The microRNA 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 RNase H-mediated degradation of MIR17HG primary transcripts and, consequently, to prevent biogenesis of miR-17-92 microRNAs (miR-17-92s). The leading LNA-ASO, named MIR17PTi, impaired proliferation of several cancer cell lines (n=48) established from both solid and hematologic tumors by on-target antisense activity, and more effectively as compared to miR-17-92s 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 induced 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 anti-tumor activity in NOD-SCID mice bearing clinically relevant models of MM, with advantageous safety and pharmacokinetics profiles in non-human primates. Altogether, MIR17PTi is a novel pharmacological tool to be tested in early-phase clinical trials against MM and other MYC-driven malignancies.

Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-mir-17-92 / E. Morelli, L. Biamonte, C. Federico, N. Amodio, M.T. Di Martino, M.E. Gallo Cantafio, M. Manzoni, F. Scionti, M.K. Samur, A. Gullà, M.A. Stamato, M.R. Pitari, D. Caracciolo, S. Sesti, N.M. Frandsen, M. Rossi, A. Neri, M. Fulciniti, N.C. Munshi, P. Tagliaferri, P. Tassone. - In: BLOOD. - ISSN 0006-4971. - 132:10(2018 Sep 06), pp. blood-2018-03-836601.1050-blood-2018-03-836601.1063. [10.1182/blood-2018-03-836601]

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

M. Manzoni;A. Neri;
2018

Abstract

The microRNA 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 RNase H-mediated degradation of MIR17HG primary transcripts and, consequently, to prevent biogenesis of miR-17-92 microRNAs (miR-17-92s). The leading LNA-ASO, named MIR17PTi, impaired proliferation of several cancer cell lines (n=48) established from both solid and hematologic tumors by on-target antisense activity, and more effectively as compared to miR-17-92s 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 induced 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 anti-tumor activity in NOD-SCID mice bearing clinically relevant models of MM, with advantageous safety and pharmacokinetics profiles in non-human primates. Altogether, MIR17PTi is a novel pharmacological tool to be tested in early-phase clinical trials against MM and other MYC-driven malignancies.
Settore MED/15 - Malattie del Sangue
11-lug-2018
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/583018
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