Cancer gene therapy最新文献

{"title":"Hemorrhagic and ischemic risks of anti-VEGF therapies in glioblastoma","authors":"Ozal Beylerli, Ilgiz Gareev, Andrey Kaprin, Aamir Ahmad, Vladimir Chekhonin, Shanshan Yang, Guang Yang","doi":"10.1038/s41417-025-00914-8","DOIUrl":"10.1038/s41417-025-00914-8","url":null,"abstract":"Glioblastoma (GBM) is one of the most aggressive primary brain tumors, characterized by extensive neovascularization and a highly infiltrative phenotype. Anti-vascular endothelial growth factor (VEGF) therapies, such as bevacizumab, have emerged as significant adjunct treatments for recurrent and high-grade GBM by targeting abnormal tumor vasculature. Despite demonstrated benefits in slowing tumor progression and alleviating peritumoral edema, these agents are associated with notable vascular complications, including hemorrhagic and ischemic events. Hemorrhagic complications range from minor intracranial microbleeds to life-threatening intracranial hemorrhages (ICH). Mechanistically, VEGF inhibition disrupts endothelial function and decreases vascular integrity, making already fragile tumor vessels prone to rupture. Glioma-associated vascular abnormalities, including disorganized vessel networks and compromised blood-brain barrier, further exacerbate bleeding risks. Concurrent use of anticoagulants, hypertension, and genetic predispositions also significantly elevate hemorrhagic risk. In addition to bleeding complications, ischemic events are increasingly recognized in patients receiving anti-VEGF therapy. Reduced vascular endothelial cells (ECs) survival and diminished microvascular density can lead to regional hypoperfusion and potentially precipitate cerebrovascular ischemia. Impaired vasoreactivity and increased vascular resistance, often accompanied by endothelial dysfunction and microvascular rarefaction, contribute to elevated stroke and arterial thrombotic risk. This review synthesizes current evidence on hemorrhagic and ischemic complications arising from anti-VEGF therapy in GBM. We discuss underlying pathophysiological mechanisms, risk factors, and clinically relevant biomarkers, as well as prevention strategies—such as rigorous blood pressure (BP) control and close monitoring of coagulation parameters. We further highlight emerging avenues in precision medicine, including pharmacogenomic profiling and targeted adjunct agents that protect vascular integrity, aimed at mitigating adverse vascular events while preserving therapeutic efficacy. The goal is to optimize outcomes for GBM patients by balancing the benefits of anti-VEGF therapy with vigilant management of its inherent vascular risks. In addition, this study analyzes existing clinical trials of the use of anti-VEGF drugs in the treatment of gliomas using data from the clinicaltirals.gov website.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 7","pages":"762-777"},"PeriodicalIF":5.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-cancer oncogenic properties and therapeutic potential of SF3B4","authors":"Yanmei Shi, Qimei Pan, Wenli Chen, Limin Xie, Shiru Tang, Zhizhi Yang, Man Zhang, Dong Yin, Lehang Lin, Jian-You Liao","doi":"10.1038/s41417-025-00910-y","DOIUrl":"10.1038/s41417-025-00910-y","url":null,"abstract":"Splicing factor 3B (SF3B) subunit 4 (SF3B4), an SF3B complex component essential for spliceosome assembly and accurate splicing, plays a major role in cancer development. However, the precise mechanism through which SF3B4 contributes to tumor growth remains unclear. Here, we demonstrate that SF3B4 is strongly expressed in patients with various cancer types and correlated with their survival. By using hepatocellular carcinoma (HCC) as a model, we reveal that SF3B4’s interactions with and regulatory influence on the checkpoint protein BUB1 are essential for appropriate cancer cell mitosis and proliferation. Our results thus demonstrate the roles of SF3B4 as both a cell-cycle regulator and an oncogenic factor in HCC, highlighting its potential as a pan-cancer therapeutic target and diagnostic biomarker.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 6","pages":"706-720"},"PeriodicalIF":5.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human endogenous retroviruses (HERVs) associated with glioblastoma risk and prognosis","authors":"Harun Mazumder, Hui-Yi Lin, Melody Baddoo, Wojciech Gałan, Diana Polania-Villanueva, Chindo Hicks, David Otohinoyi, Francesca Peruzzi, Zbigniew Madeja, Victoria P. Belancio, Erik K. Flemington, Krzysztof Reiss, Monika Rak","doi":"10.1038/s41417-024-00868-3","DOIUrl":"10.1038/s41417-024-00868-3","url":null,"abstract":"Emerging evidence suggests expression from human endogenous retrovirus (HERV) loci likely contributes to, or is a biomarker of, glioblastoma multiforme (GBM) disease progression. However, the relationship between HERV expression and GBM malignant phenotype is unclear. Applying several in silico analyses based on data from The Cancer Genome Atlas (TCGA), we derived a locus-specific HERV transcriptome for glioma that revealed 211 HERVs significantly dysregulated in the comparisons of GBM vs. normal brain (NB), GBM vs. low-grade glioma (LGG), and LGG vs. NB. Our analysis supported development of a unique HERV scoring algorithm that segregated GBM, LGG, and NB. Interestingly, lower HERV scores showed correlation with lower survival in GBM. However, HERV scores were less robust in predicting LGG survival or LGG progression to GBM. Functional prediction analysis linked the 211 HERV loci with 18 voltage-gated potassium channel genes. The functional link between dysregulated HERVs and specific potassium channel genes may contribute to better understanding of GBM pathogenesis, disease progression, and possibly drug resistance.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 6","pages":"622-632"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural regulation of PLK1 activity: implications for cell cycle function and drug discovery","authors":"Danda Chapagai, Klaus Strebhardt, Michael D. Wyatt, Campbell McInnes","doi":"10.1038/s41417-025-00907-7","DOIUrl":"10.1038/s41417-025-00907-7","url":null,"abstract":"Polo Like Kinase 1 (PLK1), a key regulator of mitosis whose overexpression is often associated with poor survival rates in cancer, continues to be widely investigated as an oncology drug target with clinical trials evaluating second and third generation inhibitors. In addition to the conserved N-terminal kinase domain (KD), a unique characteristic of the Polo-Like kinase family is the C-terminal polo-box domain (PBD). The PBD contains a phosphopeptide binding site that recognizes substrates primed by other kinases and furthermore is responsible for subcellular localization of PLK1 to specific sites in the nucleus including centrosomes and kinetochores. Another role of the PBD is its regulatory ability through domain-domain interactions with the KD to maintain an autoinhibited state of PLK1. Insights into post translational modifications and the PBD – KD domain-domain association have been obtained and show that key events in PLK1 regulation include phosphosubstrate binding, T210 phosphorylation and engagement with the Bora protein. These can induce an open and active conformation where the domain-domain inhibitory interactions no longer dominate. Further regulatory events recently described include the interchange between monomeric and dimeric forms, which can also serve to inhibit or activate PLK1 during the cell cycle. Different oligomeric forms of PLK1, existing as homodimers and heterodimers with PLK2, have been identified and likely play context dependent roles. This review provides an overview of recent information describing structural and mechanistic insights into inhibition of PLK1 and the temporal and spatial requirements of its activation and regulation. It also covers recent insights into the conformational regulation of other members of the Polo-Like kinase family. The implications of the conformational regulation of PLK1 with respect to cell cycle function and drug discovery are significant and are therefore discussed in detail.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 6","pages":"608-621"},"PeriodicalIF":5.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Old versus new: upstream and downstream of promyelocytic leukemia zinc finger protein","authors":"Kai Wang, Deyu Guo, Shijie Sun, Kang Tian, Hongchang Shen, Jiajun Du","doi":"10.1038/s41417-025-00912-w","DOIUrl":"10.1038/s41417-025-00912-w","url":null,"abstract":"Promyelocytic leukemia zinc finger (PLZF) is a member of the zinc finger protein family and has been extensively studied due to its crucial role in influencing stem cell self-renewal, spermatogenesis, T cell differentiation, tumorigenesis, and development. Its function is regulated by multidimensional and multilevel regulation. Recent studies have explored the mechanism of action of PLZF in different diseases and related treatment strategies. This study aimed to summarize the regulatory mechanisms underlying PLZF expression and function, and update the latest PLZF regulatory targets and interacting molecules. We also summarized the mechanism by which PLZF promoted the transcriptional activation of target genes, besides its role as a transcriptional repressor. This study revealed a more detailed upstream and downstream regulatory mechanism of PLZF, providing directions for future research.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 7","pages":"750-761"},"PeriodicalIF":5.0,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Nrf2 overexpression increases the resistance of acute myeloid leukemia to cytarabine by inhibiting replication factor C4","authors":"Tianzhen Hu, Chengyun Pan, Tianzhuo Zhang, Ming Ni, Weili Wang, Siyu Zhang, Ying Chen, Jishi Wang, Qin Fang","doi":"10.1038/s41417-025-00913-9","DOIUrl":"10.1038/s41417-025-00913-9","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 6","pages":"739-739"},"PeriodicalIF":5.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glioblastoma-associated macrophages in glioblastoma: from their function and mechanism to therapeutic advances","authors":"Yuqin Zhang, Hanxing He, Xin Fu, Ganzhi Liu, Huiying Wang, Wen Zhong, Xia Xu, Bo Chen, Lin Mei","doi":"10.1038/s41417-025-00905-9","DOIUrl":"10.1038/s41417-025-00905-9","url":null,"abstract":"Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults and has high mortality rates worldwide. GBM progression, treatment, and prognosis are influenced by the tumor microenvironment (TME), which includes immune, stromal, and tumor cells. Among them, glioblastoma-associated macrophages (GAMs) act as key regulators of GBM pathobiology. GAMs exhibit remarkable plasticity, as they can exhibit both protumor and antitumor effects. However, their function is determined by polarization and the TME. In this review, we provide a comprehensive overview of the current understanding of the biology of GAMs in GBM, including their origins, phenotypic diversity, and functional roles. We discuss the intricate crosstalk between GAMs and tumor cells, as well as other immune and stromal components, and highlight the mechanisms underlying GAM-mediated tumor progression, invasion, angiogenesis, and immune system evasion. Furthermore, we explore the therapeutic implications of targeting GAMs in GBM and discuss emerging strategies aimed at reprogramming GAMs toward an antitumorigenic phenotype or selectively depleting protumorigenic subsets. The final aim is to develop innovative therapeutic approaches that disrupt GBMs. By leveraging our increased understanding of GAM biology, we lay the foundation for transformative advances in GBM treatment to improve patient prognosis.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 6","pages":"595-607"},"PeriodicalIF":5.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring RNA biology in pseudomyxoma peritonei uncovers splicing dysregulation as a novel, targetable molecular vulnerability","authors":"María Trinidad Moreno-Montilla, Sergio Pedraza-Arevalo, Ana Martínez-López, Ricardo Blázquez-Encinas, Víctor García-Vioque, Lidia Rodríguez-Ortiz, Francisca Valenzuela-Molina, Blanca Rufián-Andújar, Melissa Granados-Rodríguez, Rosa Ortega-Salas, Emilia Alors-Pérez, Mari C. Vázquez-Borrego, Antonio Romero-Ruiz, Justo P. Castaño, Álvaro Arjona-Sánchez, Alejandro Ibáñez-Costa","doi":"10.1038/s41417-025-00911-x","DOIUrl":"10.1038/s41417-025-00911-x","url":null,"abstract":"Pseudomyxoma peritonei (PMP) is a rare neoplasm coursing with uncontrollable mucus accumulation, with a high relapse rate. RNA biology processes have emerged as new players in cancer development and progression, nevertheless their role in PMP remains unknown. In this study, we aimed to examine RNA-regulatory machineries in PMP and their potential contribution to this disease progression. We analyzed 62 splicing-related genes, 27 RNA exosome and 21 nonsense-mediated decay genes, in a cohort of 29 patients using a microfluidic array, comparing tumor and control/reference tissues, together with external RNA-seq and proteomic data. Our results revealed a profound dysregulation of key components, which correlated to relevant clinical parameters and enabled to distinguish between tumor and control tissues. In vitro splicing inhibition using Pladienolide-B, as well as the modulation of specific splicing factors, reduced aggressiveness parameters, enhanced the effect of clinically used drugs, and revealed a strong correlation between dysregulated genes and key cancer-related genes. This inhibition also affected mucin secretion and mucin variants production. Collectively, our findings provide the first evidence for dysregulation of the genes of pivotal RNA-regulatory processes in PMP, implying that these targetable mechanisms may be functionally altered and play a role in the disease. Hence, a thorough understanding of its RNA biology could aid in the discovery of new clinically actionable vulnerabilities in this rare disease.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 6","pages":"721-736"},"PeriodicalIF":5.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate-coated polyurea-siRNA dendriplex: a gene therapy-directed and metabolism-based strategy to impair glioblastoma (GBM)","authors":"Filipa Martins, Renata Arada, Hélio Barros, Paulo Matos, José Ramalho, Valentín Ceña, Vasco D. B. Bonifácio, Luís G. Gonçalves, Jacinta Serpa","doi":"10.1038/s41417-025-00906-8","DOIUrl":"10.1038/s41417-025-00906-8","url":null,"abstract":"Glioblastoma (GBM) is a highly lethal disease with limited treatment options due to its infiltrative nature and the lack of efficient therapy able to cross the protective blood-brain barrier (BBB). GBMs are metabolically characterized by increased glycolysis and glutamine dependence. This study explores a novel metabolism-based therapeutic approach using a polyurea generation 4 dendrimer (PUREG4) surface functionalized with lactate (LA) (PUREG4-LA24), to take advantage of glucose-dependent monocarboxylate transporters (MCTs) overexpression, loaded with selenium-chrysin (SeChry) and temozolomide (TMZ) or complexed with anti-glutaminase (GLS1) siRNAs to abrogate glutamine dependence. The nanoparticles (PUREG4-LA24) were efficient vehicles for cytotoxic compounds delivery, since SeChry@PUREG4-LA24 and TMZ@PUREG4-LA24 induced significant cell death in GBM cell lines, particularly in U251, which exhibits higher MCT1 expression. The anti-GLS1 siRNA-dendriplex with PUREG4-LA12 (PUREG4-LA12-anti-GLS1-siRNA) knocked down GLS1 in the GBM cell lines. In two in vitro BBB models, these dendriplexes successfully crossed the BBB, decreased GLS1 expression and altered the exometabolome of GBM cell lines, concomitantly with autophagy activation. Our findings highlight the potential of targeting glucose and glutamine pathways in GBM using dendrimer-based nanocarriers, overcoming the BBB and disrupting key metabolic processes in GBM cells.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 6","pages":"690-705"},"PeriodicalIF":5.0,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12245715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: The role of tumor-derived exosomal LncRNA in tumor metastasis","authors":"Zhile Yu, Jiali Fu, Vanya Mantareva, Ivica Blažević, Yusong Wu, Dianchang Wen, Tungalag Battulga, Yuqing Wang, Jianye Zhang","doi":"10.1038/s41417-025-00909-5","DOIUrl":"10.1038/s41417-025-00909-5","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 6","pages":"737-737"},"PeriodicalIF":5.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-025-00909-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}