different signaling pathways are dysregulated GBM. In review, we intended summarize discuss modalities focused on targeting A better opportunities influences malignant behavior cells might open way development novel GBM-targeted therapies.

Language: Английский

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Anti‑tumor effects of anti‑epileptic drugs in malignant glioma cells

Oncology Reports, Journal Year: 2022, Volume and Issue: 48(6)

Published: Oct. 21, 2022

Patients with glioblastoma frequently suffer epileptic seizures and often require anticonvulsant therapy during the treatment course. The present study investigated four common antiepileptic drugs, perampanel, carbamazepine (CBZ), sodium valproate (VPA) levetiracetam (LEV), which are expected to have antitumor effects, determined most beneficial drug for of malignant glioma by comparing effects such as inhibition cell proliferation suppression migration invasion (using Transwell assays). growth was using six lines (A‑172, AM‑38, T98G, U‑138MG, U‑251MG YH‑13). Significant observed in all treated three CBZ, VPA two LEV at therapeutic blood concentration levels drugs be used antiepileptics. Further combination temozolomide were T98G lines, confirmed both perampanel cells LEV, but not CBZ VPA. Cell significantly suppressed or LEV. To investigate mechanisms suppresses cells, expression mRNA related epithelial‑mesenchymal transition following analyzed reverse transcription‑quantitative PCR lines. Rac1 RhoA, constitute cytoskeleton that enhances motility, reduced Furthermore, mesenchymal marker N‑cadherin, promotes infiltration, decreased, epithelial E‑cadherin, strengthens cell‑cell adhesion reduces increased. matrix metalloproteinase‑2, a proteolytic enzyme, reduced. These may reduce motility increase between suggesting migration. In conclusion, suggests more terms efficacy than other glioma.

Language: Английский

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Revisiting Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients with Glioblastoma—Proteomic Alteration and Comparison Analysis with the Standard-of-Care Chemoirradiation

Biomolecules, Journal Year: 2023, Volume and Issue: 13(10), P. 1499 - 1499

Published: Oct. 10, 2023

Background: Glioblastoma (GBM) is the most common brain tumor with an overall survival (OS) of less than 30% at two years. Valproic acid (VPA) demonstrated benefits documented in retrospective and prospective trials, when used combination chemo-radiotherapy (CRT). Purpose: The primary goal this study was to examine if differential alteration proteomic expression pre vs. post-completion concurrent chemoirradiation (CRT) present addition VPA as compared standard-of-care CRT. second explore associations between alterations response VPA/RT/TMZ correlated patient outcomes. third use profile determine mechanism action setting. Materials Methods: Serum obtained pre- post-CRT analyzed using aptamer-based SOMAScan® assay. Twenty-nine patients received CRT plus VPA, 53 alone. Clinical data were via a database chart review. Tests for differences protein changes radiation therapy (RT) or without conducted individual proteins two-sided t-tests, considering p-values <0.05 significant. Adjustment age, sex, other clinical covariates hierarchical clustering significant differentially expressed carried out, Gene Set Enrichment analyses performed Hallmark gene sets. Univariate Cox proportional hazards models test association survival. lasso regression method 10-fold cross-validation employed combinations that could predict Predictiveness curves plotted (p-value < 0.005) show probability percentiles. Results: A total 124 identified cohorts who those factors did not confound results, distinct VPA-treated population identified. Time-dependent ROC OS PFS landmark times 20 months 6 months, respectively, revealed AUC 0.531, 0.756, 0.774 0.535, 0.723, 0.806 expression, factors, indicating proteome can provide additional risk discrimination already provided by standard greater impact on PFS. Several interest Alterations GALNT14 (increased) CCL17 (decreased) (p = 0.003 0.003, FDR 0.198 both) associated improvement both pre-CRT 480 predictive 212 0.05), which 112 overlapped However, FDR-adjusted p values high, (the smallest value 0.586) 0.998). PLCD3 had lowest p-value 0.002 0.0004 PFS, respectively), its elevation prior predicted superior administration. Cancer hallmark genesets observed administration aligned known signal transduction pathways agent malignancy non-malignancy settings, GBM signaling, included epithelial–mesenchymal transition, hedgehog Il6/JAK/STAT3, coagulation, NOTCH, apical junction, xenobiotic metabolism, complement signaling. Conclusions: Differential VPA. Using post-data, prognostic emerged analysis. data, potentially signals sets not, align biological mechanisms may allow identification novel biomarkers outcomes help advance future trials.

Language: Английский

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