Project 457642

Breast Cancer is the second most common cancer in Canada and the most common cancer among Canadian females. Poly(ADP-ribose) polymerase inhibitors have been approved by Food and Drug Administration for cancers with faults in one of the BRCA genes. But despite the patients' initial promising response to these inhibitors, cancer develops resistance due to the tumor's genomic instability and heterogeneity. So, a solution to restore tumor cells' susceptibility to these molecules is needed. microRNAs are used to down-regulate cancer-specific targets for this purpose. But safe and efficient delivery of microRNAs to the tumor sites is yet to be developed. Oncolytic viruses are exciting therapeutic agents for cancer treatment as they specifically infect and kill cancer cells and induce anti-tumor immunity. We have previously shown the ability of oncolytic rhabdoviruses to induce tumor cell expression of multiple therapeutic payloads, including microRNAs. They are packaged into exosomes, their natural carriers, and are released from the infected cell to surrounding uninfected cells. In this project, I propose to generate a multi-modal oncolytic virus-based therapy that specifically replicates in and destroys tumor cells and sensitizes uninfected cells to the mentioned inhibitors, acting in a synthetic lethal manner. It will provide the proof of principle that oncolytic viruses have multiple therapeutic mechanisms of action: the direct induction of oncolysis, the induction of host anti-tumor immunity, the delivery of therapeutic microRNAs that can be disseminated within the tumor microenvironment by exosomal delivery, and the sensitization of target cells to mentioned inhibitors irrespective to their genomic signature. The result of this study will present a one-of-a-kind novel combinational therapy modality for breast cancer. In the future, I will focus on expanding the repertoire of DNA damage response genes targeted by our oncolytic rhabdoviruses to complete this toolbox.