A group of TFRI-funded investigators based in Ottawa has discovered that suppressing the RNA interference pathway (RNAi), an antiviral response system once believed to be unique to invertebrates, fungi and plants, could make oncolytic viruses (OVs) more effective. This discovery was possible thanks to the development of a novel OV that incorporates a protein found in a virus first isolated in mosquitoes in Japan 70 years ago.
The team led by Drs. Carolina Ilkow and John Bell (Ottawa Hospital Research Institute/University of Ottawa) hypothesized that RNAi could play a roll in antiviral responses in human cancer cells: “Considering the discovery of mammalian antiviral RNAi in embryonic stem cells and the genetic similarities between cancer cells and embryonic stem cells, we hypothesized a role for antiviral RNAi in cancer cells,” they explain in their paper published in the Journal for ImmunoTherapy (June 2018).
To test for the presence of RNAi in cancer cells, the researchers engineered a virus that modified the features of a known OV – VSVΔ51 – to incorporate a protein known as B2, a viral suppresser of the RNAi pathway present in an insect virus known as the Nodamura virus. This enabled them to characterize the novel OV and to demonstrate the interplay between the B2-expressing virus and RNA processing pathways in cancer.
When they applied this novel OV to 38 different human cancer cell lines in the lab, they were amazed at the results: not only was the new OV much better at targeting and killing cancer cells, it also had the ability to rapidly proliferate within the cancer cell environment without attacking other cells. These results allowed them to conclude that suppressing RNAi may improve OV replication and could enhance cancer cell susceptibility to OVs, opening the door to the development of viruses that can target and kill human cancer cells more efficiently.
Enhanced susceptibility of cancer cells to oncolytic rhabdo-virotherapy by expression of Nodamura virus protein B2 as a suppressor of RNA interference
Donald Bastin, Amelia S. Aitken, Adrian Pelin, Larissa A. Pikor, Mathieu J. F. Crupi, Michael S. Huh, Marie-Claude Bourgeois-Daigneault, John C. Bell and Carolina S. Ilkow.
This study is partially funded by a Terry Fox New Frontiers Program Project Grant: Canadian Oncolytic Virus Consortium (COVCo)