The Role of Chronic Inflammation in Pediatric Cancer

Cancers, Journal Year: 2025, Volume and Issue: 17(1), P. 154 - 154

Published: Jan. 6, 2025

Inflammation plays a crucial role in wound healing and the host immune response following pathogenic invasion. However, unresolved chronic inflammation can result tissue fibrosis genetic alterations that contribute to pathogenesis of human diseases such as cancer. Recent scientific advancements exploring underlying mechanisms malignant cellular transformations cancer progression have exposed significant disparities between pediatric adult-onset cancers. For instance, cancers tend lower mutational burdens arise actively developing tissues, where cell-cycle dysregulation leads gene, chromosomal, fusion gene development not seen counterparts. As such, findings adult cannot be directly applied cancers, unique mutations inherent etiologies remain poorly understood. Here, we review processes chromosomal instability, tumor microenvironment, tumorigenesis transformation explore current therapeutic interventions maintain and/or restore inflammatory homeostasis.

Language: Английский

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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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BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

Molecules, Journal Year: 2023, Volume and Issue: 28(7), P. 3043 - 3043

Published: March 29, 2023

The mammalian bromodomain and extra-terminal domain (BET) family of proteins consists four conserved members (Brd2, Brd3, Brd4, Brdt) that regulate numerous cancer-related immunity-associated genes. They are epigenetic readers histone acetylation with broad specificity. BET linked to cancer progression due their interaction cellular including chromatin-modifying factors, transcription modification enzymes. spectacular growth in the clinical development small-molecule inhibitors underscores interest importance this protein as an anticancer target. Current approaches targeting for therapy rely on mimics block bromodomains from binding chromatin. However, bromodomain-targeted agents suffering dose-limiting toxicities because effects other bromodomain-containing proteins. In review, we provided updated summary about evolution inhibitors. design bivalent inhibitors, kinase dual proteolysis-targeting chimeras (PROTACs), Brd4-selective discussed. novel strategy unique C-terminal (ET) its therapeutic significance will also be highlighted. Apart single agent treatment alone, have been combined chemotherapeutic modalities demonstrating favorable outcomes. investigation specific biomarkers predicting efficacy resistance is needed fully realize potential setting.

Language: Английский

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Cohesin regulates alternative splicing

Science Advances, Journal Year: 2023, Volume and Issue: 9(9)

Published: March 1, 2023

Cohesin, a trimeric complex that establishes sister chromatid cohesion, has additional roles in chromatin organization and transcription. We report among those is the regulation of alternative splicing through direct interactions situ colocalization with factors. Degradation cohesin results marked changes splicing, independent its effects on Introduction single point mutation embryonic stem cells alters patterns, demonstrating causality. In primary human acute myeloid leukemia, mutations are highly correlated distinct patterns splicing. Cohesin also directly interacts BRD4, another regulator, to generate pattern from either factor alone, documenting their functional interaction. These findings identify role for regulating both normal leukemic provide insights into disease.

Language: Английский

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Novel gene therapy for drug-resistant melanoma: Synergistic combination of PTEN plasmid and BRD4 PROTAC-loaded lipid nanocarriers

Molecular Therapy — Nucleic Acids, Journal Year: 2024, Volume and Issue: 35(3), P. 102292 - 102292

Published: July 31, 2024

Patients suffering from BRAF mutant melanoma have tumor recurrence within merely 7 months of treatment with a potent inhibitor (BRAFi) like vemurafenib. It has been proven that diverse molecular pathways driving BRAFi resistance converge to activation c-Myc in melanoma. Therefore, we identified novel combinatorial therapeutic strategy by targeting loss phosphatase and tensin homolog deleted on chromosome 10 (PTEN) suppressor gene upregulated BRD4 oncoprotein as Myc-dependent vulnerabilities drug-resistant Being promising targets, decided concomitantly deliver PTEN plasmid targeted PROteolysis-TArgeting Chimera (ARV) drug the "undruggable" BRAFi-resistant Since ARV are distinct their physicochemical properties, fabricated PTEN-plasmid loaded lipid nanoparticles (PL-NANO) ARV-825-loaded nanoliposomes (AL-NANO) yield mean particle size less than 100 nm greater 99% encapsulation efficiency for each payload. Combination PL-NANO AL-NANO displayed synergistic growth inhibition substantial apoptosis vitro two-dimensional three-dimensional models. Importantly, simultaneous delivery achieved significant upregulation expression levels degradation protein ultimately downregulate cells. Altogether, nanocarriers delivering this lethal cocktail stands one-of-a-kind therapy target undruggable oncogene melanoma.Graphical abstract

Language: Английский

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Untangling the Role of MYC in Sarcomas and Its Potential as a Promising Therapeutic Target

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 1973 - 1973

Published: Feb. 25, 2025

MYC plays a pivotal role in the biology of various sarcoma subtypes, acting as key regulator tumor growth, proliferation, and metabolic reprogramming. This oncogene is frequently dysregulated across different sarcomas, where its expression closely intertwined with molecular features unique to each subtype. interacts critical pathways such cell cycle regulation, apoptosis, angiogenesis, amplifying aggressiveness resistance standard therapies. Furthermore, influences microenvironment by modulating cell-extracellular matrix interactions immune evasion mechanisms, further complicating therapeutic management. Despite well-established centrality pathogenesis, targeting directly remains challenging due "undruggable" protein structure. However, emerging strategies, including indirect inhibition via epigenetic modulators, transcriptional machinery disruptors, pathway inhibitors, offer new hope for treatment. review underscores importance understanding intricate roles subtypes guide development effective targeted Given MYC's central tumorigenesis progression, innovative approaches aiming at could transform landscape patients, providing much-needed avenue overcome improve clinical outcomes.

Language: Английский

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Trichostatin A augments cell migration and epithelial-mesenchymal transition in esophageal squamous cell carcinoma through BRD4/c-Myc endoplasmic reticulum-stress pathway

World Journal of Gastroenterology, Journal Year: 2025, Volume and Issue: 31(11)

Published: March 12, 2025

BACKGROUND The causes of death in patients with advanced esophageal cancer are multifactorial, tumor metastasis being one the important factors. Histone acetylation promotes migration squamous cell carcinoma (ESCC) cells, while histone deacetylase inhibitor (HDACi) shows complex effects on functions. AIM To comprehensively elucidate impact and molecular mechanisms trichostatin A (TSA), an HDACi, ESCC through bromodomain-containing protein (BRD4)/cellular myelocytomatosis oncogene (c-Myc)/endoplasmic reticulum (ER)-stress. METHODS TSA lines Eca109 EC9706 were evaluated using Transwell assays, small interfering transfection pathway-specific inhibitors to underlying mechanisms. mRNA levels involved examined by quantitative real-time polymerase chain reaction. Protein acetylated histones H3 (acH3) H4, BRD4, c-Myc, as well markers ER stress epithelial-mesenchymal transition (EMT), analyzed western blot. Additionally, this method was also used examine acH3 tissues adjacent tissues. Patient outcomes subsequently tracked identify prognostic indicators Log-Rank tests Cox multivariate analysis. RESULTS promoted cells stimulating EMT process. TSA-mediated facilitated recruitment a protein, triggering expression c-Myc. This cascade induced enhanced cells. further mechanism, we employed various interventions including 4-phenylbutyric acid, knockdown c-Myc BRD4 expression, utilization carboxylic acid 1. Mechanistically, these studies revealed that which turn triggered sequential activation EMT, thereby promoting specimens from 43 ESCC, both paired Statistical analysis unveiled negative correlation between level long-term prognosis ESCC. CONCLUSION BRD4/c-Myc/ER pathway. Moreover, elevated correlated poor prognosis. These findings enhance our understanding HDACi therapy.

Language: Английский

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Cyclin-dependent kinases as mediators of aberrant transcription in prostate cancer

Translational Oncology, Journal Year: 2025, Volume and Issue: 55, P. 102378 - 102378

Published: April 1, 2025

Language: Английский

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The de novo DNA methyltransferase 3B is a novel epigenetic regulator of MYC in multiple myeloma, representing a promising therapeutic target to counter relapse

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: April 17, 2025

Abstract Background The plasma cell malignancy multiple myeloma (MM) remains incurable due to the inevitable development of drug resistance (DR). Epigenetic modifiers are frequently mutated or deregulated in MM patients, contributing progression and relapse. Overexpression de novo DNA methyltransferase 3B (DNMT3B) has been reported, correlating with poor prognosis. However, its exact role biology relapse elusive. Methods To evaluate basal expression prognostic value DNMT3B mRNA terms overall survival publicly available gene profiling datasets GSE2658, GSE9782, GSE4581, E-MTAB-372, E-TABM-1088 E-TABM-937 were used. Both selective inhibitor Nanaomycin A genetic knockdown using a doxycycline inducible shRNA against used target DNMT3B. Viability apoptosis assessed respectively CellTiter-Glo assay AnnexinV/7AAD stainings. Cell proliferation was measured by BrdU incorporation cycle analysis, while clonogenic capacity evaluated colony formation assay. Finally, RNA-seq performed upon knockdown. Results Here, we show that is significantly increased relapsed setting high levels strongly disease high-risk disease, irrespective treatment. Targeting either inhibition impaired growth, clonogenicity. Moreover, reduced viability primary cells from newly diagnosed patients. Mechanistic studies revealed mainly affects stemness-related transcriptional programs. Notably, depletion affected stability master regulator MYC, thereby reducing c-MYC both parental overexpressing cells. (re)sensitized bortezomib, melphalan anti-CD38 monoclonal antibodies (daratumumab, isatuximab). Conclusion Collectively, our findings uncover as targetable vulnerability patients DNMT3B/MYC levels.

Language: Английский

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MYCN as an oncogene in pediatric brain tumors

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: April 29, 2025

MYCN, or N-Myc, is a member of the MYC family transcription factors, which plays key role in tumor formation by regulating genes involved proliferation, differentiation, and apoptosis. MYCN essential for neural development, especially appropriate growth differentiation progenitor cells, its aberrant expression contributes to tumorigenesis. Gene amplification mutations this gene have been observed wide variety cancer types, particularly pediatric brain non-brain tumors, such as neuroblastoma. Previous studies provided extensive insights into complex regulatory network factor. Additionally, presence alterations patient tumors serve factor risk stratification, it correlates with poorer outcomes, presents significant challenge treatment. Despite clinical significance, therapeutic targeting challenging due structure, nuclear localization, pathways. Efforts target focused on destabilizing protein, modulating epigenetic mechanisms, disrupting transcriptional network. This review explores different subtypes highlights novel ongoing approaches. However, further research necessary develop more effective therapies improve survival outcomes patients MYCN-driven tumor.

Language: Английский

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