Bergeron, Anabel2020-01-202020-01-20http://hdl.handle.net/10393/40099http://dx.doi.org/10.20381/ruor-24338Heterogeneity of response and tumor resistance are preventing oncolytic viruses from reaching their full therapeutic potential in the clinic. We recently reported that vanadium-based compounds improve oncolysis and induce long-term antitumor immunity when used in conjunction with oncolytic virus VSV∆51 in murine models of carcinoma. Given the known capacity of vanadium compounds to inhibit multiple phosphatases (PPases), we hypothesized that vanadium compounds work by altering PPase/kinase homeostasis and set out to explore this idea using a targeted screening approach. Based on previous observations, we further hypothesized that a vanadium/OV regimen could be effective in sarcoma and synergize with immune checkpoint blockade. A high-throughput screen using a library of small interfering RNAs targeting human PPases revealed multiple PPases that significantly increase VSV∆51 infection and cytotoxicity. A complementary kinase inhibitor screen and pathway analysis further unveiled kinase/PPase substrates that may contribute to vanadate’s mechanism of action, as well as novel viral sensitizers, which were validated in in vitro and ex vivo models. The vanadium/VSV∆51 combination therapy was tested in mice bearing rhabdomyosarcoma tumors. While tumor progression was delayed, no significant improvement in survival was observed in the dual vanadium/VSV∆51 test group compared to VSV∆51 monotherapy. An aggressive triple-combination regimen of vanadium-VSV∆51 with immune checkpoint blockade led to high tumor cure rates but was not well tolerated and led to serious adverse events including treatment-related deaths. Overall, this project provides insights into vanadium’s mechanism of action and identifies promising novel small molecule enhancers of VSV∆51 virotherapy. Our studies also warrant that further treatment regimen optimization and exploration be carried for the safe and effective use of vanadium-OV containing immunotherapy regimens in the context of sarcoma.enVirusCancerImmunotherapyVanadiumKinasePhosphataseThesis