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

Eugenio Morelli, Lavinia Biamonte, Cinzia Federico, Nicola Amodio, Maria Teresa Di Martino, Maria Eugenia Gallo Cantafio, Martina Manzoni, Francesca Scionti, Mehmet Kemal Samur, Annamaria Gullà, Maria Angelica Stamato, Maria Rita Pitari, Daniele Caracciolo, Settimio Sesti, Niels M. Frandsen, Marco Rossi, Antonino Neri, Mariateresa Fulciniti, Nikhil C. Munshi, Pierosandro Tagliaferri and Pierfrancesco Tassone

Key points

  • First-in-class MIR17PTi enables a 'one shot' downregulation of the entire miR-17-92 cluster in vitro and in vivo, with favorable PK profile.

  • MIR17PTi affects homeostatic MYC / miR-17-92 feedforward loops in MM cells, resulting in a strong anti-MM activity.

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.

  • Submitted March 5, 2018.
  • Accepted July 2, 2018.