A three dimensional tissue model for examining the mechanism of oncolytic herpes virus activity and synergy with chemotherapeutic agents in epithelial tumour cells.

Cancer therapy can involve radiation and/or chemotherapy strategies depending on the type of cancer under treatment. Until recently most therapies could be described as fairly non-specific: the approaches are designed to kill all growing cells in the body, not just the cancer cells which grow quickly. The body’s adverse reactions to cancer treatment is due to the toxic effects of these approaches. A more rational and directed approach to killing only cancer cells would benefit cancer patients enormously and potentially save money for the NHS as patient health will be better during treatment. Oncolytic viruses are human-infective viruses that are disabled so they grow poorly in normal cells but grow well in the rapidly dividing cells that characterise cancers. As a result, they selectively kill the cancers cells as a consequence of viral replication. One such virus is herpes simplex virus (HSV) 1716. HSV normally infects skin cells and causes cold sores, a benign condition. HSV1716 is well tolerated and shows anti-tumour properties in glioma, melanoma and head and neck squamous cell carcinoma (HNSCC). HSV1716 can be used together with chemotherapy agents as a rational approach to increase cancer cell killing. However, to date it has been difficult to study the synergy (or antagonism) of HSV1716 with chemotherapeutic agents in the laboratory using cancer cell lines. This may be due to the fact that cancer cells growing in dishes in the laboratory possess very different properties to cancer cells from real tumours. This project will use three cell lines that represent three stages of epithelial cancer progression relevant to HNSCC. These cell lines will be grown in three-dimensional culture models to mimic solid tumours. HSV1716 and chemotherapeutic drugs will be applied to the different models and the effects of the various combinations assessed by studying the expression of proteins that mark cancer cells and proteins that mark dying cells.