Abstract
Reolysin® is a naturally occurring, replication competent formulation of reovirus Type 3 Dearing (T3D), which has displayed oncolytic activity in a variety of human cancers in vitro and in clinical trials. Reolysin® shows great promise as a cancer therapeutic, but further optimisation is needed to maximise its oncolytic potential. Previous work has failed to uncover the full mechanism of reovirus oncolysis, and this has hindered the discovery of a reliable biomarker of reovirus treatment response. Through gene expression profiling, knock-down, and over-expression experiments, we have identified Yes-Associated Protein-1 (YAP1) as a host-cell factor that predicts the susceptibility of squamous cell carcinoma of the head and neck (SCCHN) cell lines to reovirus-induced cell death. YAP1 is a downstream effector of the Hippo pathway that regulates cellular growth and, sometimes, cancer progression. Mechanistic studies revealed that YAP1-mediated restriction of reovirus oncolysis may partially affect direct reovirus replication, but does not occur at the cell surface via the main reovirus receptor, JAM-A, nor is it linked to the type I interferon anti-viral response. YAP1 protein expression appears to be cancer-specific; 13% of head and neck carcinoma tissues stained positive for YAP1, but expression was negligible in tissue derived from normal organs. Therefore, YAP1 shows potential as a clinical biomarker to help characterise the most responsive SCCHN patient subgroup to reovirus treatment, which warrants further investigation. Additionally, combining reovirus with 3 weekly chemotherapy regimens at the standard maximum tolerated dose (MTD) may not be the optimum mode of administration, as the drug-free breaks often allow tumour-vasculature re-growth, resulting in disease progression. Metronomic chemotherapy (MC) primarily targets endothelial cells that support tumour-associated angiogenesis, and is less toxic than the MTD. We have investigated a novel treatment combination of reovirus and low doses of taxane chemotherapy agents in prostate cancer (PCa) cell lines. The interaction of reovirus and Cabazitaxel or Docetaxel at doses considerably less than their IC50 values was measured by using cell viability assays and the Bliss statistical model, which demonstrated synergistic anti-cancer activity. This was partly due to enhanced microtubule stabilisation. Our data provides substance to assess the efficacy of this type of combination therapy in vivo, and subsequently in human trials.