Oral Presentation 30th Lorne Cancer Conference 2018

RNA-based cancer therapeutics – are we there yet? (#5)

Peter Leedman 1
  1. Laboratory for Cancer Medicine, Western Australian Institute for Medical Research, UWA Centre for Medical Research, Perth, WA, Australia

There have been major advances in RNA-based therapeutics (siRNA, miRNA and antisense oligonucleotides) recently, so that it now offers great potential to treat a range of human disorders, including cancer. Drugs developed with 2nd generation chemistry are proving very successful in clinical trials, especially in liver disorders, best illustrated by siRNA targeting of PCSK9 which profoundly reduced LDL cholesterol in patients already on statins (NEJM, 2017, 376: 1430). Key to this advancement has been (i) the enhanced stability afforded by structural modifications; (ii) liver-specific delivery via the asialoglycoprotein receptor-GalNAc interaction and (iii) dispensing with needing a lipid carrier/vehicle, the latter a potential cause of therapy-limiting adverse effects.

            The development of miRNAs as cancer therapeutics is illustrated by miR-34a, which was the first miRNA to enter clinical trials in the US to treat solid cancers, predominantly liver (HCC) and renal cancer. The approach used 1st generation chemistry and a lipid vehicle, and although there were some promising therapeutic effects, adverse effects from the lipid carrier prevented further development.

We have been developing a microRNA for therapy, miR-7, which is a potent inhibitor of the EGF-receptor (EGFR) signaling pathway in multiple human tumors, including HCC. miR-7 powerfully inhibits HCC growth in vitro and in vivo, and can overcome resistance to the routinely used multi-tyrosine kinase inhibitor, sorafenib1. In collaboration with a US-based RNA therapeutics company, we have been evaluating 2nd generation chemistry modifications to miR-7 mimics so that they do not require a lipid vehicle and can be targeted to the liver specifically.

This talk will illustrate the potential for RNA-based therapeutics as cancer treatments, with emphasis on using miR-7 mimics as a novel therapy for HCC.

  1. Kabir T, et al. A microRNA-7/growth arrest specific 6/TYRO3 axis regulates the growth and invasiveness of sorafenib-resistant cells in human hepatocellular carcinoma. Hepatology, 2018: 67; 216.