Cobomarsen, an Oligonucleotide Inhibitor of miR-155, Slows DLBCL Tumor Cell Growth In Vitro and In Vivo

  • Clin Cancer Res. 2021 Feb 15;27(4):1139-1149. doi: 10.1158/1078-0432.CCR-20-3139.
Eleni Anastasiadou  1  2 ,  Anita G Seto  3 ,  Xuan Beatty  3 ,  Melanie Hermreck  3 ,  Maud-Emmanuelle Gilles  1 ,  Dina Stroopinsky  4 ,  Lauren C Pinter-Brown  5 ,  Linda Pestano  3 ,  Cinzia Marchese  2 ,  David Avigan  4 ,  Pankaj Trivedi  2 ,  Diana M Escolar  3 ,  Aimee L Jackson  3 ,  Frank J Slack  6
Affiliations
  • 1. HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
  • 2. Department of Experimental Medicine, Sapienza University of Rome, Italy.
  • 3. miRagen Therapeutics, Inc, Boulder, Colorado.
  • 4. Department of Hematology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
  • 5. Department of Internal Medicine, Division of Hematology/Oncology, University of California, Irvine, California.
  • 6. HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. [email protected].
PMID: 33208342 DOI: 10.1158/1078-0432.CCR-20-3139
Abstract

Purpose: 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.

Experimental design: 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.

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 derepressed 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.

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