UAlberta-Math Bio Seminar: Maya Shmulevitz and Francisca Cristi

Mammalian orthoreovirus (reovirus) is naturally an enteric virus that spreads among most mammals without causing disease. Reovirus also can infect and kill cancer cells while leaving normal cells unharmed, and is now in phase III clinical trials as a potential therapy for breast cancer. Both in animal models and human trials, reovirus fails to cure the majority of patients. Our laboratory strives to improve reovirus as a cancer therapy. Since reovirus naturally evolved to be exquisitely well-adapted to the enteric niche, we reasoned that the mutations in reovirus may encourage adaptation towards the cancer niche and promote reovirus oncolytic potency. Using positive selection, mutations that help reovirus thrive in cancer cells were selected and combined in a “supervirus 5 (SV5)”. We have three key results for which we seek mathematical solutions: (1) In an animal model of breast cancer, SV5 shows significant improvement over the wild-type reovirus. Surprisingly, mice fall into groups of “full-responders” or “weak-responders”. We seek a mathematical solution to distinguish fullresponders versus weak-responders based on the many molecular features we collect from treated mice. (2) At the molecular level, SV5 is composed of mutations that promote specific steps of reovirus replication through distinct mechanisms, and mutations tend to come with both benefits and costs to fitness of reovirus in cancer cells. We seek a mathematical formula for fitness that combines the effects of mutations on distinct aspects of virus replication. (3) Finally, mutations in reovirus that promote replication in cancer cells and tumor regression in animal models share in common the ability to disseminate/spread more rapidly and to a greater extent. We seek a mathematical solution towards understanding the relationships between virus spread in cell culture conditions versus tumor microenvironments. This will help us better understand the effect of virus spread efficiency on potency of virus as a cancer therapy. Overall, we hope to generate discussion on mathematical questions and approaches to better understand viruses as cancer therapies.