Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma.

Abstract

miR-155, a microRNA associated with poor prognosis in lymphoma and leukaemia, has been implicated in the progression of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). In this study, we developed and tested cobomarsen (MRG-106), a locked nucleic acid-modified oligonucleotide inhibitor of miR-155. In MF and human lymphotropic virus type 1 (HTLV-1+) CTCL cell lines in vitro, inhibition of miR-155 with cobomarsen de-repressed direct miR-155 targets, decreased expression of multiple gene pathways associated with cell survival, reduced survival signalling, decreased cell proliferation and activated apoptosis. We identified a set of genes that are significantly regulated by cobomarsen, including direct and downstream targets of miR-155. Using clinical biopsies from MF patients, we demonstrated that expression of these pharmacodynamic biomarkers is dysregulated in MF and associated with miR-155 expression level and MF lesion severity. Further, we demonstrated that miR-155 simultaneously regulates multiple parallel survival pathways (including JAK/STAT, MAPK/ERK and PI3K/AKT) previously associated with the pathogenesis of MF, and that these survival pathways are inhibited by cobomarsen in vitro. A first-in-human phase 1 clinical trial of cobomarsen in patients with CTCL is currently underway, in which the panel of proposed biomarkers will be leveraged to assess pharmacodynamic response to cobomarsen therapy.

• Authors: Anita G Seto, Xuan Beatty, Joshua M Lynch, Melanie Hermreck, Michael Tetzlaff, Madeleine Duvic, Aimee L Jackson
• Journal: British journal of haematology (Br J Haematol) Vol. 183 Issue 3 Pg. 428-444 (11 2018) ISSN: 1365-2141 [Electronic] England
• PMID: 30125933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 British Society for Haematology and John Wiley & Sons Ltd.

Chemical References

• MIRN155 microRNA, human
• MicroRNAs
• Oligonucleotides
• RNA, Neoplasm

Topics

• Cell Line, Tumor
• Cell Survival
• Clinical Trials, Phase I as Topic
• Disease-Free Survival
• Female
• HTLV-I Infections (drug therapy, metabolism, mortality, pathology)
• Human T-lymphotropic virus 1
• Humans
• Lymphoma, T-Cell, Cutaneous (drug therapy, metabolism, mortality, pathology)
• Male
• MicroRNAs (antagonists & inhibitors, metabolism)
• Oligonucleotides (pharmacology)
• RNA, Neoplasm (antagonists & inhibitors, metabolism)
• Survival Rate