Cobomarsen, an Oligonucleotide Inhibitor of miR-155, Slows DLBCL Tumor Cell Growth In Vitro and In Vivo.
Cobomarsen, an Oligonucleotide Inhibitor of miR-155, Slows DLBCL Tumor Cell Growth In Vitro and In Vivo.
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DOI：
10.1158/1078-0432.ccr-20-3139
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发表时间：
2021-02-15
期刊：
影响因子：
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通讯作者：
Slack FJ
中科院分区：
文献类型：
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作者：
Anastasiadou E;Seto AG;Beatty X;Hermreck M;Gilles ME;Stroopinsky D;Pinter-Brown LC;Pestano L;Marchese C;Avigan D;Trivedi P;Escolar DM;Jackson AL;Slack FJ
miRNA-155是在B细胞恶性肿瘤中高度表达的致癌miRNA，特别是在弥漫性大B细胞淋巴瘤（ABC-DLBCL）的非生发中心B细胞或活化B细胞亚型中，其中它被认为是潜在的诊断和预后生物标志物。因此，miR-155抑制代表了B细胞淋巴瘤的重要治疗策略。在这项研究中，我们测试了miR-155的寡核苷酸抑制剂cobomarsen在ABC-DLBCL细胞系和相应的异种移植小鼠模型中的功效和药效学活性。此外，我们评估了cobomarsen在诊断为侵袭性ABC-DLBCL患者中的治疗效果和安全性。临床前研究包括将cobomarsen递送至高度表达miR-155的ABC-DLBCL细胞系以评估任何表型变化，以及在携带ABC-DLBCL异种移植物的NSG小鼠中静脉注射cobomarsen，以研究该化合物随时间的肿瘤生长和药效学。为了开始测试它的安全性和治疗效果，招募了一名接受了5个周期的cobomarsen治疗的患者。Cobomarsen在ABC-DLBCL细胞系中降低细胞增殖并诱导细胞凋亡。在ABC-DLBCL的异种移植NSG小鼠模型中静脉给予cobomarsen减少了肿瘤体积，触发了细胞凋亡，并解除了直接miR-155靶基因的抑制。最后，该化合物减少并稳定了肿瘤生长，对患者没有任何毒性作用。我们的研究结果支持cobomarsen在ABC-DLBCL和其他类型的miR-155表达升高的淋巴瘤中的潜在治疗应用。
miRNA-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 (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. Preclinical studies included the 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. 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 derepressed direct miR-155 target genes. Finally, the compound reduced and stabilized tumor growth without any toxic effects for the patient. Our findings support the potential therapeutic application of cobomarsen in ABC-DLBCL and other types of lymphoma with elevated miR-155 expression.