Grant: Operating Grant

We identified a new property of the statin family of drugs that are used extensively to treat high serum cholesterol levels through targeting of the mevalonate pathway. This pathway's end products including cholesterol play important roles in controlling cell growth and survival. Our work has shown that high doses of statins that can be achieved clinically can specifically kill cells from a number of tumour types including head and neck cancers. This work led to a clinical trial in which lovastatin was tested as a single agent and could stabilize the growth of this disease (greater than 3 months) in 25% of patients with aggressive cancer that failed standard therapies. These results suggested that statin use in combination with other active agents is required to show greater activity in a wider range of patients. To this end, we recently demonstrated that statins in combination with inhibitors of growth factor receptors showed significantly enhanced tumour cell killing particularly in lung and in head and neck cancer cells. A further clinical evaluation at our Institute employing this new combination of agents has just been completed. While clinical activity was demonstrated, toxicity induced by this combination limited this approach. More refined therapies that remain active but avoid these toxicities is required. In this study, we will assess the potential of targeting downstream mevalonate pathway enzymes as therapeutic targets that retain the anti-cancer effects of statins without the toxicities limiting their use clinically. Our preliminary work suggests that downstream mevalonate pathway targets represent such an approach that requires further evaluation. Overall this study is an excellent example of the re-iterative nature of drug development where laboratory bench discoveries lead to bedside clinical evaluations that further drive laboratory studies that further refine clinical evaluations.