Off-Target Effects Turn Off Tumors
At SMi’s Conference on RNA Therapeutics (London, 5-6 June 2013), a striking talk was delivered by Prof. Nagy Habib of Imperial College London. Habib is a liver surgeon who has also worked extensively with nucleic acid therapeutics. For this project, his team simply sought to improve the number of liver cancer patients eligible for surgery: currently, fewer than 10% of patients are considered eligible for surgery because their liver function is so low already. One of the important functions of the liver is albumin production, and he initially hoped to upregulate albumin production in liver cancer patients to the extent that they could tolerate surgery.
The team developed a small activating RNA that targeted the promoter of CCAAT/enhancer-binding protein alpha (CEBPA), an activator of albumin production. Indeed, upon duplex treatment, albumin production was upregulated several fold. Serendipitously, however, the team also observed a striking reduction in tumor burden in treated animals. To follow up on this observation, the team monitored changes in gene expression. Among the many genes whose expression changed significantly by the duplex, over 20 tumor suppressor genes were upregulated (including BAX, p53, PTEN) and 66 oncogenes were downregulated. None of this was apparently intended and the oncogene silencing could not be explained simply by seed sequence complementarity to their 3’-UTRs. Yet these “off-target effects” give the duplex tremendous potential for treating liver cancer. Moreover it appears to show anti-cancer activity in a number of other cancer types (particularly those associated with a low level of CEBPA). Indeed, some of the duplex’s anticancer activity may be mediated by CEPBA activation – this gene shows reduced expression in a number of cancers, and it is considered a tumor suppressor. However, it seems likely that direct effects of the duplex on expression of other genes also contribute to its antitumor activity.
The RNA duplex is being developed by Mina Therapeutics and is currently in a Phase I clinical trial. It is interesting to wonder how many other oligonucleotide drugs will be able to harness their “off-target effects” to improve their range of therapeutic benefits in such a dramatic way.
Reported by Jonathan Watts, Department of Chemistry and Institute for Life Sciences, University of Southampton, UK.