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Br J Haematol. 2018 Nov;183(3):428-444. doi: 10.1111/bjh.15547. Epub 2018 Aug 20.

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

Author information

1
miRagen Therapeutics, Inc., Boulder, CO, USA.
2
Section of Dermatopathology, Department of Pathology, Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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.

KEYWORDS:

Sézary syndrome; cobomarsen; cutaneous T-cell lymphoma; miR-155; mycosis fungoides

PMID:
30125933
DOI:
10.1111/bjh.15547

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