Cancer gene therapy最新文献_第3页

A conditionally replicative adenovirus vector containing the synNotch receptor gene for the treatment of muscle-invasive bladder cancer

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-02-26 DOI: 10.1038/s41417-025-00879-8

Ruhan A, Hideto Ueki, Shunya Nishioka, Rion Yamazaki, Marina Maekawa, Koichi Kitagawa, Hideaki Miyake, Toshiro Shirakawa

{"title":"A conditionally replicative adenovirus vector containing the synNotch receptor gene for the treatment of muscle-invasive bladder cancer","authors":"Ruhan A, Hideto Ueki, Shunya Nishioka, Rion Yamazaki, Marina Maekawa, Koichi Kitagawa, Hideaki Miyake, Toshiro Shirakawa","doi":"10.1038/s41417-025-00879-8","DOIUrl":"10.1038/s41417-025-00879-8","url":null,"abstract":"Muscle-invasive bladder cancer (MIBC), a highly heterogeneous disease, shows genomic instability and a high mutation rate, making it difficult to treat. Recent studies revealed that cancer stem cells (CSCs) play a critical role in MIBC frequent recurrence and high morbidity. Previous research has shown that Cyclooxygenases-2 (COX-2) is particularly highly expressed in bladder cancer cells. In recent years, the development of oncolytic adenoviruses and their use in clinical trials have gained increased attention. In this study, we composed a conditionally replicative adenovirus vector (CRAd-synNotch) that carries the COX-2 promotor driving adenoviral E1 gene, the synNotch receptor therapeutic gene, and the Ad5/35 fiber gene. Activation of the COX-2 promoter gene causes replication only within COX-2 expressing cancer cells, thereby leading to tumor oncolysis. Also, CD44 and HIF signals contribute to cancer stemness and maintaining CSCs in bladder cancer, and the transduced synNotch receptor inhibits both CD44 and HIF signals simultaneously. We performed an in vivo study using a mouse xenograft model of T24 human MIBC cells and confirmed the significant antitumor activity of CRAd-synNotch. Our findings in this study warrant the further development of CRAd-synNotch for treating patients with MIBC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 3","pages":"306-317"},"PeriodicalIF":4.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00879-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514788","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}

引用次数: 0

The role of tumor-derived exosomal LncRNA in tumor metastasis

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-02-26 DOI: 10.1038/s41417-024-00852-x

Zhile Yu, Jiali Fu, Vanya Mantareva, Ivica Blažević, Yusong Wu, Dianchang Wen, Tungalag Battulga, Yuqing Wang, Jianye Zhang

引用次数: 0

FXYD5 regulates gastric cancer cell metastasis and drug resistance by EMT modulation

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-02-21 DOI: 10.1038/s41417-025-00878-9

Yuning Mao, Yaohua Hu, Han Meng, Jing Qin, Qingling An, Caiqin Zhang, Chenbo Guo, Yong Zhao, Dengxu Tan, Xu Ge, Changhong Shi

{"title":"FXYD5 regulates gastric cancer cell metastasis and drug resistance by EMT modulation","authors":"Yuning Mao, Yaohua Hu, Han Meng, Jing Qin, Qingling An, Caiqin Zhang, Chenbo Guo, Yong Zhao, Dengxu Tan, Xu Ge, Changhong Shi","doi":"10.1038/s41417-025-00878-9","DOIUrl":"10.1038/s41417-025-00878-9","url":null,"abstract":"Gastric cancer (GC) is the third leading cause of cancer-related mortality and the fourth most prevalent malignancy globally. The high prevalence and mortality rates of GC are attributed to various factors, including drug resistance, local recurrence, and distant metastases. There is an urgent need to identify novel therapeutic targets for GC. Patient-derived xenografts (PDX) model offers unique advantages in maintaining the molecular heterogeneity and tumor microenvironment of primary tumors, offering significant advantages for the screening of personalized therapeutic targets. In this study, we established GC PDX models with metastatic potential through orthotopic transplantation and investigated the different gene expressions between primary and metastatic tumors using PCR-array analysis. We found that the metastatic tumors displayed elevated levels of FXYD domain-containing ion transport regulator 5 (FXYD5) compared to the primary tumors. Additionally, reducing FXYD5 expression was found to inhibit the invasion, metastasis, and proliferation of GC cells. Silencing FXYD5 also reversed the resistance of GC cells to doxorubicin and vincristine by modulating the epithelial–mesenchymal transition (EMT) process and the expression of multidrug resistance protein 2. This study indicates that FXYD5 is involved in GC progression and regulates chemotherapy resistance, suggesting its potential as a novel therapeutic target for the clinical treatment of GC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 3","pages":"318-326"},"PeriodicalIF":4.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472150","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}

引用次数: 0

SMARCB1-driven EGFR-GLI1 epigenetic alterations in lung cancer progression and therapy are differentially modulated by MEOX2 and GLI-1

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-02-19 DOI: 10.1038/s41417-025-00873-0

Octavio A. Trejo-Villegas, Priscila Pineda-Villegas, Leonel Armas-López, Criselda Mendoza-Milla, Irlanda Peralta-Arrieta, Oscar Arrieta, Irene H. Heijink, Joaquín Zúñiga, Federico Ávila-Moreno

{"title":"SMARCB1-driven EGFR-GLI1 epigenetic alterations in lung cancer progression and therapy are differentially modulated by MEOX2 and GLI-1","authors":"Octavio A. Trejo-Villegas, Priscila Pineda-Villegas, Leonel Armas-López, Criselda Mendoza-Milla, Irlanda Peralta-Arrieta, Oscar Arrieta, Irene H. Heijink, Joaquín Zúñiga, Federico Ávila-Moreno","doi":"10.1038/s41417-025-00873-0","DOIUrl":"10.1038/s41417-025-00873-0","url":null,"abstract":"Lung cancer remains the leading cause of cancer-related mortality globally, with genes such as SMARCB1, MEOX2, and GLI-1 playing significant roles in its malignancy. Despite their known involvement, the specific molecular contributions of these genes to lung cancer progression, particularly their effects on epigenetic modifications on oncogenes sequences as EGFR and GLI-1, and their influence in the response to EGFR-TKI-based therapies, have not been fully explored. Our study reveals how MEOX2 and GLI-1 are key molecular modulators of the GLI-1 and EGFR-epigenetic patterns, which in turn transcriptionally and epigenetically affect EGFR gene expression in lung cancer. Additionally, MEOX2 was found to significantly promote in vivo lung tumor progression and diminish the effectiveness of EGFR-TKI therapies. Conversely, mSWI/SNF derived subunit SMARCB1 was detected to suppress tumor growth and enhance the oncological therapeutic response in in vivo studies by inducing epigenetic modifications in the GLI-1 and EGFR genetic sequences. Furthermore, our results suggest that BRD9 may contribute to the activation of both lung cancer oncogenes GLI-1 and EGFR. Such findings suggest that SMARCB1 and MEOX2 could serve as important prognosis biomarkers and target genes in human lung cancer therapy, offering new opportunities for the development of more effective and selective treatment strategies in the field of lung malignant diseases.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 3","pages":"327-342"},"PeriodicalIF":4.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00873-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456951","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}

引用次数: 0

Editorial Expression of Concern: p73β-expressing recombinant adenovirus: a potential anticancer agent

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-02-13 DOI: 10.1038/s41417-025-00877-w

Sanjeev Das, Srikanth Nama, Sini Antony, Kumaravel Somasundaram

引用次数: 0

Biodistribution and toxicity evaluation of oncolytic adenovirus Adf35(OGN) in Syrian hamster and mouse

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-02-11 DOI: 10.1038/s41417-025-00875-y

Erik Yngve, Malin Eriksson, Anders Hedin, Arwa Ali, Chuan Jin, Olle Korsgren, Di Yu

{"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}

引用次数: 0

Bacteria, stem cells and cancer

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-02-06 DOI: 10.1038/s41417-025-00876-x

Giovambattista Pani

引用次数: 0

Methylstat sensitizes ovarian cancer cells to PARP-inhibition by targeting the histone demethylases JMJD1B/C

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-02-06 DOI: 10.1038/s41417-025-00874-z

Franziska Maria Schwarz, Daniel Martin Klotz, Ruming Yang, Melanie Brux, Frank Buchholz, Hani Harb, Theresa Link, Pauline Wimberger, Mirko Theis, Jan Dominik Kuhlmann

{"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}

引用次数: 0

Emerging roles of exosomes in diagnosis, prognosis, and therapeutic potential in ovarian cancer: a comprehensive review

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-01-22 DOI: 10.1038/s41417-025-00871-2

Thunwipa Tuscharoenporn, Nattayaporn Apaijai, Kittipat Charoenkwan, Nipon Chattipakorn, Siriporn C. Chattipakorn

{"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}

引用次数: 0

CRISPR knock-in of a chimeric antigen receptor into GAPDH 3’UTR locus generates potent B7H3-specific NK-92MI cells CRISPR敲入GAPDH 3'UTR位点的嵌合抗原受体产生有效的b7h3特异性NK-92MI细胞。

IF 4.8 3区医学

Cancer gene therapy Pub Date : 2025-01-20 DOI: 10.1038/s41417-025-00872-1

Liujiang Dai, Pengchao Zhang, Xiangyun Niu, Xixia Peng, Rabiatu Bako Suleiman, Guizhong Zhang, Xiaochun Wan

{"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}

引用次数: 0