Molecular Therapy: Oncology最新文献_第2页

IL-12-mediated toxicity from localized oncolytic virotherapy can be reduced using systemic TNF blockade 利用全身 TNF 阻断剂可降低局部溶瘤病毒疗法由 IL-12 介导的毒性

Molecular Therapy: Oncology Pub Date : 2024-08-27 DOI: 10.1016/j.omton.2024.200866

Miriam Valenzuela-Cardenas, Carrie Fisher, Mee Y. Bartee, Eric Bartee

{"title":"IL-12-mediated toxicity from localized oncolytic virotherapy can be reduced using systemic TNF blockade","authors":"Miriam Valenzuela-Cardenas, Carrie Fisher, Mee Y. Bartee, Eric Bartee","doi":"10.1016/j.omton.2024.200866","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200866","url":null,"abstract":"Cytokine therapy represents an attractive option to improve the outcomes of cancer patients. However, the systemic delivery of these agents often leads to severe immune-related toxicities, which can prevent their efficient clinical use. One approach to address this issue is the use of recombinant oncolytic viruses to deliver various cytokines directly to the tumor. This improves the biodistribution of the secreted cytokine-transgenes, both augmenting antitumor immune responses and decreasing systemic toxicities. We have shown recently that a doubly recombinant oncolytic myxoma virus that secretes a soluble version of PD1 as well as an interleukin-12 (IL-12) fusion protein (vPD1/IL-12) can cause potent regression of disseminated cancers. Here we show that, despite the predominant localization of both transgenes within the infected tumor, treatment with vPD1/IL-12 still results in systemic, IL-12-mediated toxicities. Interestingly, these toxicities are independent of interferon-γ and instead appear to be mediated by the interaction of tumor necrosis factor α with tumor necrosis factor receptor 2 on hematopoietic cells. Critically, this unique mechanism allows for vPD1/IL-12-mediated toxicities to be alleviated through the use of US Food and Drug Administration (FDA)-approved tumor necrosis factor (TNF) blockers such as etanercept.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"128 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gene expression signatures predict the sensitivity of pediatric brain tumors to different oncolytic viruses 基因表达特征可预测小儿脑肿瘤对不同溶瘤病毒的敏感性

Molecular Therapy: Oncology Pub Date : 2024-08-26 DOI: 10.1016/j.omton.2024.200860

Fatma Turna Demir, Hiroaki Wakimoto

引用次数: 0

Lemur tail kinase 3 serves as a predictor of patient outcomes and a target for the treatment of ovarian cancer 狐尾激酶 3 是预测患者预后的指标，也是治疗卵巢癌的靶点

Molecular Therapy: Oncology Pub Date : 2024-08-26 DOI: 10.1016/j.omton.2024.200864

Ghassan M. Saed, Nicole M. Fletcher, Harvey Sharma, Axel Stenmark Tullberg, Ella Ittner, Toshima Z. Parris, Daniella Pettersson, Anikó Kovács, Elisabeth Werner Rönnerman, Pernilla Dahm-Kähler, Anna Portela, Pamela D. Garzone, Robert Morris, Khalil Helou

{"title":"Lemur tail kinase 3 serves as a predictor of patient outcomes and a target for the treatment of ovarian cancer","authors":"Ghassan M. Saed, Nicole M. Fletcher, Harvey Sharma, Axel Stenmark Tullberg, Ella Ittner, Toshima Z. Parris, Daniella Pettersson, Anikó Kovács, Elisabeth Werner Rönnerman, Pernilla Dahm-Kähler, Anna Portela, Pamela D. Garzone, Robert Morris, Khalil Helou","doi":"10.1016/j.omton.2024.200864","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200864","url":null,"abstract":"Lemur tail kinase 3 (LMTK3) belongs to a family of tyrosine kinases that are known to correlate with tumor grade and patient survival in some cancers. Here, we validated LMTK3 as a specific target and a prognostic biomarker in ovarian cancer (OC). In samples from 204 stage I–II OC patients, immunohistochemical studies revealed a higher cytoplasmic-to-nuclear staining intensity of LMTK3, which correlated with worse overall survival ( < 0.001). Efficacy studies utilizing novel LMTK3 binding peptides (LMTK3BPs) showed that all chemosensitive and chemoresistant OC cells were killed without affecting normal cells ( < 0.005), with synergistic effects shown following cisplatin and docetaxel treatment. In an orthotopic xenograft mouse model of OC, we saw a 35% tumor reduction in response to intravenous injections of 2 mg/kg LMTK3BP given three times a week for 3 weeks. Furthermore, safety studies showed no signs of toxicity after LMTK3BP treatment, even at doses as high as 40 mg/kg. This study highlights LMTK3 as a predictor of patient clinical outcomes. More importantly, novel LMTK3BPs represent potential safe treatment options, either alone or in combination with therapies, for OC.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy 从溶瘤腺病毒的penton碱基中删除RGD基序可增强CAR T细胞联合疗法的抗肿瘤疗效

Molecular Therapy: Oncology Pub Date : 2024-08-23 DOI: 10.1016/j.omton.2024.200863

Alvaro Morales-Molina, Miguel Angel Rodriguez-Milla, Patricia Garcia-Rodriguez, Laura Hidalgo, Ramon Alemany, Javier Garcia-Castro

{"title":"Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy","authors":"Alvaro Morales-Molina, Miguel Angel Rodriguez-Milla, Patricia Garcia-Rodriguez, Laura Hidalgo, Ramon Alemany, Javier Garcia-Castro","doi":"10.1016/j.omton.2024.200863","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200863","url":null,"abstract":"Oncolytic viruses often face challenges in achieving optimal antitumor immunity as standalone therapies. The penton base RGD-integrin interactions play a significant role in wild-type adenovirus-induced innate immune responses. To modify these responses, we present ISC301, a novel oncolytic adenovirus engineered by deleting the natural RGD motifs in the penton base while incorporating artificial RGD motifs in the fiber knobs. ISC301 demonstrated comparable infectivity, cytotoxic effects, and signaling profiles across various cell types to its parental ICOVIR-5, which retains the penton base RGD motif. In immunodeficient and immunocompetent mouse models, ISC301 exhibited similar antitumor efficacy to ICOVIR-5. However, ISC301 induced higher intratumoral inflammation through NF-κB activation, leading to increased levels of tumor-infiltrating leukocytes and higher proportion of cytotoxic CD8 T cells. In addition, ISC301 elicits a heightened pro-inflammatory response in peripheral blood. Importantly, when combined with CAR T cell therapy, ISC301 exhibited superior antitumor efficacy, surpassing monotherapy outcomes. These findings emphasize the impact of adenoviral modifications on antitumor immune responses. The deletion of penton base RGD motifs enhances ISC301’s pro-inflammatory profile and boosts CAR T cell therapy efficacy. This study enhances understanding of oncolytic virus engineering strategies, positioning ISC301 as a promising candidate for combined immunotherapeutic approaches in cancer treatment.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TYRP1 directed CAR T cells control tumor progression in preclinical melanoma models TYRP1 引导的 CAR T 细胞可控制临床前黑色素瘤模型的肿瘤进展

Molecular Therapy: Oncology Pub Date : 2024-08-22 DOI: 10.1016/j.omton.2024.200862

Christopher S. Hackett, Daniel Hirschhorn, Meixian S. Tang, Terence J. Purdon, Yacine Marouf, Alessandra Piersigilli, Narasimhan P. Agaram, Cailian Liu, Sara E. Schad, Elisa de Stanchina, Sarwish Rafiq, Sebastien Monette, Jedd D. Wolchok, Taha Merghoub, Renier J. Brentjens

引用次数: 0

Primary murine high-grade glioma cells derived from RCAS/tv-a diffuse glioma model reprogram naive T cells into immunosuppressive regulatory T lymphocytes 源自 RCAS/tv-a 弥漫性胶质瘤模型的原代小鼠高级别胶质瘤细胞将天真 T 细胞重编程为免疫抑制调节性 T 淋巴细胞

Molecular Therapy: Oncology Pub Date : 2024-08-13 DOI: 10.1016/j.omton.2024.200861

Alessandro Canella, Mykyta Artomov, Aleksandr Ukhatov, Sakthi Rajendran, Phillip Perez, Uksha Saini, Jack Hedberg, Kevin Cassady, Prajwal Rajappa

{"title":"Primary murine high-grade glioma cells derived from RCAS/tv-a diffuse glioma model reprogram naive T cells into immunosuppressive regulatory T lymphocytes","authors":"Alessandro Canella, Mykyta Artomov, Aleksandr Ukhatov, Sakthi Rajendran, Phillip Perez, Uksha Saini, Jack Hedberg, Kevin Cassady, Prajwal Rajappa","doi":"10.1016/j.omton.2024.200861","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200861","url":null,"abstract":"High-grade gliomas (HGGs) and glioblastomas (GBMs) are the most aggressive and lethal brain tumors. The standard of care (SOC) currently includes gross safe surgical resection followed by chemoradiotherapy. The main chemotherapeutic agents are the DNA alkylating agent temozolomide (TMZ) and adjuvants. Due to the outdated therapeutic protocols and lack of specific treatments, there is an urgent and rising need to improve our understanding of tumor biology and design more effective therapeutic strategies. models are essential for investigating glioma biology and testing novel therapeutic approaches. While the use of commercially available and patient-derived glioma cell lines for studies is a common practice, they exhibit several limitations, including failing to maintain the genetic and phenotypic diversity of primary tumors, going through genetic drift over time, and often lacking the invasive and stem-like characteristics of patient tumors. These limitations can lead to inconsistent and non-reproducible results, hampering translational research progress. In this study, we established a novel primary murine HGG cell line, isolated from an immunocompetent HGG-bearing RCAS/T-va mouse. We characterized the transcriptome and phenotype to ensure that this cell line resembles the nature of HGGs and retains the ability to reprogram primary murine T lymphocytes.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"135 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Senescence-associated secretory phenotype regulation by dual drug delivery biomimetic nanoplatform for enhanced tumor chemotherapy 通过双重给药生物仿生纳米平台调控衰老相关分泌表型，增强肿瘤化疗效果

Molecular Therapy: Oncology Pub Date : 2024-08-08 DOI: 10.1016/j.omton.2024.200856

Anni Wang, Shiyi Li, Ru Zhang, Xing Chen, Ying Zhu, Jiaxuan Xia, Jianxin Wang

{"title":"Senescence-associated secretory phenotype regulation by dual drug delivery biomimetic nanoplatform for enhanced tumor chemotherapy","authors":"Anni Wang, Shiyi Li, Ru Zhang, Xing Chen, Ying Zhu, Jiaxuan Xia, Jianxin Wang","doi":"10.1016/j.omton.2024.200856","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200856","url":null,"abstract":"Many chemotherapies, which are still the main clinical treatment for primary tumors, will induce persistent DNA damage in non-tumor stromal cells, especially cancer-associated fibroblasts (CAFs), and activate them to secrete senescence-associated secretory phenotype (SASP). The transition could further result in the formation of tumor immunosuppressive microenvironment and cause drug resistance of neighboring tumor cells. To solve this dilemma, a multi-functional biomimetic drug delivery system (named mPtP@Lipo) was rationally developed by combining CAFs reshaper ginsenoside 20(S)-protopanaxadiol (PPD) and cisplatin prodrug (PtLA) to inhibit tumor progression and the formation of SASP. To achieve effective delivery of these molecules deep into the desmoplastic tumor, fibroblast membrane was fused with liposomes as a targeting carrier. and results showed that mPtP@Lipo could penetrate deep into the tumor, reverse CAFs phenotype and inhibit SASP formation, which then blocked the immunosuppressive progress and thus reinforced anti-tumor immune response. The combination of chemotherapeutics and CAFs regulator could achieve both tumor inhibition and tumor immune microenvironment remodeling. In conclusion, mPtP@Lipo provides a promising strategy for the comprehensive stromal-desmoplastic tumor treatment.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Galunisertib promotes bevacizumab-induced vascular normalization in nasopharyngeal carcinoma: Multi-parameter MRI evaluation 加仑尼塞替布促进贝伐珠单抗诱导的鼻咽癌血管正常化：多参数磁共振成像评估

Molecular Therapy: Oncology Pub Date : 2024-08-08 DOI: 10.1016/j.omton.2024.200858

Jing Yu, Xia Du, Shuai Zhang, Jinhua Long, Peng Wu, Zongxue Li, Xinyue Lyu, Qin Hong, Pengyu Chen, Bo Gao

{"title":"Galunisertib promotes bevacizumab-induced vascular normalization in nasopharyngeal carcinoma: Multi-parameter MRI evaluation","authors":"Jing Yu, Xia Du, Shuai Zhang, Jinhua Long, Peng Wu, Zongxue Li, Xinyue Lyu, Qin Hong, Pengyu Chen, Bo Gao","doi":"10.1016/j.omton.2024.200858","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200858","url":null,"abstract":"Tumor vascular normalization (TVN) is associated with antitumor therapeutic efficacy in nasopharyngeal carcinoma (NPC). However, the short time window of TVN is the biggest hindrance to its wide clinical application. We investigated whether targeting transforming growth factor beta can enhance the TVN effect of bevacizumab (BEV)-induced patient-derived xenograft (PDX) models of NPC. We constructed mouse subcutaneous PDX models of NPC and classified the mice into four drug-treatment groups, namely placebo control, galunisertib, BEV, and galunisertib + BEV. We performed MRI multi-parameter examinations at different time points and evaluated the vascular density, vascular structure, and tumor hypoxia microenvironment by histopathology. The efficacy of chemotherapy and drug delivery was evaluated by administering cisplatin. We found that combined therapy with galunisertib and BEV significantly delayed tumor growth, enhanced the TVN effect, and improved chemotherapeutic efficacy compared with monotherapy. Mechanistically, galunisertib reversed the epithelial-mesenchymal transition process and inhibited the expression of hypoxia-inducible factor 1α and vascular endothelial growth factor by downregulating LAMC2. Correlation analysis of MRI data and pathological indicators showed that there was a good correlation between them.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of novel inhibitors of the transcriptional coactivator MRTF-A for HCC therapy 鉴定用于治疗 HCC 的转录辅激活因子 MRTF-A 的新型抑制剂

Molecular Therapy: Oncology Pub Date : 2024-08-06 DOI: 10.1016/j.omton.2024.200855

Miriam Jasmin Franz, Pia Wenisch, Petra Wohlleben, Laura Rupprecht, Vladimir Chubanov, Thomas Gudermann, Salla Kyheröinen, Maria Kristina Vartiainen, Markus R. Heinrich, Susanne Muehlich

{"title":"Identification of novel inhibitors of the transcriptional coactivator MRTF-A for HCC therapy","authors":"Miriam Jasmin Franz, Pia Wenisch, Petra Wohlleben, Laura Rupprecht, Vladimir Chubanov, Thomas Gudermann, Salla Kyheröinen, Maria Kristina Vartiainen, Markus R. Heinrich, Susanne Muehlich","doi":"10.1016/j.omton.2024.200855","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200855","url":null,"abstract":"Myocardin-related transcription factor A (MRTF-A) is a coactivator of serum response factor (SRF), which regulates the expression of genes involved in cell proliferation, migration, and differentiation and has been implicated in hepatocellular carcinoma (HCC) progression. We recently established inhibition of the transcriptional activity of MRTF-A by NS8593 as a novel therapeutic approach for HCC therapy. NS8593 is a negative gating modulator of the transient receptor potential cation channel TRPM7. In this report, we identify an aminobenzimidazole that is highly potent in inhibiting TRPM7 and its interaction with RhoA, leading to decreased SRF transcriptional activity and enhanced nuclear export of MRTF-A, as determined by fluorescence loss in photobleaching (FLIP). This resulted in reduced expression of the MRTF/SRF target genes transforming growth factor β1 (TGF-β1) and tetraspanin 5 (TSPAN5), senescence induction, and growth arrest in HCC cells. Replacement of the tetraline core by a 3-aminophenyl substructure yielded inhibitor with higher potency than inhibitor and further structural modifications yielded highly potent inhibitors of SRF activity, and . Both compounds were capable of inhibiting cell proliferation and inducing senescence in HCC cells with improved efficacy compared to NS8593. These inhibitors represent valuable tools for understanding the molecular basis of drug development targeting TRPM7 and MRTFs.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unveiling promising targets in gastric cancer therapy: A comprehensive review 揭示胃癌治疗的前景目标：全面回顾

Molecular Therapy: Oncology Pub Date : 2024-08-05 DOI: 10.1016/j.omton.2024.200857

Wenke Li, Jing Wei, Mo Cheng, Ming Liu

引用次数: 0