Oncolytic viruses (OV) are a promising alternative cancer therapy due to their specificity and lack of debilitating side effects, such as those which typically accompany conventional therapeutics such as chemotherapy and radiation. Bovine herpesvirus type 1 (BHV-1) is an alphaherpesvirus with the ability to infect and kill multiple human tumor cell types. In comparison to other species-specific viruses, for which deficiencies in type I interferon signalling pathways dictates cellular sensitivity to infection, mutations in KRAS were found to correlate with high levels of BHV-1 replication. Interestingly, BHV-1 is able to induce cellular cytotoxicity in the absence of a productive infection. In contrast to current breast cancer (BC) treatments, which are largely based on receptor expression status, BHV-1 is able to infect and kill BC cells and breast cancer initiating cells (BCICs) from luminal and basal subtypes. Furthermore, BHV-1-infected BC cells are significantly diminished in their capacity to form tumors in vivo, suggesting that BHV-1 reduces the tumor forming capacity of BCICs. Combination therapy involving OVs has been used to exploit differences in the mechanism of tumor cell death elicited by individual treatments. Treatment with epigenetic modifiers such as 5-Azacytidine (5-Aza), a DNA methyltransferase inhibitor, has been shown to increase the antitumor activity of OVs. Our data indicates that 5-Aza strongly synergises with BHV-1, increasing virus replication and cytotoxicity in vitro. In vivo, BHV-1 monotherapy did not significantly impact tumor growth or survival of CR bearing subcutaneous breast tumors; however, combination therapy with 5-Aza significantly decreased the number of secondary lesions compared to BHV-1 monotherapy. Overall, the data presented in this dissertation indicate that BHV-1 is a promising broad spectrum OV with a unique mechanism of tumor cell targeting, and the ability to infect and kill tumor cells independent of a productive infection.

Doctor of Philosophy (Medical Science)

Thesis