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

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.

The Non-Coding RNA Landscape of Plasma Cell Dyscrasias

“…Importantly, c-MYC acts in concert with Sp1 to down-regulate the expression of tumor suppressor miR-23b in MM and WM cells [128], and miR-23b enforcement dampened in vitro and in vivo MM or WM growth. Additionally, c-MYC strongly induces the expression of miR-17-92 oncogenic cluster, which in turn regulates the expression of MYC target genes-including BCL2L11 (BIM)-establishing a homeostatic feed-forward loop (FFL) [129].…”

MicroRNA‐mediated regulation of T follicular helper and T follicular regulatory cell identity

“…84,85,159,160 For example, antagomiRs targeting the miR-17~92 cluster members miR-17 and miR-19b effectively reduced allogeneic T cell expansion and IFNγ production that occur during acute GVHD, leading to prolonged survival of transplant recipients after BMT. 84,85,159,160 For example, antagomiRs targeting the miR-17~92 cluster members miR-17 and miR-19b effectively reduced allogeneic T cell expansion and IFNγ production that occur during acute GVHD, leading to prolonged survival of transplant recipients after BMT.…”

“…85 An an-tagomiR against miR-92a was further shown to be effective in reducing immune cell infiltration into the pancreas in two mouse models of type 1 diabetes. 159 MIR17PTi showed strong antitumor activity against human multiple myeloma in vitro and in vivo, without any signs of toxicity, thus representing a promising new drug candidate. 159 MIR17PTi showed strong antitumor activity against human multiple myeloma in vitro and in vivo, without any signs of toxicity, thus representing a promising new drug candidate.…”

“…84 Recently, a novel inhibitor of pri-miR-17~92 (MIR17PTi), which mediates RNase H-dependent downregulation of the entire miR-17~92 cluster, was developed. 159 Further research is needed though to overcome three critical caveats associated with current antagomiR strategies: the lack of cell-type specific delivery, the relative inefficiency of cell penetration, and the potentially diverse effects in different target cell types. 159 Further research is needed though to overcome three critical caveats associated with current antagomiR strategies: the lack of cell-type specific delivery, the relative inefficiency of cell penetration, and the potentially diverse effects in different target cell types.…”

“…Indeed, recent studies reported successful application of antagomiRs or miRNA inhibitors against miR-17~92 cluster members for the treatment of acute and chronic GVHD, type 1 diabetes, or cancer. 84,85,159,160 For example, antagomiRs targeting the miR-17~92 cluster members miR-17 and miR-19b effectively reduced allogeneic T cell expansion and IFNγ production that occur during acute GVHD, leading to prolonged survival of transplant recipients after BMT. 85,160 Additionally, application of a miR-17 antagomiR in a lupus-like chronic GVHD mouse model alleviated clinical manifestations and proteinuria by inhibition of lymphocyte expansion and B cell activation as well as dampening of the GC response.…”