Cancer gene therapy最新文献

{"title":"Editorial Expression of Concern: p73β-expressing recombinant adenovirus: a potential anticancer agent","authors":"Sanjeev Das, Srikanth Nama, Sini Antony, Kumaravel Somasundaram","doi":"10.1038/s41417-025-00877-w","DOIUrl":"10.1038/s41417-025-00877-w","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 3","pages":"355-355"},"PeriodicalIF":4.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00877-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413237","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":"Biodistribution and toxicity evaluation of oncolytic adenovirus Adf35(OGN) in Syrian hamster and mouse","authors":"Erik Yngve, Malin Eriksson, Anders Hedin, Arwa Ali, Chuan Jin, Olle Korsgren, Di Yu","doi":"10.1038/s41417-025-00875-y","DOIUrl":"10.1038/s41417-025-00875-y","url":null,"abstract":"Oncolytic adenovirus has been widely evaluated as a cancer treatment agent with tolerable toxicity profile. We have recently developed a new oncolytic adenovirus Adf35(OGN) with two immunostimulatory transgenes alpha-1,3-galactosyltransferase (GGTA1) from Sus scrofa and neutrophil-activating protein (NAP) from Helicobacter pylori. Adf35(OGN) can kill tumor cells and trigger a strong immune response against tumor antigens. Here, we report the toxicity and biodistribution of Adf35(OGN) in Syrian hamster and GGTA1-knockout mouse. The virus was delivered subcutaneously in naïve hamsters and intratumorally in GGTA1-knockout mouse in multiple doses at dosages of 1–5 × 1011 viral particles (VP)/kg. The virus did not replicate in any tissues, evidenced as low or no viral copies detected by qPCR. The virus was also found at low levels in biofluids (saliva, urine, and feces), indicating that spread to the environment is low with a low risk of secondary infections via shedding. The virus did not cause any biochemical, hematological, or histopathological alterations. In summary, Adf35(OGN) has a good safety profile in these animal models and these results support future clinical evaluation for Adf35(OGN).","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 3","pages":"297-305"},"PeriodicalIF":4.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00875-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398237","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":"Bacteria, stem cells and cancer","authors":"Giovambattista Pani","doi":"10.1038/s41417-025-00876-x","DOIUrl":"10.1038/s41417-025-00876-x","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 3","pages":"269-272"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363786","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":"Methylstat sensitizes ovarian cancer cells to PARP-inhibition by targeting the histone demethylases JMJD1B/C","authors":"Franziska Maria Schwarz, Daniel Martin Klotz, Ruming Yang, Melanie Brux, Frank Buchholz, Hani Harb, Theresa Link, Pauline Wimberger, Mirko Theis, Jan Dominik Kuhlmann","doi":"10.1038/s41417-025-00874-z","DOIUrl":"10.1038/s41417-025-00874-z","url":null,"abstract":"PARP-inhibitors (PARPi) are an integral part of ovarian cancer treatment. However, overcoming acquired PARPi resistance or increasing the benefit of PARPi in patients without homologous recombination deficiency (HRD) remains an unmet clinical need. We sought to identify genetic modulators of PARPi response, guiding pharmacological PARPi sensitization. CRISPR-Cas9 mediated loss-of-function screen with a focused sgRNA library revealed that DNA-demethylases JMJD1B/JMJD1C, targetable by the small inhibitor methylstat, promote PARPi resistance. Methylstat synergistically interacted with olaparib, and (re-)sensitized ovarian cancer cells to PARPi treatment, surpassing the efficacy of common demethylase inhibitors. Genetic knockout of JMJD1B and/or JMJD1C phenocopied the effect of methylstat in an additive manner. Validation studies revealed methylstat to be a universal PARPi-sensitizing drug, effective, regardless of PARPi resistance status or BRCA1 mutational background. Methylstat modulated clonal cancer dynamics by mitigating positive selection of PARPi-resistant or BRCA1-proficient cells under olaparib treatment. Using a model of PARPi-induced cellular toxicity, we showed that methylstat impairs cellular DNA repair, indicated by an increased susceptibility of ovarian cancer cells to olaparib-induced DNA double strand breaks after methylstat exposure. This study proposes the histone demethylase inhibitor methylstat as an epigenetic drug for overcoming PARPi-resistance or for increasing efficacy of PARPi beyond HRD in ovarian cancer patients.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 3","pages":"286-296"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00874-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363789","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":"Emerging roles of exosomes in diagnosis, prognosis, and therapeutic potential in ovarian cancer: a comprehensive review","authors":"Thunwipa Tuscharoenporn, Nattayaporn Apaijai, Kittipat Charoenkwan, Nipon Chattipakorn, Siriporn C. Chattipakorn","doi":"10.1038/s41417-025-00871-2","DOIUrl":"10.1038/s41417-025-00871-2","url":null,"abstract":"Ovarian cancer is a leading cause of cancer-related deaths in women, and the development of chemoresistance remains a major challenge during and after its treatment. Exosomes, small extracellular vesicles involved in intercellular communication, have emerged as potential biomarkers and therapeutic targets in ovarian cancer. This review summarizes the current literature on differences in exosomal protein/gene expression between chemosensitive and chemoresistant ovarian cancer, and the effects of exosomal modifications on chemotherapeutic response. Clinical studies have identified alterations in several exosomal components from ovarian cancer tissues and serum samples arising as a consequence of chemosensitivity, which indicates their potential usefulness as potential biomarkers for predicting the development of chemoresistance. Interventional investigations from in vitro and in vivo studies demonstrated that modulation of specific exosomal components can influence ovarian cancer cell phenotypes and individual responses to chemotherapy. Exosomal delivery of chemotherapeutic agents, such as cisplatin, has presented as a potential targeted drug delivery strategy for overcoming chemoresistance in preclinical models. In summary, this review highlights the potential for exosomal proteins and genes to be useful biomarkers for predicting chemotherapy response and being therapeutic targets for overcoming chemoresistance in ovarian cancer. However, future research is still needed to validate these findings and explore the clinical utility of exosomal biomarkers and therapeutics in ovarian cancer management. In addition, understanding the molecular mechanisms underlying exosome-mediated chemoresistance may provide valuable insights for the development of personalized therapeutic strategies, improving outcomes for patients with ovarian cancer.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"149-164"},"PeriodicalIF":4.8,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00871-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022201","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":"CRISPR knock-in of a chimeric antigen receptor into GAPDH 3’UTR locus generates potent B7H3-specific NK-92MI cells","authors":"Liujiang Dai, Pengchao Zhang, Xiangyun Niu, Xixia Peng, Rabiatu Bako Suleiman, Guizhong Zhang, Xiaochun Wan","doi":"10.1038/s41417-025-00872-1","DOIUrl":"10.1038/s41417-025-00872-1","url":null,"abstract":"CAR-NK therapy is becoming a promising approach to treat solid tumors. However, the random insertion of the CAR gene and inflexible CAR expression caused by common preparation methods significantly impact its efficacy and safety. Here we successfully established a novel type of CAR-NK cells by integrating CAR sequences into the GAPDH 3’UTR locus of NK-92MI cells (CRISPR-CAR-NK), achieving site-specific integration of the CAR gene and allowing endogenous regulatory components to govern CAR expression. CRISPR-CAR-NK cells had comparable growth capacity but displayed superior anti-tumor activity compared with their lentiviral counterparts. They activated and degranulated more effectively when co-cultured with tumor cells, due to increased expression of activating receptors and decreased expression of inhibitory molecules. They also enhanced the production of Granzyme B and IFN-γ, and more effectively triggered the IFN-γ pathway. Moreover, CRISPR-CAR-NK cells demonstrated distinct properties from conventional CAR-NK concerning metabolic features and signal dependence. Notably, CRISPR-CAR-NK cells exhibited lower metabolic levels without compromising antitumor activity, and their function was less reliant on the PI3K-AKT pathway, implying that the CRISPR-CAR-NK cells have significant potential for enhanced synergy with AKT inhibitors and adaptation to nutrient stress within the tumor microenvironment. These findings provide a novel potential strategy for cancer immunotherapy and an experimental foundation and paradigm for optimizing CAR-NK cells utilizing CRISPR technology, highlighting the potential of CRISPR to advance immunotherapies.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"227-239"},"PeriodicalIF":4.8,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00872-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000642","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":"FBXO22 promotes HCC angiogenesis and metastasis via RPS5/AKT/HIF-1α/VEGF-A signaling axis","authors":"Zhen Lei, Yiming Luo, Junli Lu, Qinggang Fu, Chao Wang, Qian Chen, Zhiwei Zhang, Long Zhang","doi":"10.1038/s41417-024-00861-w","DOIUrl":"10.1038/s41417-024-00861-w","url":null,"abstract":"The gene F-box only protein 22 (FBXO22) has been discovered to promote the development of liver cancer tumors. Nevertheless, there remains considerable ambiguity regarding the involvement of FBXO22 in the processes of angiogenesis and metastasis in hepatocellular carcinoma (HCC). Our study has confirmed a significant upregulation of FBXO22 expression in both HCC samples and cellular models. The increased level of FBXO22 correlates strongly with the number of tumors, presence of vascular invasion, and poor prognosis. Experimental investigations have shown that FBXO22 significantly enhances angiogenesis and metastasis of HCC both in vitro and in vivo. Mechanistically, FBXO22 interacts with and ubiquitinates 40S ribosomal protein S5 (RPS5) on Lys85, thereby promoting its K48-linked ubiquitin-mediated degradation in the cytoplasm. Following a decrease in the expression of RPS5, activation of downstream PI3K/AKT signaling pathway occurs, leading to elevated levels of HIF-1α and vascular endothelial growth factor A (VEGF-A). Our study has shown that FBXO22 facilitates HCC angiogenesis and metastasis via the RPS5/AKT/HIF-1α/VEGF-A signaling axis. Notably, inhibition of FBXO22 enhances the efficacy of Lenvatinib both in vitro and in vivo. Therefore, FBXO22 may present itself as a potential target for therapeutic intervention in the treatment of HCC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"198-213"},"PeriodicalIF":4.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00861-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982764","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":"Exploring metabolic reprogramming in esophageal cancer: the role of key enzymes in glucose, amino acid, and nucleotide pathways and targeted therapies","authors":"Xue-Man Dong, Lin Chen, Yu-Xin Xu, Pu Wu, Tian Xie, Zhao-Qian Liu","doi":"10.1038/s41417-024-00858-5","DOIUrl":"10.1038/s41417-024-00858-5","url":null,"abstract":"Esophageal cancer (EC) is one of the most common malignancies worldwide with the character of poor prognosis and high mortality. Despite significant advancements have been achieved in elucidating the molecular mechanisms of EC, for example, in the discovery of new biomarkers and metabolic pathways, effective treatment options for patients with advanced EC are still limited. Metabolic heterogeneity in EC is a critical factor contributing to poor clinical outcomes. This heterogeneity arises from the complex interplay between the tumor microenvironment and genetic factors of tumor cells, which drives significant metabolic alterations in EC, a process known as metabolic reprogramming. Understanding the mechanisms of metabolic reprogramming is essential for developing new antitumor therapies and improving treatment outcomes. Targeting the distinct metabolic alterations in EC could enable more precise and effective therapies. In this review, we explore the complex metabolic changes in glucose, amino acid, and nucleotide metabolism during the progression of EC, and how these changes drive unique nutritional demands in cancer cells. We also evaluate potential therapies targeting key metabolic enzymes and their clinical applicability. Our work will contribute to enhancing knowledge of metabolic reprogramming in EC and provide new insights and approaches for the clinical treatment of EC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"165-183"},"PeriodicalIF":4.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00858-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963865","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":"Has_circ_ASH1L acts as a sponge for miR-1254 to promote the malignant progression of cervical cancer by targeting CD36","authors":"Jun Zhang, Yan Zhang, Xing Li, Yindi Bao, Jing Yang","doi":"10.1038/s41417-024-00866-5","DOIUrl":"10.1038/s41417-024-00866-5","url":null,"abstract":"Cervical cancer (CC) is a prevalent gynecological malignancy. Increasing evidence suggests that circular RNAs (circRNAs) play a pivotal role in the pathogenesis of CC. However, the regulatory function of circ_ASH1L in CC remains elusive. In this study, we aim to elucidate the precise role and underlying mechanism of circ_ASH1L in the malignant progression of CC. The human CC dataset GSE102686 was extracted from the Gene Expression Omnibus (GEO) database for the analysis of differentially expressed circRNAs. Target gene prediction softwares were utilized to predict the binding of miRNAs to circ_ASH1L sponge. The expression level of circ_ASH1L in CC tissues and cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The characteristics of circ_ASH1L were determined by RNase R digestion, actinomycin D, and nucleo-plasmic separation assays. The effects of circ_ASH1L, miR-1254, and CD36 gain-and-loss on the malignant progression of CC were investigated using Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, wound scratch, transwell, and Western blot assay. The effect of circ_ASH1L on tumorigenicity of CC cells in vivo was evaluated in nude mice through tumor xenograft assay. The targeted regulatory relationship between circ_ASH1L/miR-1254 as well as miR-1254/CD36 was validated by dual-luciferase reporter assay. We screened the differentially expressed circ_ASH1L from the GEO dataset GSE102686 and confirmed its circular structure. Furthermore, we observed a significant upregulation of circ_ASH1L in both CC tissues and cells. Overexpression of circ_ASH1L promotes proliferation, invasion, and migration of CC cells while inhibiting cell apoptosis. However, silencing circ_ASH1L showed opposite results and inhibited tumorigenicity of CC cells in nude mice. Furthermore, we have identified circ_ASH1L as a miR-1254 sponge in CC cells. Notably, our in vitro experiments demonstrated that exogenously modulating the expression of miR-1254 effectively counteracted the impact of circ_ASH1L on the malignant phenotypic characteristics of CC cells. Similarly, modulation of CD36 expression efficiently counteracted the effect of miR-1254 on the malignant biological behavior of CC cells. In conclusion, circ_ASH1L promoted the malignant progression of CC via upregulating CD36 expression through sponging miR-1254.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"214-226"},"PeriodicalIF":4.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920886","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":"PIK3CA mutation fortifies molecular determinants for immune signaling in vascular cancers","authors":"Donghee Lee, Emma C. Kozurek, Md Abdullah, Ethan J. Wong, Rong Li, Zhiyan Silvia Liu, Hai Dang Nguyen, Erin B. Dickerson, Jong Hyuk Kim","doi":"10.1038/s41417-024-00867-4","DOIUrl":"10.1038/s41417-024-00867-4","url":null,"abstract":"Angiosarcomas are a group of vascular cancers that form malignant blood vessels. These malignancies are seemingly inflamed primarily due to their pathognomonic nature, which consists of irregular endothelium and tortuous blood channels. PIK3CA mutations are oncogenic and disrupt the PI3K pathway. In this study, we aimed to define the molecular and functional consequences of oncogenic PIK3CA mutations in angiosarcoma. We first generated two isogenic hemangiosarcoma cell lines harboring the H1047R hotspot mutations in PIK3CA gene using CRISPR/Cas9. We found PIK3CA-mutant cells established distinct molecular signatures in global gene expression and chromatin accessibility, which were associated with enrichment of immune cytokine signaling, including IL-6, IL-8, and MCP-1. These molecular processes were disrupted by the PI3K-α specific inhibitor, alpelisib. We also observed that the molecular distinctions in PIK3CA-mutant cells were linked to metabolic reprogramming in glycolytic activity and mitochondrial respiration. Our multi-omics analysis revealed that activating PIK3CA mutations regulate molecular machinery that contributes to phenotypic alterations and resistance to alpelisib. Furthermore, we identified potential therapeutic vulnerabilities of PIK3CA mutations in response to PI3K-α inhibition mediated by MAPK signaling. In summary, we demonstrate that PIK3CA mutations perpetuate PI3K activation and reinforce immune enrichment to promote drug resistance in vascular cancers.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"254-267"},"PeriodicalIF":4.8,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00867-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871577","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}