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

2018/08/20 by Anita G. Seto, Xuan Beatty, Joshua M. Lynch +5 · 320 citations
Immunology and Microbiology · Materials Science · Medicine · #Apoptosis #Biology #Cancer research #Cell biology #Cell growth #Cutaneous lymphoproliferative disorders research #Gene #Immunology #Lymphoma #MAPK/ERK pathway #Medicine #Mycosis fungoides #PI3K/AKT/mTOR pathway #Signal transduction #Silk-based biomaterials and applications #T-cell and Retrovirus Studies #microRNA

paper · pdf · doi:10.1111/bjh.15547

published in British Journal of Haematology 183(3), 428-444 (Wiley)

openalex publication_date 2018/08/20 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

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.

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