Cobomarsen, an Oligonucleotide Inhibitor of miR-155, Slows DLBCL Tumor Cell Growth In Vitro and In Vivo.
体外
生物
癌症
分子生物学
作者
Eleni Anastasiadou,Anita G. Seto,Xuan Beatty,Melanie Hermreck,Maud-Emmanuelle Gilles,Dina Stroopinsky,Lauren C. Pinter-Brown,Linda A Pestano,Cinzia Marchese,David Avigan,Pankaj Trivedi,Diana Escolar,Aimee L. Jackson,Frank J. Slack
出处
期刊:Clinical Cancer Research [American Association for Cancer Research] 日期:2021-02-15卷期号:27 (4): 1139-1149被引量:19
Purpose: MicroRNA-155, is an oncogenic miRNA, highly expressed in B-cell malignancies, particularly in the non-Germinal Center B-cell or activated B-cell subtype of Diffuse Large B-cell Lymphoma (non-GCB/ABC-DLBCL), where it is considered a potential diagnostic and prognostic biomarker. Thus, miR-155 inhibition represents an important therapeutic strategy for B-cell lymphomas. In this study, we tested the efficacy and pharmacodynamic activity of an oligonucleotide inhibitor of miR-155, cobomarsen, in ABC-DLBCL cell lines and in corresponding xenograft mouse models. In addition, we assessed the therapeutic efficacy and safety of cobomarsen in a patient diagnosed with aggressive ABC-DLBCL. Experimental design: Pre-clinical studies includedthe delivery of cobomarsen to highly miR-155 expressing ABC-DLBCL cell lines to assess any phenotypic changes as well as intravenous injections of cobomarsen in NSG mice carrying ABC-DLBCL xenografts to study tumor growth and pharmacodynamics of the compound over time. To begin to test its safety and therapeutic efficacy, a patient was recruited who underwent five cycles of cobomarsen treatment. Results: Cobomarsen decreased cell proliferation, and induced apoptosis in ABC-DLBCL cell lines. Intravenous administration of cobomarsen in a xenograft NSG mouse model of ABC-DLBCL reduced tumor volume, triggered apoptosis, and de-repressed direct miR-155 target genes. Finally, the compound reduced and stabilized tumor growth without any toxic effects for the patient. Conclusions: Our findings support the potential therapeutic application of cobomarsen in ABC-DLBCL and other types of lymphoma with elevated miR-155 expression.