Glioblastoma (GBM) is the commonest primary malignant brain cancer. It kills approximately 800 Australians annually. It is not known to be a preventable disease, has no cure and GBM sufferers have little prospect of long-term survival. Glioma stem cells (GSCs) are a small component cell population of GBM tumours that are resistant to both radiotherapy and chemotherapy and are believed to be responsible for disease progression or recurrence following treatment. Using cell lines we have established from GBM patient tumours and by enriching for GSCs, we have found increased expression in GSCs of many genes encoding enzymes involved in cholesterol synthesis. Preliminary experiments with GBM cells show that CRISPR/Cas9-targeted inhibition of HMGCR, the rate-limiting enzyme for cholesterol synthesis, inhibits GBM cell proliferation in vitro and tumour formation in vivo. Simvastatin, a statin that crosses the blood-brain barrier, shows similar effects. This project will investigate both in vitro and in vivo whether these preliminary observations extend to patient-derived GBM cell lines representing the four described molecular subtypes of GBM.
As statins are approved drugs with well characterised toxicity profiles, used by millions of Australians to treat hypercholesterolemia, this project has the potential to provide important pre-clinical data for future clinical trials to investigate the use of statins that cross the blood-brain barrier (simvastatin and fluvastatin) as an adjuvant treatment for GBM. In addition, this project will investigate whether use of simvastatin and fluvastatin, rather than atorvastatin and rosuvastatin (the statins most commonly used to manage hypercholesterolaemia but which do not cross the blood-brain barrier), protects against the development GBM.