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Blood. 2018 Sep 6;132(10):1050-1063. doi: 10.1182/blood-2018-03-836601. Epub 2018 Jul 11.

Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-miR-17-92.

Author information

1
Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
2
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
3
Cancer Biology Division, Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO.
4
Department of Oncology and Oncoematology, University of Milan, Milan, Italy.
5
UOC Ematologia, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico, Milan, Italy.
6
Department of Biology, Ecology and Earth Science, University of Calabria, Cosenza, Italy.
7
Exiqon A/S, Vedbaek, Denmark; and.
8
VA Boston Healthcare System, Boston, MA.

Abstract

The microRNA (miRNA) cluster miR-17-92 is oncogenic and represents a valuable therapeutic target in c-MYC (MYC)-driven malignancies. Here, we developed novel LNA gapmeR antisense oligonucleotides (ASOs) to induce ribonuclease H-mediated degradation of MIR17HG primary transcripts and consequently prevent biogenesis of miR-17-92 miRNAs (miR-17-92s). The leading LNA ASO, MIR17PTi, impaired proliferation of several cancer cell lines (n = 48) established from both solid and hematologic tumors by on-target antisense activity, more effectively as compared with miR-17-92 inhibitors. By focusing on multiple myeloma (MM), we found that MIR17PTi triggers apoptosis via impairment of homeostatic MYC/miR-17-92 feed-forward loops (FFLs) in patient-derived MM cells and induces MYC-dependent synthetic lethality. We show that alteration of a BIM-centered FFL is instrumental for MIR17PTi to induce cytotoxicity in MM cells. MIR17PTi exerts strong in vivo antitumor activity in nonobese diabetic severe combined immunodeficient mice bearing clinically relevant models of MM, with advantageous safety and pharmacokinetic profiles in nonhuman primates. Altogether, MIR17PTi is a novel pharmacological tool to be tested in early-phase clinical trials against MM and other MYC-driven malignancies.

Comment in

PMID:
29997223
PMCID:
PMC6128086
DOI:
10.1182/blood-2018-03-836601
[Indexed for MEDLINE]
Free PMC Article

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