Marie-Claude Bourgeois-Daigneault, CRCHUM, University of Montreal

Karen Geoffroy1,2,3*, Elline Meuriot1,2,3*, Alexandra Buccilli1,2,3, Victor Mullins-Dansereau1,2,3, Marie-Lou Myre1,2,3, Stamatios Paradisis1,2,3, Angelina Bardoul1,3, Emma Mary Kalin1,2,3, Bruna Araripe Saraiva1,2,3, Mélissa Viens1,2,3, Kim Leclerc Desaulniers1, Huy-Dung Hoang4,5, John Cameron Bell5,6, Barbara Vanderhyden6,7, Tommy Alain4,5, Dominic Guy Roy1,3, David Parker Cook6,7 and Marie-Claude Bourgeois-Daigneault1,2,3**1 Cancer axis and Institut du cancer de Montreal, CHUM research center, Montreal, H2X 0A9, Canada. 2 Immunopathology axis, CHUM research center, Montreal, H2X 0A9, Canada. 3 Department of microbiology, infectious diseases and immunology, University of Montreal, Montreal, H3C 3J7. 4 Children's Hospital of Eastern Ontario Research Institute, Ottawa, K1H 8L1. 5 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, K1N 6N5 6 Cancer Research Program, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Canada 7 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, K1N 6N5

Damaging & Spreading

Oncolytic viruses are bio-therapeutics with cancer killing abilities. The Vesicular stomatitis virus (VSV) is a clinical trial candidate for cancer treatment and our model virus is an oncolytic variant of VSV (oVSV) with a deletion in its matrix protein that improves its safety profile. Using an extensive panel of breast cancer cell lines of all types, we observed that breast cancers that express the estrogen receptor were particularly sensitive to oVSV. Further investigations revealed that estradiol, the main estrogen in women, could enhance virus replication in these cancers. Given that estradiol drives breast cancer proliferation, its combination with oncolytic virotherapy is not an option. In fact, estrogen receptor-positive breast cancers are treated with estrogen-antagonizing endocrine therapies, which we found impair oVSV efficacy. Nevertheless, further investigations revealed that other estrogens, as well as testosterone, also had virus-enhancing effects. Notably, estetrol and testosterone both have anti-cancer activity and therapies combining estetrol or testosterone with oVSV could therefore constitute an effective treatment by promoting enhanced virus replication and cancer killing by both the hormone and the virus. Mechanistic studies revealed that all estrogens and testosterone block NF-kB activation upon virus infection. Furthermore, NF-kB-blocking drugs could sensitive hormone-unresponsive breast cancer cells to oVSV, therefore conferring an improved virus-based therapy for these oncolytic virus-resistant cancers. Our in vitro data is supported by ex-vivo experiments using breast cancer patient samples. Understanding and exploiting sex hormone modulation of oncolytic virotherapy is important as it could impact patient responses and allow for improved therapies for breast cancer treatment.