Molecular therapy. Oncology最新文献_第3页

Bringing in cytokine support troops with an OV Trojan horse. 带着OV木马的细胞因子支援部队。

Molecular therapy. Oncology Pub Date : 2025-02-26 eCollection Date: 2025-03-20 DOI: 10.1016/j.omton.2025.200947

Dean A Lee, Marcelo S F Pereira

引用次数: 0

CD147-CAR-NK cell therapy shows minimal toxicities in human CD147 transgenic mouse model with solid tumors. CD147-CAR-NK 细胞疗法在人类 CD147 转基因实体瘤小鼠模型中毒性极小。

Molecular therapy. Oncology Pub Date : 2025-02-26 eCollection Date: 2025-03-20 DOI: 10.1016/j.omton.2025.200957

Youssef Sabha, Sang Hoon Kim, Hsiang-Chi Tseng, Maeve Elizabeth Byrne, Wei-Chung Tsao, Sang Hoon Lee, Zhongren Zhou, Mi-Hyeon Jang, Dongfang Liu

{"title":"CD147-CAR-NK cell therapy shows minimal toxicities in human CD147 transgenic mouse model with solid tumors.","authors":"Youssef Sabha, Sang Hoon Kim, Hsiang-Chi Tseng, Maeve Elizabeth Byrne, Wei-Chung Tsao, Sang Hoon Lee, Zhongren Zhou, Mi-Hyeon Jang, Dongfang Liu","doi":"10.1016/j.omton.2025.200957","DOIUrl":"10.1016/j.omton.2025.200957","url":null,"abstract":"The toxicity of chimeric antigen receptor-natural killer (CAR-NK) therapy has not been tested in solid tumors, compared with CAR-T therapy side by side. To address this, we investigated the CD147-CAR-NK \"on-target/off-tumor\" toxicity and neurotoxicity in human CD147-transgenic (hCD147TG) mice with hepatocellular carcinoma (HCC). We first tested the in vitro cytotoxicity of CD147-CAR-NK against CD147+ tumor and CD147+ healthy cells. Both CD147-CAR-NK cells and CD147-IL15-CAR-NK (autocrine expressing interleukin [IL]-15) can kill tumor cells specifically but not CD147+ healthy lung and spleen tissue from hCD147TG mice. In vivo assays show minimal systemic toxicities against CD147+ healthy tissues but 1-week-longer persistence times in tumor than non-tumor tissues. To evaluate neurotoxicity, we compared the expression of ionized calcium-binding adaptor protein 1 (IBA1), glial fibrillary acidic protein (GFAP), and inducible nitric oxide synthase (iNOS) between CD147-CAR-T- and CD147-CAR-NK-treated hCD147TG mice with HCC. Both CD147-CAR-T- and CD147-CAR-NK-treated mice exhibited higher GFAP and IBA1 expression than control groups. CD147-CAR-T-treated mice showed an increase in iNOS compared to the control groups. The behavioral studies testing spatial memory showed that mice treated with CD147-CAR-NK exhibit better memory function than CD147-CAR-T-treated mice. This study provides a deeper understanding of the CD147-CAR-NK systemic toxicities and neurotoxicity of CD147-CAR-NK relative to CD147-CAR-T therapy.","PeriodicalId":519884,"journal":{"name":"Molecular therapy. Oncology","volume":"33 1","pages":"200957"},"PeriodicalIF":0.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preclinical development and clinical safety assessment of a synthetic peptide conjugate enabling endogenous antibody binding to promote innate receptor engagement. 一种合成肽偶联物的临床前开发和临床安全性评估，使内源性抗体结合促进先天受体结合。

Molecular therapy. Oncology Pub Date : 2025-02-20 eCollection Date: 2025-06-18 DOI: 10.1016/j.omton.2025.200954

Erika A K Fletcher, Robert A Cordfunke, Aikaterini Nasi, Gunilla Törnqvist, Rob R P M Valentijn, Anna Bergqvist, Marita Westhrin, Wenche Rasch, Frida Lindqvist, Inken Dillmann, Martin Lord, Neanke Bouwman, Jacques J Neefjes, Kees L M C Franken, Stephanie McArdle, Murrium Ahmad, Silvia Johansson, Ferry Ossendorp, Michael Haggman, Maria Lampinen, Gustav Ullenhag, Sam Ladjevardi, Justyna Leja-Jarblad, Wolfgang Lilleby, Jan Wouter Drijfhout, Sara M Mangsbo

{"title":"Preclinical development and clinical safety assessment of a synthetic peptide conjugate enabling endogenous antibody binding to promote innate receptor engagement.","authors":"Erika A K Fletcher, Robert A Cordfunke, Aikaterini Nasi, Gunilla Törnqvist, Rob R P M Valentijn, Anna Bergqvist, Marita Westhrin, Wenche Rasch, Frida Lindqvist, Inken Dillmann, Martin Lord, Neanke Bouwman, Jacques J Neefjes, Kees L M C Franken, Stephanie McArdle, Murrium Ahmad, Silvia Johansson, Ferry Ossendorp, Michael Haggman, Maria Lampinen, Gustav Ullenhag, Sam Ladjevardi, Justyna Leja-Jarblad, Wolfgang Lilleby, Jan Wouter Drijfhout, Sara M Mangsbo","doi":"10.1016/j.omton.2025.200954","DOIUrl":"10.1016/j.omton.2025.200954","url":null,"abstract":"Peptide-based vaccines can be used to deliver tumor-specific antigens to dendritic cells (DCs), leading to tumor-directed T cell responses. We previously developed a peptide-peptide conjugate technology enabling in vivo cross-linking of pre-existing tetanus toxin-directed antibodies, facilitating antigen delivery to, and activation of DCs. To achieve this, multiple identical tetanus toxin-derived B cell epitopes (MTTEs) are conjugated to synthetically produce target antigens of choice. Herein, we describe the generation of a prostate cancer vaccine candidate (TENDU) based on this technology. It includes long synthetic peptides harboring epitopes (CD4 and CD8) from prostate-specific antigen (PAP) and prostate-specific membrane antigen (PSMA). The preclinical efficacy of TENDU was assessed in experimental systems, and safety was evaluated in a rabbit toxicity study and a human whole blood loop assay. We also report the first clinical safety assessment of TENDU. Experimental studies showed that prostate cancer patients mounted anti-MTTE antibodies in response to tetanus vaccination with recall T cell responses detected in two patients. Transgenic humanized HLA-DR4 mice displayed T cell responses and increased anti-MTTE IgG levels after vaccination with a peptide construct including an HLA-DR4 epitope. The vaccine candidate was found safe, and a positive correlation between T cell responses and anti-MTTE antibodies was noted in the first-in-human study.","PeriodicalId":519884,"journal":{"name":"Molecular therapy. Oncology","volume":"33 2","pages":"200954"},"PeriodicalIF":0.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Anti-lymphoma peptide is inspired by mapping a sequence of four amino acids of KRAI motif as nuclear localization signal of Crlz-1. 抗淋巴瘤肽的灵感来自于KRAI基序的4个氨基酸序列作为Crlz-1的核定位信号。

Molecular therapy. Oncology Pub Date : 2025-02-20 eCollection Date: 2025-03-20 DOI: 10.1016/j.omton.2025.200953

Joo Hyun Pi, Seung Young Choi, Sung-Kyun Park, Junghyun Lim, Chang Joong Kang

{"title":"Anti-lymphoma peptide is inspired by mapping a sequence of four amino acids of KRAI motif as nuclear localization signal of Crlz-1.","authors":"Joo Hyun Pi, Seung Young Choi, Sung-Kyun Park, Junghyun Lim, Chang Joong Kang","doi":"10.1016/j.omton.2025.200953","DOIUrl":"https://doi.org/10.1016/j.omton.2025.200953","url":null,"abstract":"Peptides of Crlz-1 nuclear localization signal as mapped to be a short KRAI sequence inhibited the proliferation of germinal center-derived Ramos cells from Burkitt's lymphoma patient. This anti-proliferative effect was mechanistically explained by a cascade of the block of Crlz-1 nuclear movement and consequential failure of CBFβ nuclear mobilization, resulting in the absence of bound Runx/CBFβ heterodimer on the enhancer-promoter of the Bcl-6 GC master gene. As a consequence of this heterodimer absence, the Bcl-6 expression was abolished, leading to the down-regulation of cyclins D1-D3 and the up-regulation of IRF-4, Blimp-1, and IgJ genes. Furthermore, this peptide decreased the production of rRNA in these cells, indicating that the nuclear Crlz-1 as a UTP-3 constituent of ribosomal small subunit processome might be necessary to regulate the biogenesis and/or processing of rRNA, and thereby produce ribosomes necessary for their rapid proliferation. Surprisingly, the KRAI motif peptides had an intrinsic cell-membrane permeability by themselves, and therefore their anti-proliferative and anti-tumor effects were also demonstrated in both the cultured cells and Ramos-xenografted mice just by adding them directly to the culture media or injecting them into tail veins. This definitely paved the prospective road to developing a novel anti-cancer peptide drug against the germinal center-derived B cell lymphoma.","PeriodicalId":519884,"journal":{"name":"Molecular therapy. Oncology","volume":"33 1","pages":"200953"},"PeriodicalIF":0.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dual CARM1-and IKZF3-targeting: A novel approach to multiple myeloma therapy synergy between CARM1 inhibition and IMiDs. 双重靶向CARM1和ikzf3: CARM1抑制和IMiDs之间多发性骨髓瘤治疗协同作用的新途径

Molecular therapy. Oncology Pub Date : 2025-02-20 eCollection Date: 2025-03-20 DOI: 10.1016/j.omton.2025.200952

Wei Ni, Swati Garg, Basudev Chowdhury, Martin Sattler, Dana Sanchez, Chengcheng Meng, Taisei Akatsu, Katherine A Donovan, Jun Qi, Michelle Y Wang, Cara Ann Starnbach, Xiaoxi Liu, Maria Tarazona Guzman, Wei Pin Teh, Richard Stone, James D Griffin, Sara Buhrlage, Ellen Weisberg

{"title":"Dual CARM1-and IKZF3-targeting: A novel approach to multiple myeloma therapy synergy between CARM1 inhibition and IMiDs.","authors":"Wei Ni, Swati Garg, Basudev Chowdhury, Martin Sattler, Dana Sanchez, Chengcheng Meng, Taisei Akatsu, Katherine A Donovan, Jun Qi, Michelle Y Wang, Cara Ann Starnbach, Xiaoxi Liu, Maria Tarazona Guzman, Wei Pin Teh, Richard Stone, James D Griffin, Sara Buhrlage, Ellen Weisberg","doi":"10.1016/j.omton.2025.200952","DOIUrl":"10.1016/j.omton.2025.200952","url":null,"abstract":"Advancements in the treatment of multiple myeloma (MM) have resulted in an improvement in the survival rate. However, there continues to be an urgent need for improved therapies. The protein arginine methyltransferase, CARM1 (coactivator associated arginine methyltransferase 1), is emerging as a potential cancer therapy target and inhibitors have been developed. MM cell lines are particularly dependent on CARM1 for cell survival. Here, we show that targeting of CARM1 through small molecule inhibition potentiates the activity of immunomodulatory drugs (IMiDs) in cell line models of MM. This likely occurs through synergistic targeting of Aiolos (IKZF3) and MYC expression. Rational design of a new molecule, 074, which consists of a CARM1 inhibitor linked to the IMiD pomalidomide, was carried out and treatment with this agent led to more potent killing of MM cells than either the CARM1 inhibitor or the IMiD as single agents. Importantly, 074 was able to override IMiD resistance. Taken together, our results demonstrate that dual CARM1/IKZF3-targeting agents represent a promising novel therapeutic strategy for MM and IMiD-resistant disease.","PeriodicalId":519884,"journal":{"name":"Molecular therapy. Oncology","volume":"33 1","pages":"200952"},"PeriodicalIF":0.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery and preclinical development of a SdAb-based CAR-T technology for targeting CD33 in AML. 基于sdb靶向CD33的AML CAR-T技术的发现和临床前开发。

Molecular therapy. Oncology Pub Date : 2025-02-11 eCollection Date: 2025-03-20 DOI: 10.1016/j.omton.2025.200949

Franco Bernasconi-Bisio, Eva Molina, Vianca Ibarra, Inés Ibáñez-Sala, Federica Rochira, Patricia Jauregui, Saray Rodríguez-Diaz, Rebeca Martínez-Turrillas, Iñigo Azagra-Barber, Nuria Gómez-Cebrián, Juan José Lasarte, Leonor Puchades-Carrasco, Lucía Vanrell, Juan Roberto Rodríguez-Madoz, Felipe Prósper, Antonio Pineda-Lucena

{"title":"Discovery and preclinical development of a SdAb-based CAR-T technology for targeting CD33 in AML.","authors":"Franco Bernasconi-Bisio, Eva Molina, Vianca Ibarra, Inés Ibáñez-Sala, Federica Rochira, Patricia Jauregui, Saray Rodríguez-Diaz, Rebeca Martínez-Turrillas, Iñigo Azagra-Barber, Nuria Gómez-Cebrián, Juan José Lasarte, Leonor Puchades-Carrasco, Lucía Vanrell, Juan Roberto Rodríguez-Madoz, Felipe Prósper, Antonio Pineda-Lucena","doi":"10.1016/j.omton.2025.200949","DOIUrl":"10.1016/j.omton.2025.200949","url":null,"abstract":"Chimeric antigen receptor T cell (CAR-T) therapies have revolutionized cancer immunotherapy. Traditional single-chain variable fragments (ScFvs) used as CAR recognition moieties face challenges such as high tonic signaling, compromised binding epitopes, and suboptimal affinity. Single-domain antibodies (SdAbs) offer an attractive alternative due to their smaller size, stability, and reduced immunogenicity. In this work, we developed an SdAb-CAR-T cell discovery platform integrating generation, characterization, and selection of SdAbs based on various properties. This approach was demonstrated by developing CAR-T cells with SdAbs against CD33, a target for acute myeloid leukemia (AML). We identified diverse SdAbs against CD33, with affinities ranging from 3.9-115 nM, and characterized their binding kinetics and epitope recognition. Using SdAb-based second-generation CARs, we assessed tonic signaling, T cell phenotypes, cytotoxicity and cytokine release in vitro, resulting in reduced tonic signaling and increased cytokine production. In vivo, SdAb-based CAR-T cells exhibited enhanced efficacy at lower doses, in a xenograft AML mouse model, demonstrating advantages over ScFv-based CD33 CAR-T cells.","PeriodicalId":519884,"journal":{"name":"Molecular therapy. Oncology","volume":"33 1","pages":"200949"},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural insights and clinical advances in small-molecule inhibitors targeting TGF-β receptor I. 靶向TGF-β受体I的小分子抑制剂的结构见解和临床进展。

Molecular therapy. Oncology Pub Date : 2025-02-03 eCollection Date: 2025-03-20 DOI: 10.1016/j.omton.2025.200945

Carlota Leonardo-Sousa, Rodrigo Barriga, Helena F Florindo, Rita C Acúrcio, Rita C Guedes

{"title":"Structural insights and clinical advances in small-molecule inhibitors targeting TGF-β receptor I.","authors":"Carlota Leonardo-Sousa, Rodrigo Barriga, Helena F Florindo, Rita C Acúrcio, Rita C Guedes","doi":"10.1016/j.omton.2025.200945","DOIUrl":"10.1016/j.omton.2025.200945","url":null,"abstract":"The dysregulation of the transforming growth factor β (TGF-β) signaling pathway plays a critical role in the onset and progression of several diseases, including cancer. Notably, TGF-β has emerged as a significant barrier to effective outcomes in cancer immunotherapies, particularly those using immune checkpoint inhibitors. In response to this challenge, small-molecule inhibitors targeting the TGF-β receptor I (TGF-βRI) have garnered attention as promising candidates for modulating the TGF-β signaling pathway. This comprehensive review focuses on the development of small-molecule inhibitors targeting TGF-βRI. We provide a detailed analysis of the structural biology of TGF-βRI, highlighting key binding interactions and structural insights derived from high-resolution X-ray crystal structures. Additionally, we review the current landscape of TGF-βRI inhibitors in clinical trials, including eight promising inhibitors, and discuss their mechanisms of action, selectivity, and therapeutic potential. Our investigation extends to the patent literature, summarizing over 2 decades of innovation from leading pharmaceutical companies, spanning January 2000-May 2024. This consolidated structural and biochemical knowledge aims to facilitate the design of next-generation TGF-βRI inhibitors, addressing unmet clinical needs in oncology and fibrosis treatment. The synergistic potential of combining TGF-βRI and immune checkpoint inhibitors is also explored, offering promising avenues for enhancing cancer immunotherapy efficacy.","PeriodicalId":519884,"journal":{"name":"Molecular therapy. Oncology","volume":"33 1","pages":"200945"},"PeriodicalIF":0.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

miRNA-dependent resistance mechanisms to anti-hormonal therapies in estrogen receptor-positive breast cancer patients. 雌激素受体阳性乳腺癌患者抗激素治疗的mirna依赖性耐药机制

Molecular therapy. Oncology Pub Date : 2025-01-28 eCollection Date: 2025-03-20 DOI: 10.1016/j.omton.2025.200941

Zainab Salam Al Hashami, Bert van der Vegt, Marian J E Mourits, Joost Kluiver, Anke van den Berg

{"title":"miRNA-dependent resistance mechanisms to anti-hormonal therapies in estrogen receptor-positive breast cancer patients.","authors":"Zainab Salam Al Hashami, Bert van der Vegt, Marian J E Mourits, Joost Kluiver, Anke van den Berg","doi":"10.1016/j.omton.2025.200941","DOIUrl":"10.1016/j.omton.2025.200941","url":null,"abstract":"The estrogen receptor (ERα) is expressed in 70%-80% of breast cancers and is a target of endocrine therapy. However, resistance to endocrine therapy poses a significant clinical challenge. MicroRNAs (miRNAs) have emerged as critical players in oncogenesis and as modulators of therapy response. This review provides an overview of miRNAs that modulate anti-hormonal drug responses. We identified 56 miRNAs associated with resistance to endocrine therapy. These miRNAs had a total of 40 proven target genes that were grouped based on their function under currently known resistance mechanisms, including ER modulation, signaling pathway activation, cell-cycle modulation, and other mechanisms. For a limited number of miRNA-target gene interactions, the relevance of the identified target gene(s) was confirmed by copy or rescue of the miRNA-induced phenotype. Overall, this review highlights critical roles of miRNAs as crucial mediators of resistance to anti-hormonal therapy. The identified miRNA-target gene interactions can serve as a foundation for future functional studies exploring the potential of selected miRNAs in overcoming drug resistance, which might improve outcomes for breast cancer patients.","PeriodicalId":519884,"journal":{"name":"Molecular therapy. Oncology","volume":"33 1","pages":"200941"},"PeriodicalIF":0.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Resistance signatures to oncolytic vesiculoviruses in pancreatic ductal adenocarcinoma. 胰腺导管腺癌对溶瘤性囊泡病毒的抗性特征。

Molecular therapy. Oncology Pub Date : 2025-01-17 eCollection Date: 2025-03-20 DOI: 10.1016/j.omton.2025.200937

Chelsae R Watters, Oumar Barro, Musa Gabere, Mia Y Masuda, Natalie M Elliott, Elizabeth A Raupach, Khandoker Usran Ferdous, Mulu Z Tesfay, Omeed Moaven, Yumei Zhou, Michael T Barrett, Kenneth H Buetow, Bolni Marius Nagalo, Mitesh J Borad

{"title":"Resistance signatures to oncolytic vesiculoviruses in pancreatic ductal adenocarcinoma.","authors":"Chelsae R Watters, Oumar Barro, Musa Gabere, Mia Y Masuda, Natalie M Elliott, Elizabeth A Raupach, Khandoker Usran Ferdous, Mulu Z Tesfay, Omeed Moaven, Yumei Zhou, Michael T Barrett, Kenneth H Buetow, Bolni Marius Nagalo, Mitesh J Borad","doi":"10.1016/j.omton.2025.200937","DOIUrl":"10.1016/j.omton.2025.200937","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) shows limited response to conventional therapies and immunotherapy due to dense stromal barriers and poor immunogenicity. Oncolytic vesiculoviruses hold therapeutic potential for PDAC by lysis of PDAC cells to release tumor-associated antigens, increasing tumor immunogenicity. We previously reported the efficacy of a chimeric vesicular stomatitis virus (VSV) expressing Morreton virus (MorV) glycoprotein in sarcoma. Here, we evaluated the oncolytic potency of MorV and chimeric virus, VMG, in PDAC models. VMG exhibited heterogeneous oncolysis across human PDAC cell lines and PDX cells, similar to parental viruses VSV and MorV. To evaluate potential signatures correlated with resistance to oncolytic vesiculoviruses, we compared transcriptomes of cell lines characterized as sensitive or resistant to oncolysis in vitro. We identified epithelial development and biological adhesion gene sets were significantly associated with vesiculovirus resistance. Additionally, escaped PDAC cells surviving two cycles of infection with VSV showed significant upregulation of stress keratins and downregulation of genes involved in retinoic acid metabolism and cell cycle. An overlapping 39 genes were higher in resistant cell lines at baseline as well as upregulated in escaped PDAC cells. Several resistance-associated genes are targets of anti-cancer therapies in development, offering potential combination approaches with oncolytic vesiculoviruses.","PeriodicalId":519884,"journal":{"name":"Molecular therapy. Oncology","volume":"33 1","pages":"200937"},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","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 adenovirus inhibits TNBC tumor growth/metastasis in mice by targeting TGFB and overexpressing GM-CSF. 溶瘤腺病毒通过靶向TGFB和过表达GM-CSF抑制小鼠TNBC肿瘤生长/转移。

Molecular therapy. Oncology Pub Date : 2025-01-17 eCollection Date: 2025-03-20 DOI: 10.1016/j.omton.2025.200936

Nguyễn Thị Thanh Nhàn, Soon Cheon Shin, Beniamin Filimon, Yuefeng Yang, Zebin Hu, Bruce Brockstein, Weidong Xu

{"title":"Oncolytic adenovirus inhibits TNBC tumor growth/metastasis in mice by targeting TGFB and overexpressing GM-CSF.","authors":"Nguyễn Thị Thanh Nhàn, Soon Cheon Shin, Beniamin Filimon, Yuefeng Yang, Zebin Hu, Bruce Brockstein, Weidong Xu","doi":"10.1016/j.omton.2025.200936","DOIUrl":"10.1016/j.omton.2025.200936","url":null,"abstract":"Despite therapeutic advancements, metastatic triple-negative breast cancer (TNBC) remains mostly incurable and is a frequent cause of cancer-related deaths. We tested the hypothesis that inhibiting suppressive signals sustained by transforming growth factor (TGF)-β and concurrently stimulating recruitment of inflammatory cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) by oncolytic viruses would result in improved anti-tumor responses. Thus, we developed a new oncolytic adenovirus rAd.sT.GM (AMUN-003) that expresses both sTGFβRIIFc (a TGF-β decoy), and GM-CSF and tested it in a mouse TNBC (4T1) subcutaneous model. rAd.sT.GM was safe to use and more effective in controlling tumor progression and lung metastasis following intratumoral injections when compared with control adenoviruses without modifications. In the same model, combinations of immune checkpoint inhibitor (ICI) therapy with rAd.sT.GM resulted in better inhibition of tumor growth and metastasis. Furthermore, we examined key immune response and prognosis biomarkers in sera, lungs, spleens, and tumors to evaluate the treatment efficacy. We found several key anti-tumor Th1 cytokines such as interleukin (IL)-2, IL-4, and interferon-γ, were stimulated by the combination therapy either systemically or in tumors or both, as well as anti-tumor biomarkers such as Granzyme B and perforin. These results support advancement to clinical testing with the combination therapy of rAd.sT.GM and ICIs for TNBC patients.","PeriodicalId":519884,"journal":{"name":"Molecular therapy. Oncology","volume":"33 1","pages":"200936"},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0