Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B DOI Creative Commons
Doha Shokry,

Mehwish Khan,

Christine Powell

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 18, 2024

Abstract Testicular germ cell tumors (TGCTs) can be treated with cisplatin-based therapy. However, a clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Curative cisplatin therapy results in acute and life-long toxicities the young TGCT patient population providing rationale to decrease exposure. In contrast genetic alterations, recent evidence suggests that epigenetics is major driving factor for formation, progression, response chemotherapy. Hence, targeting epigenetic pathways “epidrugs” one potential relatively unexplored strategy advance treatment beyond cisplatin. this report, we demonstrate first time polycomb demethylases KDM6A KDM6B epidrug GSK-J4 treat both cisplatin-sensitive -resistant TGCTs. While had minimal effects alone on tumor growth vivo, it dramatically sensitized TGCTs We validated KDM6A/KDM6B target since depletion similar effect cisplatin-mediated anti-tumor activity transcriptome alterations. Pharmacologic potentiated or primed p53-dominant transcriptional cisplatin, also basal activation p53. Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, methyltransferases, were repressed only KDM6A/KDM6B-targeted cells, implying inhibition sets stage extensive remodeling cells upon treatment. Our findings new potent pharmacologic treating resistant warrants clinical development.

Language: Английский

EZH2: The roles in targeted therapy and mechanisms of resistance in breast cancer DOI Open Access
Y. Chen, Hongyan Zhu,

Yi Luo

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 175, P. 116624 - 116624

Published: April 25, 2024

Drug resistance presents a formidable challenge in the realm of breast cancer therapy. Accumulating evidence suggests that enhancer zeste homolog 2 (EZH2), component polycomb repressive complex (PRC2), may serve as key regulator controlling drug resistance. EZH2 overexpression has been observed and many other malignancies, showing strong correlation with poor outcomes. This review aims to summarize mechanisms by which regulates resistance, specific focus on cancer, order provide comprehensive understanding underlying molecular processes. Additionally, we will discuss current strategies outcomes targeting using both single agents combination therapies, goal offering improved guidance for clinical treatment patients who have developed

Language: Английский

Citations

8
Recent advances in EZH2-based dual inhibitors in the treatment of cancers DOI

Xiaojuan Yang,

Xu Lu, Yang Li

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 256, P. 115461 - 115461

Published: May 5, 2023

Language: Английский

Citations

13
Safety profile of EZH2 inhibitors for cancer: a systematic review and meta-analysis DOI Creative Commons
Zhou Zhao, Xiufeng Chen,

Hua‐Yang Pang

et al.

PeerJ, Journal Year: 2025, Volume and Issue: 13, P. e18871 - e18871

Published: Jan. 27, 2025

To evaluate the safety profiles of EZH2-targeted inhibitors in cancer treatment, focusing on treatment-related adverse events (TRAEs) across various clinical trials. We conducted a systematic review and meta-analysis using data from trials involving EZH2 reported up to May 31, 2024. Databases searched included PubMed, Embase, CENTRAL (Cochrane Central Register Controlled Trials), ClinicalTrials.gov. Studies were those patients treated with as monotherapy or combination, specifically detailing incidence TRAEs. Data all-grade TRAEs, grade 3 higher severe TRAEs extracted analyzed random-effects models. Our 22 studies encompassing 1,002 who met inclusion criteria. commonly observed during inhibitor therapy, affecting 86% (95% CI [79-94%]%; I2 = 89.5%). The was 33% [21-44%]; 93.5%), while occurred 15% cases [9-22%]; 87.5%). most frequently pooled analysis neutropenia (8%), thrombocytopenia anemia (6%). Specifically, for tazemetostat, common TRAE (5%). For SHR2554, prevalent (17%), (7%). Notably, fatalities rare, only 0.9% experiencing potentially fatal outcomes due therapy. demonstrate manageable profile low emphasizing their potential safe therapeutic options treatment. rate rare occurrences deaths support continued use further investigation inhibitors.

Language: Английский

Citations

0
Targeting EZH2 in SMARCB1-deficient sarcomas: Advances and opportunities to potentiate the efficacy of EZH2 inhibitors DOI
Cinzia Lanzi, Noemi Arrighetti, Sandro Pasquali

et al.

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 215, P. 115727 - 115727

Published: Aug. 2, 2023

Language: Английский

Citations

12
Enhancer of Zeste Homolog 2 Inhibitor SHR2554 in Relapsed or Refractory Peripheral T-cell Lymphoma: Data from the First-in-Human Phase I Study DOI
Yuqin Song, Zhengming Jin, Zhiming Li

et al.

Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 30(7), P. 1248 - 1255

Published: Jan. 8, 2024

Patients with peripheral T-cell lymphomas (PTCL) in the relapsed or refractory (r/r) setting have only a limited number of therapies available, and prognosis is extremely poor. SHR2554 an oral inhibitor against EZH2, rational therapeutic target for lymphomas.

Language: Английский

Citations

4
Discovery of 2,4-Quinazolinedione Derivatives as LC3B Recruiters in the Facilitation of Protein Complex Degradations DOI
Yanping Zeng, Jian Xiao, Shi Li

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 287, P. 117293 - 117293

Published: Jan. 19, 2025

Language: Английский

Citations

0
Glutathione-responsive FA-CMC-GNA nanoparticles: a novel approach for enhanced delivery of gambogenic acid in lung cancer treatment DOI Creative Commons

Xiaoling Xu,

Lisha Ye, Chaohui Bao

et al.

Advanced Composites and Hybrid Materials, Journal Year: 2025, Volume and Issue: 8(1)

Published: Feb. 1, 2025

Language: Английский

Citations

0
Polycomb repressive complex 2 (PRC2) pathway’s role in cancer cell plasticity and drug resistance DOI
Pouya Goleij, Mohammad Mahdi Heidari, Mohammad Amin Khazeei Tabari

et al.

Functional & Integrative Genomics, Journal Year: 2025, Volume and Issue: 25(1)

Published: March 6, 2025

Language: Английский

Citations

0
Genetic insights into idiopathic pulmonary fibrosis: a multi-omics approach to identify potential therapeutic targets DOI Creative Commons

Zhuofeng Wen,

Wenpeng Liang, Zhongxia Yang

et al.

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 16, 2025

To identify potential therapeutic targets and evaluate the safety profiles for Idiopathic Pulmonary Fibrosis (IPF) using a comprehensive multi-omics approach. We integrated genomic transcriptomic data to IPF. First, we conducted transcriptome-wide association study (TWAS) Omnibus Transcriptome Test Expression Reference Summary (OTTERS) framework, combining plasma expression quantitative trait loci (eQTL) with IPF Genome-Wide Association Studies (GWAS) summary statistics from Global Biobank (discovery) Finngen (duplication). then applied Mendelian randomization (MR) explore causal relationships. RNA-seq co-expression analysis (bulk, single-cell spatial transcriptomics) was used critical genes, followed by molecular docking their druggability. Finally, phenome-wide MR (PheW-MR) GWAS 679 diseases in UK assessed adverse effects of identified genes. 696 genes associated discovery dataset 986 duplication dataset, 126 overlapping through TWAS. revealed 29 13 linked increased 16 decreased risk. data-based (SMR) confirmed six essential genes: ANO9, BRCA1, CCDC200, EZH1, FAM13A, SFR1. Bulk showed FAM13A upregulation SFR1 EZH1 downregulation Single-cell gene changes across cell types. Molecular binding solid affinities respiratory drugs, PheW-MR highlighted side effects. key genes—ANO9, SFR1—as drug strong affinities, while risks. These findings offer new insights treatment further investigation

Language: Английский

Citations

0
Identification of N6-methyladenosine-associated ferroptosis biomarkers in cervical cancer DOI Creative Commons
Jin-Zhe Liu, Buwei Han, Xijiao Hu

et al.

Hereditas, Journal Year: 2025, Volume and Issue: 162(1)

Published: April 7, 2025

Abstract Background Cervical cancer (CC) stands as a major contributor to female mortality. The pathogenesis of CC is linked with various factors. Our research aimed unravel the underlying mechanisms ferroptosis and m6A RNA methylation in through bioinformatics analysis. Methods Three datasets, including GSE9750, GSE63514, TCGA-CESC, were incorporated. m6A-related genes derived from published sources, while ferroptosis-related obtained FerrDb database. Differential expression correlation analyses performed identify differentially expressed (DE-MRFGs) CC. Subsequently, biomarkers further identified using machine learning techniques. Gene Set Enrichment Analysis (GSEA) Kaplan–Meier (KM) survival analysis also comprehend these biomarkers. Furthermore, competing endogenous RNAs (ceRNA) network involving was established. Finally, verified by real-time quantitative polymerase chain reaction (RT-qPCR). Results From DE-MRFGs, six genes, ALOX12 , EZH2 CA9 CDCA3 CDC25A HSPB1 selected. A nomogram constructed based on exhibited potential clinical diagnostic value for CC, good accuracy confirmed calibration curves. GSEA unveiled associations cell proliferation, spliceosome, base excision repair. KM demonstrated significant differences outcomes between high low expressions samples. ceRNA three biomarkers, such 29 miRNAs, 25 lncRNAs. In RT-qPCR verification, significantly higher samples, control Conclusion Six namely m6A-regulated These findings offer valuable insights into disease hold promise advancing treatment prognosis.

Language: Английский

Citations

0