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

Summary 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‐modifie...

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Bibliographic Details
Published in:British journal of haematology 2018-11, Vol.183 (3), p.428-444
Main Authors: Seto, Anita G., Beatty, Xuan, Lynch, Joshua M., Hermreck, Melanie, Tetzlaff, Michael, Duvic, Madeleine, Jackson, Aimee L.
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Apoptosis
Biomarkers
Cell Line, Tumor
Cell proliferation
Cell Survival
Clinical Trials, Phase I as Topic
cobomarsen
cutaneous T‐cell lymphoma
Disease-Free Survival
Female
Hematology
HTLV-I Infections - drug therapy
HTLV-I Infections - metabolism
HTLV-I Infections - mortality
HTLV-I Infections - pathology
Human T-lymphotropic virus 1
Humans
Leukemia
Lymphoma
Lymphoma, T-Cell, Cutaneous - drug therapy
Lymphoma, T-Cell, Cutaneous - metabolism
Lymphoma, T-Cell, Cutaneous - mortality
Lymphoma, T-Cell, Cutaneous - pathology
Male
MAP kinase
Medical prognosis
MicroRNAs - antagonists & inhibitors
MicroRNAs - metabolism
miRNA
miR‐155
Mycosis
Mycosis fungoides
Nucleic acids
Oligonucleotides
Oligonucleotides - pharmacology
Pathogenesis
Pharmacodynamics
RNA, Neoplasm - antagonists & inhibitors
RNA, Neoplasm - metabolism
Signal transduction
Survival Rate
Sézary syndrome
T-cell lymphoma
Viruses
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Summary:Summary 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.
ISSN:0007-1048
1365-2141
DOI:10.1111/bjh.15547