Molecular Therapy: Oncology最新文献

The therapeutic effect of DX2 inhibition in nicotine-induced lung cancer progression DX2 抑制剂对尼古丁诱导的肺癌进展的治疗作用

Molecular Therapy: Oncology Pub Date : 2024-09-10 DOI: 10.1016/j.omton.2024.200875

Soyoung Park, Ah-Young Oh, Byung-Su Hong, Yun-Jeong Shin, Hyewon Jang, Hyunghwan Seo, So-mi Kang, Tae-Gyun Woo, Hyo-Pin Park, Jiwon Jeong, Hye-Ju Kim, Bae-Hoon Kim, Yonghoon Kwon, Bum-Joon Park

{"title":"The therapeutic effect of DX2 inhibition in nicotine-induced lung cancer progression","authors":"Soyoung Park, Ah-Young Oh, Byung-Su Hong, Yun-Jeong Shin, Hyewon Jang, Hyunghwan Seo, So-mi Kang, Tae-Gyun Woo, Hyo-Pin Park, Jiwon Jeong, Hye-Ju Kim, Bae-Hoon Kim, Yonghoon Kwon, Bum-Joon Park","doi":"10.1016/j.omton.2024.200875","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200875","url":null,"abstract":"Alternative splicing products of AIMP2 and AIMP2-DX2 (DX2) have been reported to be associated with human lung cancer. In fact, DX2 expression is elevated in human lung cancers, and DX2 transgenic mice also develop lung cancer, in particular small cell lung cancer (SCLC). However, the mechanism by which DX2 is induced during cancer progression has not been clearly elucidated. Here, we show that DX2 is induced by nicotine, the main component of smoking-related chemicals, which can stabilize the human epidermal growth factor receptor 2 (HER2) protein and transcriptionally increase sonic hedgehog (Shh). Indeed, nicotine showed tumorigenicity via DX2 by promoting spheroid formation and <ce:italic>in vivo</ce:italic> lung and kidney cancer progression. Moreover, the elimination of DX2 using small interfering RNA (siRNA) or an optimized inhibitor (SNU-14) blocked the induction of HER2 and Shh and completely suppressed tumor sphere formation in response to nicotine. These results indicate that DX2 is critical for lung cancer progression, and a specific DX2 inhibitor would be useful for the treatment of human cancers, including SCLC and non-SCLC (NSCLC).","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249521","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

CAR-T cell therapy: Advances in digestive system malignant tumors CAR-T 细胞疗法：消化系统恶性肿瘤的研究进展

Molecular Therapy: Oncology Pub Date : 2024-09-10 DOI: 10.1016/j.omton.2024.200872

Nan Xu, Zhonglin Wu, Jun Pan, Xiao Xu, Qiang Wei

{"title":"CAR-T cell therapy: Advances in digestive system malignant tumors","authors":"Nan Xu, Zhonglin Wu, Jun Pan, Xiao Xu, Qiang Wei","doi":"10.1016/j.omton.2024.200872","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200872","url":null,"abstract":"Malignant tumors of the digestive system have had a notoriously dismal prognosis throughout history. Immunotherapy, radiotherapy, surgery, and chemotherapy are the primary therapeutic approaches for digestive system cancers. The rate of recurrence and metastasis, nevertheless, remains elevated. As one of the immunotherapies, chimeric antigen receptor T cell (CAR-T) therapy has demonstrated a promising antitumor effect in hematologic cancer. Despite undergoing numerous clinical trials, the ineffective antitumor effect and adverse effects of CAR-T cell therapy in the treatment of digestive system cancers continue to impede its clinical translation. It is necessary to surmount the restricted options for targeting proteins, the obstacles that impede CAR-T cell infiltration into solid tumors, and the limited survival time <ce:italic>in vivo</ce:italic>. We examined and summarized the developments, obstacles, and countermeasures associated with CAR-T therapy in digestive system cancers. Emphasis was placed on the regulatory functions of potential antigen targets, the tumor microenvironment, and immune evasion in CAR-T therapy. Thus, our analysis has furnished an all-encompassing comprehension of CAR-T cell therapy in digestive system cancers, which will generate tremendous enthusiasm for subsequent in-depth research into CAR-T-based therapies in digestive system cancers.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249522","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

Exploring prognostic implications of miRNA signatures and telomere maintenance genes in kidney cancer 探索肾癌中 miRNA 特征和端粒维持基因对预后的影响

Molecular Therapy: Oncology Pub Date : 2024-09-10 DOI: 10.1016/j.omton.2024.200874

Srinivasulu Yerukala Sathipati, Sohyun Jeong, Param Sharma, John Mayer, Rohit Sharma, Shinn-Ying Ho, Scott Hebbring

{"title":"Exploring prognostic implications of miRNA signatures and telomere maintenance genes in kidney cancer","authors":"Srinivasulu Yerukala Sathipati, Sohyun Jeong, Param Sharma, John Mayer, Rohit Sharma, Shinn-Ying Ho, Scott Hebbring","doi":"10.1016/j.omton.2024.200874","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200874","url":null,"abstract":"Kidney cancer, particularly clear cell renal cell carcinoma (KIRC), presents significant challenges in disease-specific survival. This study investigates the prognostic potential of microRNAs (miRNAs) in kidney cancers, including KIRC and kidney papillary cell carcinoma (KIRP), focusing on their interplay with telomere maintenance genes. Utilizing data from The Cancer Genome Atlas, miRNA expression profiles of 166 KIRC and 168 KIRP patients were analyzed. An evolutionary learning-based kidney survival estimator identified robust miRNA signatures predictive of 5-year survival for both cancer types. For KIRC, a 37-miRNA signature showed a correlation coefficient (R) of 0.82 and mean absolute error (MAE) of 0.65 years. Similarly, for KIRP, a 23-miRNA signature exhibited an R of 0.82 and MAE of 0.64 years, demonstrating comparable predictive accuracy. These signatures also displayed diagnostic potential with receiver operating characteristic curve values between 0.70 and 0.94. Bioinformatics analysis revealed targeting of key telomere-associated genes such as <ce:italic>TERT</ce:italic>, <ce:italic>DKC1</ce:italic>, <ce:italic>CTC1</ce:italic>, and <ce:italic>RTEL1</ce:italic> by these miRNAs, implicating crucial pathways such as cellular senescence and proteoglycans in cancer. This study highlights the significant link between miRNAs and telomere genes in kidney cancer survival, offering insights for therapeutic targets and improved prognostic markers.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249519","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

APOBEC3B expression in 293T lentiviral producer cells drives mutations in chimeric antigen receptors and reduces CAR T cell efficacy 在 293T 慢病毒生产细胞中表达 APOBEC3B 会导致嵌合抗原受体发生突变，并降低 CAR T 细胞的功效

Molecular Therapy: Oncology Pub Date : 2024-09-10 DOI: 10.1016/j.omton.2024.200873

Jack Swanson, Jason Tonne, Thanich Sangsuwannukul, Jill Thompson, Benjamin Kendall, Olivia Liseth, Muriel Metko, Richard Vile

{"title":"APOBEC3B expression in 293T lentiviral producer cells drives mutations in chimeric antigen receptors and reduces CAR T cell efficacy","authors":"Jack Swanson, Jason Tonne, Thanich Sangsuwannukul, Jill Thompson, Benjamin Kendall, Olivia Liseth, Muriel Metko, Richard Vile","doi":"10.1016/j.omton.2024.200873","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200873","url":null,"abstract":"Chimeric antigen receptor (CAR) T cells are a clinically approved therapy for blood cancers. To produce clinical-grade CAR T cells, a retroviral or lentiviral vector is used to deliver the CAR and associated genes to patient T cells. Apolipoprotein B editing enzyme, catalytic polypeptide 3 (APOBEC3) enzymes are known to be upregulated after transfection and retroviral infection and to deaminate cytidine to uracil in nucleic acids, resulting in cytidine-to-thymine mutations in DNA. Here, we hypothesized that APOBEC3 enzymes, induced during the production of CAR T cells, impact the efficacy of the resulting CAR T cells. We demonstrated that APOBEC3 family member APOBEC3B was upregulated at the RNA and protein levels after transfection of HEK293T cells with plasmids to make lentivirus, and that APOBEC3 signature mutations were present in the CAR construct. APOBEC3B overexpression in HEK293T cells led to further mutations in the resulting CAR T cells, and significantly decreased CAR T cell killing. APOBEC3B knockout in HEK293T cells led to reduced mutations in the CAR construct and significantly increased in CAR T cell killing. These results suggest that generation of CAR-expressing viruses from producer cell lines deficient in genome-modifying proteins such as APOBEC3B could enhance the quality of CAR T cell production.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249520","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

Nature is the best designer: A novel variant of oncolytic reovirus 大自然是最好的设计师溶瘤再病毒的新型变体

Molecular Therapy: Oncology Pub Date : 2024-09-05 DOI: 10.1016/j.omton.2024.200865

Raghad Khaleafi, Yotam Bar-On

引用次数: 0

Bulk and single-cell transcriptomics identify gene signatures of stem cell-derived NK cell donors with superior cytolytic activity 大量和单细胞转录组学识别出具有卓越细胞溶解活性的干细胞衍生 NK 细胞供体的基因特征

Molecular Therapy: Oncology Pub Date : 2024-09-02 DOI: 10.1016/j.omton.2024.200870

Amanda A. van Vliet, Mirjam G.C.N. van den Hout, Daniëlle Steenmans, Adil D. Duru, Anna-Maria Georgoudaki, Tanja D. de Gruijl, Wilfred F.J. van IJcken, Jan Spanholtz, Monica Raimo

{"title":"Bulk and single-cell transcriptomics identify gene signatures of stem cell-derived NK cell donors with superior cytolytic activity","authors":"Amanda A. van Vliet, Mirjam G.C.N. van den Hout, Daniëlle Steenmans, Adil D. Duru, Anna-Maria Georgoudaki, Tanja D. de Gruijl, Wilfred F.J. van IJcken, Jan Spanholtz, Monica Raimo","doi":"10.1016/j.omton.2024.200870","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200870","url":null,"abstract":"Allogeneic natural killer (NK) cell therapies are a valuable treatment option for cancer, given their remarkable safety and favorable efficacy profile. Although the use of allogeneic donors allows for off-the-shelf and timely patient treatment, intrinsic interindividual differences put clinical efficacy at risk. The identification of donors with superior anti-tumor activity is essential to ensure the success of adoptive NK cell therapies. Here, we investigated the heterogeneity of 10 umbilical cord blood stem cell-derived NK cell batches. First, we evaluated the donors’ cytotoxic potential against tumor cell lines from solid and hematological cancer indications, to distinguish a group of superior, “excellent” killers (4/10), compared with “good” killers (6/10). Next, bulk and single-cell RNA sequencing, performed at different stages of NK differentiation, revealed distinct transcriptomic features of the two groups. Excellent donors showed an enrichment in cytotoxicity pathways and a depletion of myeloid traits, linked to the presence of a larger population of effector-like NK cells early on during differentiation. Consequently, we defined a multi-factorial gene expression signature able to predict the donors’ cytotoxic potential. Our study contributes to the identification of key traits of superior NK cell batches, supporting the development of efficacious NK therapeutics and the achievement of durable anti-tumor responses.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199240","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

Genetic dysregulation of EP300 in cancers in light of cancer epigenome control – Perspectives of specific targeting of p300-proficient and -deficient cancers 从癌症表观基因组调控看 EP300 在癌症中的遗传调控失调--特定靶向 p300 阳性和阴性癌症的视角

Molecular Therapy: Oncology Pub Date : 2024-09-02 DOI: 10.1016/j.omton.2024.200871

Karolina Gronkowska, Agnieszka Robaszkiewicz

{"title":"Genetic dysregulation of EP300 in cancers in light of cancer epigenome control – Perspectives of specific targeting of p300-proficient and -deficient cancers","authors":"Karolina Gronkowska, Agnieszka Robaszkiewicz","doi":"10.1016/j.omton.2024.200871","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200871","url":null,"abstract":"Some cancer types including bladder, cervical, and uterine cancers are characterized by frequent mutations in EP300 that encode histone acetyltransferase p300. This enzyme can act both as a tumor suppressor and oncogene. In this review, we describe the role of p300 in cancer initiation and progression regarding EP300 aberrations that have been identified in TGCA Pan-Cancer Atlas studies and we also discuss possible anticancer strategies that target EP300 mutated cancers. Copy number alterations, truncating mutations, and abnormal EP300 transcriptions that affect p300 abundance and activity are associated with several pathological features such as tumor grading, metastases, and patient survival. Elevated EP300 correlates with a higher mRNA level of other epigenetic factors and chromatin remodeling enzymes that co-operate with p300 in creating permissive conditions for malignant transformation, tumor growth and metastases. The status of EP300 expression can be considered as a prognostic marker for anticancer immunotherapy efficacy, as EP300 mutations are followed by an increased expression of PDL-1.HAT activators such as CTB or YF2 can be applied for p300-deficient patients, whereas the natural and synthetic inhibitors of p300 activity, as well as dual HAT/bromodomain inhibitors and the PROTAC degradation of p300, may serve as strategies in the fight against p300-fueled cancers.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199239","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

Muc16CD is a novel CAR T cell target antigen for the treatment of pancreatic cancer Muc16CD 是治疗胰腺癌的新型 CAR T 细胞靶抗原

Molecular Therapy: Oncology Pub Date : 2024-09-02 DOI: 10.1016/j.omton.2024.200868

Heather K. Lin, Dejah A. Blake, Tongrui Liu, Ruby Freeman, Gregory B. Lesinski, Lily Yang, Sarwish Rafiq

引用次数: 0

ADEVO: Proof-of-concept of adenovirus-directed EVOlution by random peptide display on the fiber knob ADEVO：在纤维旋钮上随机显示多肽的腺病毒定向 EVOlution 概念验证

Molecular Therapy: Oncology Pub Date : 2024-08-30 DOI: 10.1016/j.omton.2024.200867

Erwan Sallard, Julian Fischer, Katrin Schroeer, Lisa-Marie Dawson, Nissai Beaude, Arsalene Affes, Eric Ehrke-Schulz, Wenli Zhang, Adrian Westhaus, Marti Cabanes-Creus, Leszek Lisowski, Zsolt Ruszics, Anja Ehrhardt

{"title":"ADEVO: Proof-of-concept of adenovirus-directed EVOlution by random peptide display on the fiber knob","authors":"Erwan Sallard, Julian Fischer, Katrin Schroeer, Lisa-Marie Dawson, Nissai Beaude, Arsalene Affes, Eric Ehrke-Schulz, Wenli Zhang, Adrian Westhaus, Marti Cabanes-Creus, Leszek Lisowski, Zsolt Ruszics, Anja Ehrhardt","doi":"10.1016/j.omton.2024.200867","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200867","url":null,"abstract":"Directed evolution of viral vectors involves the generation of randomized libraries followed by artificial selection of improved variants. Directed evolution only yielded limited results in adenovirus (AdV) engineering until now, mainly due to insufficient complexities of randomized libraries. Meanwhile, clinical applications of AdVs as gene therapy or oncolytic vectors are still hampered by the predetermined tropism of natural types. To overcome this challenge, we hypothesized that randomized peptide insertions on the capsid surface can be incorporated into the AdV bioengineering toolbox for retargeting. Here we developed AdV-directed EVOlution protocols based on fiber knob peptide display. Human AdV-C5-derived libraries were constructed following three distinct protocols and selected on a panel of cancer cell lines, with the goal of identifying variants able to infect and lyse these tumor cells more efficiently. All protocols enabled the construction of high complexity libraries with up to 9.6 × 10 unique variants, an approximate 100-fold improvement compared with previously published AdV libraries. After selection, the most enriched variants, which were robustly selected in various cancer cell lines, did not display enhanced infectivity but rather more efficient replication and cell lysis. Selected inserts also conferred enhanced lysis ability to oncolytic AdVs restricted to telomerase-expressing cell lines.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"671 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199241","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

Targeting hepatocellular carcinoma heterogeneity with FAP and GPC3-specific tandem CAR-T cells 利用 FAP 和 GPC3 特异性串联 CAR-T 细胞靶向肝细胞癌异质性

Molecular Therapy: Oncology Pub Date : 2024-08-28 DOI: 10.1016/j.omton.2024.200859

Dan Li, Wei Wang

引用次数: 0