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Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma.
- Source :
-
British journal of haematology [Br J Haematol] 2018 Nov; Vol. 183 (3), pp. 428-444. Date of Electronic Publication: 2018 Aug 20. - Publication Year :
- 2018
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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.<br /> (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)
- Subjects :
- Cell Line, Tumor
Cell Survival
Clinical Trials, Phase I as Topic
Disease-Free Survival
Female
Humans
Male
MicroRNAs metabolism
RNA, Neoplasm metabolism
Survival Rate
HTLV-I Infections drug therapy
HTLV-I Infections metabolism
HTLV-I Infections mortality
HTLV-I Infections pathology
Human T-lymphotropic virus 1
Lymphoma, T-Cell, Cutaneous drug therapy
Lymphoma, T-Cell, Cutaneous metabolism
Lymphoma, T-Cell, Cutaneous mortality
Lymphoma, T-Cell, Cutaneous pathology
MicroRNAs antagonists & inhibitors
Oligonucleotides pharmacology
RNA, Neoplasm antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2141
- Volume :
- 183
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- British journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 30125933
- Full Text :
- https://doi.org/10.1111/bjh.15547