Grant: Project Grant

Oncolytic viruses infect and kill cancer cells, and are considered a promising form of cancer therapy. While the treatment of some patients with oncolytic viruses in clinical trials has yielded promising results, there are some patients that do not respond to the treatment and so there is much room for improvement. Having a better understanding of the factors that contribute to the success, or failure, of oncolytic virotherapy may lead to the development of new treatment strategies that maximize the potency of oncolytic viruses and ultimately improve patient outcomes. One of the factors we believe plays an important rule during oncolytic virotherapy is cancer metabolism. Viruses rely on the cells they infect to provide the building blocks to replicate and make more viruses, and these building blocks are provided by metabolism. By studying how tumor cell metabolism influences oncolytic virus replication, we identified a metabolite produced by tumor cells known as itaconate that plays an important role in inhibiting oncolytic virus replication, and thus limiting the effectiveness of the treatment. The goal of the proposed research is to understand how itaconate limits virus replication, and to develop strategies to prevent tumor cells, as well as immune cells in the tumor microenvironment, from making itaconate, thereby increasing the cancer killing potential of oncolytic viruses. If successful, our research may lead to the development of therapeutic strategies aimed at manipulating tumor cell metabolism to boost the effectiveness of oncolytic viruses.