Antisense Oligonucleotide Therapy for Liver Cancer

-Two independent antisense oligonucleotides (ASOs) targeting GREB1 and Arl4c gene-

Abstract

  • GREB1 was identified as one of the important factors controlling a cell proliferation and as a therapeutic target of hepatoblastoma.
  • Arl4c overexpressed in hepatocellular carcinoma tumors and colorectal cancer liver metastases, and was detected as a key factor for motility, invasion and proliferation of the cancer cells.
  • GREB1- or Arl4c-targeted ASOs successfully decreased and suppressed the tumors growth.

Background

Researchers focus on comprehensively understanding the molecular mechanisms of the Wnt signaling regulated with other pathway, such as TGF-β, EGF, and Hedgehog signaling.
Hepatoblastoma (HB) is a rare form of liver cancer, affecting just a few individuals per million, it is the leading cause of liver cancer in infants and young children. Researchers realized that a large number of HB patients — up to 90% in some cases — expressed Growth Regulating Estrogen Receptor Binding 1 (GREB1) in the nucleus of tumor lesions. Additionally, researchers revealed the molecular mechanisms which Wnt signaling abnormal activation promotes HB growth with GREB1 expression.
According to Researches, ADP-ribosylation factor-like 4c (Arl4c) was identified as a small molecule GTP-binding protein, which is expressed by Wnt and EGF signaling, plays an important role in tubulogenesis of cultured cells and the ureters. Arl4c is highly expressed in hepatocellular carcinoma (HCC), lung cancer, and colorectal cancer.

Technology and Data / Methods

Researchers investigated the suppressing tumor formation effect and inhibiting growth effect in vivo study using GREB1- and Arl4c-targeted AmNA-modified ASOs (*) injected by i.p.
* AmNA-modified ASO: In these projects, Amido-bridged nucleic acid (AmNA) was used to Improve nuclease resistance and decrease hepatotoxicity.

  • The therapeutic effect of GREB1 ASO was investigated by implantation of HepG2 cells into the liver of nude mice. In ASO treated mice, suppressed tumor formation compared with control. See Fig. (a).
  • The therapeutic effect of Arl4c ASO-1316 was investigated by metastatic colorectal cancer in the liver (implantation of HCT116 cells into spleen). Arl4c ASO inhibited the growth of tumor. See Fig. (b).

Publications

  • Matsumoto et al., Nat Commun. 2019 Aug 28;10(1):3882.
    doi: 10.1038/s41467-019-11533-x.
  • Takeshi Harada et al., Mol Cancer Ther; 18(3) March 2019.
    doi: 10.1158/1535-7163.MCT-18-082.

Patents

  • GREB1 Project: Applied in JPO (Japan, unpublished)
  • Arl4c Project: Applied in JPO (Japan, unpublished)

Researcher

Dr. Akira Kikuchi (Professor, Osaka University, Japan.)

Expectations

Tech Manage Corp. (TMC) is looking for a pharmaceutical company entering collaboration with the researchers to develop and commercialize this technology further by patent licensing. TMC also appreciates any consideration of collaborative/supportive research or exclusive/non-exclusive evaluation for a defined period (setting up as options).

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