Lipoprotein Deprivation Reveals a Cholesterol-Dependent Therapeutic Vulnerability in Diffuse Glioma Metabolism

SIMPLE SUMMARY: High-grade gliomas are aggressive cancers that arise in children and adults, for which there is an urgent need for more effective drug therapies. Targeting the energy requirements (‘metabolism’) of these cancer cells may offer a new avenue for therapy. Cholesterol is a fatty substance found on the surface of cancer cells. Our research shows that childhood high-grade gliomas require cholesterol for their energy needs. By repurposing a drug called LXR-623 to reduce the levels of cholesterol inside high-grade glioma cancer cells, we could impair the growth of these cells in laboratory conditions. These results provide evidence for future experiments using LXR-623 to test whether this drug is able to increase the survival of mice with similar high-grade gliomas. ABSTRACT: Poor outcomes associated with diffuse high-grade gliomas occur in both adults and children, despite substantial progress made in the molecular characterisation of the disease. Targeting the metabolic requirements of cancer cells represents an alternative therapeutic strategy to overcome the redundancy associated with cell signalling. Cholesterol is an integral component of cell membranes and is required by cancer cells to maintain growth and may also drive transformation. Here, we show that removal of exogenous cholesterol in the form of lipoproteins from culture medium was detrimental to the growth of two paediatric diffuse glioma cell lines, KNS42 and SF188, in association with S-phase elongation and a transcriptomic program, indicating dysregulated cholesterol homeostasis. Interrogation of metabolic perturbations under lipoprotein-deficient conditions revealed a reduced abundance of taurine-related metabolites and cholesterol ester species. Pharmacological reduction in intracellular cholesterol via decreased uptake and increased export was simulated using the liver X receptor agonist LXR-623, which reduced cellular viability in both adult and paediatric models of diffuse glioma, although the mechanism appeared to be cholesterol-independent in the latter. These results provide proof-of-principle for further assessment of liver X receptor agonists in paediatric diffuse glioma to complement the currently approved therapeutic regimens and expand the options available to clinicians to treat this highly debilitating disease.