Abstract 5636: Preclinical data of a microRNA-based therapy for hepatocellular carcinoma

Abstract

Abstract MicroRNA (miRNA) mimics have emerged as a novel class of therapeutics with promising anti-oncogenic activity. These mimics are modeled after naturally occurring tumor suppressor miRNAs that are ubiquitously expressed in normal cells but frequently show a loss-of-function in human malignancies. The premise for the strong inhibitory activity is based on the observation these endogenous miRNAs control multiple oncogenic pathways commonly deregulated in cancer. Therefore, “miRNA replacement therapy” acts in accordance with our current understanding of cancer as a pathway disease that can only be successfully treated when intervening with multiple cancer pathways. We have identified a series of key tumor suppressor miRNAs, including miR-34, and validated the therapeutic potential in cultured cancer cells and mouse models of cancer. The translation of this potential into future medicines, however, was hampered by the lack of a robust clinically relevant delivery system. To facilitate a rapid route to the clinic, we have screened a panel of external delivery systems that are in pre-clinical development or have already reached the clinic featuring another oligonucleotide. Here, we present the pharmacologic and pharmacodynamic parameters of miRNA mimics complexed in ionizable NOV340 liposomes (SMARTICLEs, Marina Biotech, Bothell, WA) in an orthotopic tumor model of hepatocellular carcinoma. Treatment of mice carrying existing tumors mimics led to significant tumor regression, prolonged survival and lacked notable drug-related side effects. Some of the mice appeared to be tumor-free. The data demonstrate the therapeutic utility of the NOV340/miRNA formulation and support the initiation of IND-enabling studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5636. doi:1538-7445.AM2012-5636