Molecular Therapy Oncolytics最新文献_第4页

Oncolytic virotherapy with intratumoral injection of vaccinia virus TG6002 and 5-fluorocytosine administration in dogs with malignant tumors. 肿瘤内注射牛痘病毒TG6002及5-氟胞嘧啶对犬恶性肿瘤的溶瘤病毒治疗。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-09-21 DOI: 10.1016/j.omto.2023.07.005

Jérémy Béguin, Eve Laloy, Sandrine Cochin, Murielle Gantzer, Isabelle Farine, Christelle Pichon, Baptiste Moreau, Johann Foloppe, Jean-Marc Balloul, Christelle Machon, Jérôme Guitton, Dominique Tierny, Bernard Klonjkowski, Eric Quéméneur, Christelle Maurey, Philippe Erbs

{"title":"Oncolytic virotherapy with intratumoral injection of vaccinia virus TG6002 and 5-fluorocytosine administration in dogs with malignant tumors.","authors":"Jérémy Béguin, Eve Laloy, Sandrine Cochin, Murielle Gantzer, Isabelle Farine, Christelle Pichon, Baptiste Moreau, Johann Foloppe, Jean-Marc Balloul, Christelle Machon, Jérôme Guitton, Dominique Tierny, Bernard Klonjkowski, Eric Quéméneur, Christelle Maurey, Philippe Erbs","doi":"10.1016/j.omto.2023.07.005","DOIUrl":"https://doi.org/10.1016/j.omto.2023.07.005","url":null,"abstract":"TG6002 is an oncolytic vaccinia virus expressing FCU1 protein, which converts 5-fluorocytosine into 5-fluorouracil. The study objectives were to assess tolerance, viral replication, 5-fluorouracil synthesis, and tumor microenvironment modifications to treatment in dogs with spontaneous malignant tumors. Thirteen dogs received one to three weekly intratumoral injections of TG6002 and 5-fluorocytosine. The viral genome was assessed in blood and tumor biopsies by qPCR. 5-Fluorouracil concentrations were measured in serum and tumor biopsies by liquid chromatography or high-resolution mass spectrometry. Histological and immunohistochemical analyses were performed. The viral genome was detected in blood (7/13) and tumor biopsies (4/11). Viral replication was suspected in 6/13 dogs. The median intratumoral concentration of 5-fluorouracil was 314 pg/mg. 5-Fluorouracil was not detected in the blood. An increase in necrosis (6/9) and a downregulation of intratumoral regulatory T lymphocytes (6/6) were observed. Viral replication, 5-fluorouracil synthesis, and tumor microenvironment changes were more frequently observed with higher TG6002 doses. This study confirmed the replicative properties, targeted chemotherapy synthesis, and reversion of the immunosuppressive tumor microenvironment in dogs with spontaneous malignant tumors treated with TG6002 and 5-fluorocytosine.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"103-116"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e4/68/main.PMC10448017.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10105811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Enhancing the effectiveness of γδ T cells by mRNA transfection of chimeric antigen receptors or bispecific T cell engagers. 通过转染嵌合抗原受体或双特异性T细胞接合体的mRNA增强γδ T细胞的有效性。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-09-21 DOI: 10.1016/j.omto.2023.08.003

John Anderson, Marta Barisa

引用次数: 0

Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody. 利用PRL3在儿童实体瘤中的频繁和特异性表达，首次在儿童中使用PRL3-zumab人源化抗体。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-09-21 DOI: 10.1016/j.omto.2023.08.006

Amos Hong Pheng Loh, Min Thura, Abhishek Gupta, Sheng Hui Tan, Kelvin Kam Yew Kuan, Koon Hwee Ang, Khurshid Merchant, Kenneth Tou En Chang, Hui Yi Yon, Yong Chen, Mathew Hern Wang Cheng, Arjandas Mahadev, Matthew Chau Hsien Ng, Michaela Su-Fern Seng, Prasad Iyer, Pei Ling Chia, Shui Yen Soh, Qi Zeng

{"title":"Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody.","authors":"Amos Hong Pheng Loh, Min Thura, Abhishek Gupta, Sheng Hui Tan, Kelvin Kam Yew Kuan, Koon Hwee Ang, Khurshid Merchant, Kenneth Tou En Chang, Hui Yi Yon, Yong Chen, Mathew Hern Wang Cheng, Arjandas Mahadev, Matthew Chau Hsien Ng, Michaela Su-Fern Seng, Prasad Iyer, Pei Ling Chia, Shui Yen Soh, Qi Zeng","doi":"10.1016/j.omto.2023.08.006","DOIUrl":"https://doi.org/10.1016/j.omto.2023.08.006","url":null,"abstract":"Phosphatase of regenerating liver 3 (PRL3) is a specific tumor antigen overexpressed in a broad range of adult cancer types. However, its physiological expression in pediatric embryonal and mesenchymal tumors and its association with clinical outcomes in children is unknown. We sought to profile the expression of PRL3 in pediatric tumors in relation to survival outcomes, expression of angiogenesis markers, and G-protein-coupled receptor (GPCR)-mitogen-activated protein kinase (MAPK) signaling targets. PRL3-zumab, a first-in-class humanized antibody, was administered in a dose escalation schedule in a first-in-child clinical trial to study toxicity, pharmacokinetics, and clinical outcomes. Among 64 pediatric tumors, PRL3 was most frequently expressed in neuroblastoma (100%), rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas (71%), and renal sarcomas (60%) but absent in paired normal tissues. PRL3 was expressed in 75% of relapsed tumors and associated with shorter median event-free survival. Microarray profiling of PRL3-positive tumors showed elevation of angiogenin, TIMP1 and TIMP2, and GPCR-MAPK signaling proteins that commonly interacted with PRL3. The first use of PRL3-zumab in a pediatric patient saw no adverse events. A 28.6% reduction in maximum target lesion diameter was achieved when PRL3-zumab was administered concurrently with hypofractionated radiation. These findings support wider exploration of PRL3 expression in embryonal and mesenchymal tumors and further clinical application of PRL3-zumab in pediatric patients.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"153-166"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10533285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Hypoxia-regulated secretion of IL-12 enhances antitumor activity and safety of CD19 CAR-T cells in the treatment of DLBCL. 低氧调节IL-12分泌增强CD19 CAR-T细胞治疗DLBCL的抗肿瘤活性和安全性。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-09-21 DOI: 10.1016/j.omto.2023.08.009

Wenping Zhou, Jinxin Miao, Zhenguo Cheng, Zhimin Wang, Jianyao Wang, Haoran Guo, Pengju Wang, Shuangshuang Lu, Lingling Si, Zhongxian Zhang, Louisa Chard Dunmall, Yanyan Liu, Nicholas R Lemoine, Yaohe Wang

{"title":"Hypoxia-regulated secretion of IL-12 enhances antitumor activity and safety of CD19 CAR-T cells in the treatment of DLBCL.","authors":"Wenping Zhou, Jinxin Miao, Zhenguo Cheng, Zhimin Wang, Jianyao Wang, Haoran Guo, Pengju Wang, Shuangshuang Lu, Lingling Si, Zhongxian Zhang, Louisa Chard Dunmall, Yanyan Liu, Nicholas R Lemoine, Yaohe Wang","doi":"10.1016/j.omto.2023.08.009","DOIUrl":"https://doi.org/10.1016/j.omto.2023.08.009","url":null,"abstract":"CD19-targeted chimeric antigen receptor-modified T (CD19 CAR-T) cell therapy has been demonstrated as one of the most promising therapeutic strategies for treating B cell malignancies. However, it has shown limited treatment efficacy for diffuse large B cell lymphoma (DLBCL). This is, in part, due to the tumor heterogeneity and the hostile tumor microenvironment. Human interleukin-12 (IL-12), as a potent antitumor cytokine, has delivered encouraging outcomes in preclinical studies of DLBCL. However, potentially lethal toxicity associated with systemic administration precludes its clinical application. Here, an armed CD19 CAR expressing hypoxia-regulated IL-12 was developed (CAR19/hIL12ODD). In this vector, IL-12 secretion was restricted to hypoxic microenvironments within the tumor site by fusion of IL-12 with the oxygen degradation domain (ODD) of HIF1α. In vitro, CAR19/hIL12ODD-T cells could only secrete bioactive IL-12 under hypoxic conditions, accompanied by enhanced proliferation, robust IFN-γ secretion, increased abundance of CD4+, and central memory T cell phenotype. In vivo, adoptive transfer of CAR19/hIL12ODD-T cells significantly enhanced regression of large, established DLBCL xenografts in a novel immunodeficient Syrian hamster model. Notably, this targeted and controlled IL-12 treatment was without toxicity in this model. Taken together, our results suggest that armed CD19 CARs with hypoxia-controlled IL-12 (CAR19/hIL12ODD) might be a promising and safer approach for treating DLBCL.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"216-226"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10471514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10154717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 quest for effective immunotherapies against malignant peripheral nerve sheath tumors: Is there hope? 对恶性周围神经鞘肿瘤有效免疫疗法的探索:有希望吗?

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-09-21 DOI: 10.1016/j.omto.2023.07.008

Siddhi N Paudel, Brian Hutzen, Timothy P Cripe

{"title":"The quest for effective immunotherapies against malignant peripheral nerve sheath tumors: Is there hope?","authors":"Siddhi N Paudel, Brian Hutzen, Timothy P Cripe","doi":"10.1016/j.omto.2023.07.008","DOIUrl":"https://doi.org/10.1016/j.omto.2023.07.008","url":null,"abstract":"Immune-based therapies represent a new paradigm in the treatment of multiple cancers, where they have helped achieve durable and safe clinical responses in a growing subset of patients. While a wealth of information is available concerning the use of these agents in treating the more common malignancies, little has been reported about the use of immunotherapies against malignant peripheral nerve sheath tumors (MPNSTs), a rare form of soft tissue sarcoma that arises from the myelin sheaths that protect peripheral nerves. Surgical resection has been the mainstay of therapy in MPNSTs, but the recurrence rate is as high as 65%, and chemotherapy is generally ineffective. The immune contexture of MPNSTs, replete with macrophages and a varying degree of T cell infiltration, presents multiple opportunities to design meaningful therapeutic interventions. While preliminary results with macrophage-targeting strategies and oncolytic viruses are promising, identifying the subset of patients that respond to immune-based strategies will be a milestone. As part of our effort to help advance the use of immunotherapy for MPNSTs, here we describe recent insights regarding the immune contexture of MPNSTs, discuss emerging immune-based strategies, and provide a brief overview of potential biomarkers of response.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"227-237"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/45/d0/main.PMC10480481.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10192479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung cancers. 靶向EGFR的基于配体的piggyBac工程CAR-T细胞对非小细胞肺癌是安全有效的。

IF 5.3 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-09-16 eCollection Date: 2023-12-19 DOI: 10.1016/j.omto.2023.100728

Thanyavi Chinsuwan, Koichi Hirabayashi, Shuji Mishima, Aiko Hasegawa, Miyuki Tanaka, Hidemi Mochizuki, Akihito Shimoi, Takashi Murakami, Shigeki Yagyu, Kimihiro Shimizu, Yozo Nakazawa

{"title":"Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung cancers.","authors":"Thanyavi Chinsuwan, Koichi Hirabayashi, Shuji Mishima, Aiko Hasegawa, Miyuki Tanaka, Hidemi Mochizuki, Akihito Shimoi, Takashi Murakami, Shigeki Yagyu, Kimihiro Shimizu, Yozo Nakazawa","doi":"10.1016/j.omto.2023.100728","DOIUrl":"10.1016/j.omto.2023.100728","url":null,"abstract":"Epidermal growth factor receptor (EGFR) is overexpressed in various cancers, including non-small cell lung cancer (NSCLC), and in some somatic cells at a limited level, rendering it an attractive antitumor target. In this study, we engineered chimeric antigen receptor (CAR)-T cells using the piggyBac transposon system, autologous artificial antigen-presenting cells, and natural ligands of EGFR. We showed that this approach yielded CAR-T cells with favorable phenotypes and CAR positivity. They exhibited potent antitumor activity against NSCLC both in vitro and in vivo. When administered to tumor-bearing mice and non-tumor-bearing cynomolgus macaques, they did not elicit toxicity despite their cross-reactivity to both murine and simian EGFRs. In total we tested three ligands and found that the CAR candidate with the highest affinity consistently displayed greater potency without adverse events. Taken together, our results demonstrate the feasibility and safety of targeting EGFR-expressing NSCLCs using ligand-based, piggyBac-engineered CAR-T cells. Our data also show that lowering the affinity of CAR molecules is not always beneficial.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"31 ","pages":"100728"},"PeriodicalIF":5.3,"publicationDate":"2023-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/54/0a/main.PMC10562194.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41205539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Allogeneic tumor cell-derived extracellular vesicles stimulate CD8 T cell response in colorectal cancer. 同种异体肿瘤细胞来源的细胞外囊泡刺激CD8 T细胞在结直肠癌中的应答。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-09-16 eCollection Date: 2023-12-19 DOI: 10.1016/j.omto.2023.100727

Travis J Gates, Dechen Wangmo, Xianda Zhao, Subbaya Subramanian

{"title":"Allogeneic tumor cell-derived extracellular vesicles stimulate CD8 T cell response in colorectal cancer.","authors":"Travis J Gates, Dechen Wangmo, Xianda Zhao, Subbaya Subramanian","doi":"10.1016/j.omto.2023.100727","DOIUrl":"10.1016/j.omto.2023.100727","url":null,"abstract":"Most colorectal cancer (CRC) patients present with a microsatellite-stable phenotype, rendering them resistant to immune checkpoint inhibitors (ICIs). Among the contributors to ICI resistance, tumor-derived extracellular vesicles (TEVs) have emerged as critical players. Previously we demonstrated that autologous transfer of TEVs without miR-424 can induce tumor antigen-specific immune responses in CRC models. Therefore, we postulated that allogeneic TEVs, modified to lack miR-424 and derived from an MC38 cells, could induce CD8+ T cell responses while restraining CT26 cell-based tumor. Here, we show that prophylactic administration of MC38 TEVs, without miR-424, showed a significant augmentation in CD8+ T-cells within CT26 tumors. This allogenic TEV effect was evident in CT26 tumors but not B16-F10 melanoma. Furthermore, we demonstrated the capacity of dendritic cells (DCs) to internalize TEVs, a possible mechanism to elicit immune response. Our investigation of autologously administered DCs, which had been exposed to modified TEVs, underscores their potential to dampen tumor growth while elevating CD8+ T cell levels vis-a-vis MC38 wild-type TEVs exposed to DCs. Notably, the modified TEVs were well tolerated and did not increase peripheral blood cytokine levels. Our findings underscore the potential of modified allogeneic TEVs without immune-suppressive factors to elicit robust T cell responses and limit tumor growth.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"31 ","pages":"100727"},"PeriodicalIF":5.7,"publicationDate":"2023-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10562189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41205529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Oncolytic myxoma virus is effective in murine models of triple negative breast cancer despite poor rates of infection. 溶癌性粘液瘤病毒在癌症三阴性小鼠模型中是有效的，尽管感染率很低。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-09-01 eCollection Date: 2023-09-21 DOI: 10.1016/j.omto.2023.08.014

Raquela J Thomas, Mee Y Bartee, Miriam Valenzuela-Cardenas, Eric Bartee

引用次数: 0

Transgenic viral expression of PH-20, IL-12, and sPD1-Fc enhances immune cell infiltration and anti-tumor efficacy of an oncolytic virus. PH-20、IL-12和sPD1-Fc的转基因病毒表达增强了溶瘤病毒的免疫细胞浸润和抗肿瘤功效。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-08-31 eCollection Date: 2023-09-21 DOI: 10.1016/j.omto.2023.08.013

Soon-Oh Hong, Joonsung Kim, Sungmin Lee, Jaeil Shin, Hwanjun Choi, Eunjin Lee, Hyesoo Kang, Hyesun Lee, Soondong Lee, Naeun Yun, Jiwon An, Heonsik Choi, Hyeree Kim, Wonseok Kang, Yeup Yoon, Sujeong Kim

{"title":"Transgenic viral expression of PH-20, IL-12, and sPD1-Fc enhances immune cell infiltration and anti-tumor efficacy of an oncolytic virus.","authors":"Soon-Oh Hong, Joonsung Kim, Sungmin Lee, Jaeil Shin, Hwanjun Choi, Eunjin Lee, Hyesoo Kang, Hyesun Lee, Soondong Lee, Naeun Yun, Jiwon An, Heonsik Choi, Hyeree Kim, Wonseok Kang, Yeup Yoon, Sujeong Kim","doi":"10.1016/j.omto.2023.08.013","DOIUrl":"https://doi.org/10.1016/j.omto.2023.08.013","url":null,"abstract":"Oncolytic viruses are of significant clinical interest due to their ability to directly infect and kill tumors and enhance the anti-tumor immune response. Previously, we developed KLS-3010, a novel oncolytic virus derived from the International Health Department-White (IHD-W) strain vaccinia virus, which has robust tumoricidal effects. In the present study, we generated a recombinant oncolytic virus, KLS-3020, by inserting three transgenes (hyaluronidase [PH-20], interleukin-12 [IL-12], and soluble programmed cell death 1 fused to the Fc domain [sPD1-Fc]) into KLS-3010 and investigated its anti-tumor efficacy and ability to induce anti-tumor immune responses in CT26.WT and B16F10 mouse tumor models. A single injection of KLS-3020 significantly decreased tumor growth. The roles of the transgenes were investigated using viruses expressing each single transgene alone and KLS-3020. PH-20 promoted virus spread and tumor immune cell infiltration, IL-12 activated and reprogrammed T cells to inflammatory phenotypes, and sPD1-Fc increased intra-tumoral populations of activated T cells. The tumor-specific systemic immune response and the abscopal tumor control elicited by KLS-3020 were demonstrated in the CT26.WT tumor model. The insertion of transgenes into KLS-3020 increased its anti-tumor efficacy, supporting further clinical investigation of KLS-3020 as a novel oncolytic immunotherapy.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"301-315"},"PeriodicalIF":5.7,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3d/53/main.PMC10506102.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41125328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Smoking induces WEE1 expression to promote docetaxel resistance in esophageal adenocarcinoma. 吸烟诱导食管腺癌中WEE1的表达以促进多西他赛的耐药性。

IF 5.3 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-08-28 eCollection Date: 2023-09-21 DOI: 10.1016/j.omto.2023.08.012

Md Obaidul Islam, Krishnapriya Thangaretnam, Heng Lu, Dunfa Peng, Mohammed Soutto, Wael El-Rifai, Silvia Giordano, Yuguang Ban, Xi Chen, Daniel Bilbao, Alejandro V Villarino, Stephan Schürer, Peter J Hosein, Zheng Chen

{"title":"Smoking induces WEE1 expression to promote docetaxel resistance in esophageal adenocarcinoma.","authors":"Md Obaidul Islam, Krishnapriya Thangaretnam, Heng Lu, Dunfa Peng, Mohammed Soutto, Wael El-Rifai, Silvia Giordano, Yuguang Ban, Xi Chen, Daniel Bilbao, Alejandro V Villarino, Stephan Schürer, Peter J Hosein, Zheng Chen","doi":"10.1016/j.omto.2023.08.012","DOIUrl":"10.1016/j.omto.2023.08.012","url":null,"abstract":"Esophageal adenocarcinoma (EAC) patients have poor clinical outcomes, with an overall 5-year survival rate of 20%. Smoking is a significant risk factor for EAC. The role of WEE1, a nuclear kinase that negatively regulates the cell cycle in normal conditions, in EAC tumorigenesis and drug resistance is not fully understood. Immunohistochemistry staining shows significant WEE1 overexpression in human EAC tissues. Nicotine, nicotine-derived nitrosamine ketone, or 2% cigarette smoke extract treatment induces WEE1 protein expression in EAC, detected by western blot and immunofluorescence staining. qRT-PCR and reporter assay indicates that smoking induces WEE1 expression through miR-195-5p downregulation in EAC. ATP-Glo cell viability and clonogenic assay confirmed that WEE1 inhibition sensitizes EAC cells to docetaxel treatment in vitro. A TE-10 smoking machine with EAC patient-derived xenograft mouse model demonstrated that smoking induces WEE1 protein expression and resistance to docetaxel in vivo. MK-1775 and docetaxel combined treatment improves EAC patient-derived xenograft mouse survival in vivo. Our findings demonstrate, for the first time, that smoking-induced WEE1 overexpression through miRNA dysregulation in EAC plays an essential role in EAC drug resistance. WEE1 inhibition is a promising therapeutic method to overcome drug resistance and target treatment refractory cancer cells.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"286-300"},"PeriodicalIF":5.3,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/66/86/main.PMC10507159.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41139219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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