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.

RNA-Based Therapeutics: From Antisense Oligonucleotides to miRNAs

“…MRG-106, a LNA antagomiR that targets miR-155, is in phase 1 (NCT02580552) and phase 2 clinical trials (NCT03713320). miR-155 regulates differentiation and proliferation of blood and lymphoid cells and is a suitable target for treating certain kinds of lymphoma and leukaemia [186]. MRG-107 also targets miR-155 but has promise in treating patients with amyotrophic lateral sclerosis (ALS).…”

miRNAs as Influencers of Cell–Cell Communication in Tumor Microenvironment

“…In particular, in MesomiR-1, the TargomiR is composed of the following three elements: (i) a synthetic double-stranded RNA molecule which mimics the tumor suppressor miR-16 [198]; (ii) bacterial vesicles for the delivery of the RNA molecule; and (iii) an anti-Epidermal Growth Factor Receptor (EGFR) antibody which recognizes the EGFR expressed on only cancer cells. Cobomarsen (also termed MRG-106), an LNA-modified oligonucleotide inhibitor of miR-155, is another anti-miR that recently entered clinical trial (NCT03837457) for the treatment of patients with mycosis fungoides, the most widespread type of cutaneous T-cell lymphoma [199].…”

MicroRNAs in Tumor Cell Metabolism: Roles and Therapeutic Opportunities

“…A similar example is the MesomiR-1 drug, which reintroduces miR-16, a miRNA that regulates Aldolase A in glycolysis process (278,279). Another, drug delivery system being evaluated in stage 1 clinical trial is the locked oligonucleotide acid-modified inhibitor for miR-155 (MRG-106), as part of the clinical intervention for cutaneous T-cell lymphoma patients (280,281). This therapeutic intervention re-expresses miR-155 targets such as miR-143, that negatively regulates HK2 and consequently limits the active glycolytic phenotype (77).…”