Liver X Receptor Ligands Can Inhibit Glioblstoma Cells in A Cholesterol-Dependent Fashion

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Glioblastoma is the most common and most aggressive form of brain cancer, which is extremely difficult to treat. The median survival rate is just over 14 months, with few treated patients living five years or more past diagnosis.

Researchers led by Paul Mischel of Ludwig San Diego and Benjamin Cravatt of The Scripps Research Institute, demonstrates that glioblastoma cells import vast amounts of cholesterol to survive and that the mechanisms they use to do so can be specifically and effectively by blocking liver X receptor. Their paper appears in the current issue of Cancer Cell.

Glioblastoma cells are extremely dependent on imported cholesterol, as they don’t make their own and they need lots of it to keep dividing. The cancer cells make sure they keep getting it by shutting down their import controls. When normal cells have sufficient cholesterol, they convert some of it into molecules known as oxysterols. These molecules activate a receptor in the cell’s nucleus called the liver X receptor (LXR), which helps halt the uptake of cholesterol.

They showed that glioblastoma cells do this by suppressing the production of oxysterols, thus ensuring that liver X receptor remain inactive. The authors reasoned that tumor cells in the brain may behave in a parasitic fashion with regard to cholesterol, obtaining CNS-derived cholesterol while suppressing endogenous liver X receptor ligand synthesis, enabling glioblastoma cells to access a nearly limitless supply of cholesterol to fuel their growth.

They hypothesize, glioblastoma cells may be exquisitely vulnerable to synthetic brain-crossing liver X receptor ligands that would otherwise spare normal brain cell constituents, including astrocytes and neurons. Using tissue microarray analyses the authors showed that LDLR protein was significantly elevated in glioblastoma clinical samples relative to normal brain  indicating glioblastoma cells do obtain cholesterol primarily through uptake.

When the synthetic liver X receptor agonist, LXR-623 was tested in a panel of established glioblastoma cell lines and patient-derived glioblastoma neurosphere cultures they found that LXR-623 suppressed LDLR expression, increased expression of the ABCA1 efflux transporter, and induced substantial cell death in all of the glioblastoma samples tested. The authors used a small molecule called LXR-623 that activates liver X receptor. After showing that it crosses the blood-brain barrier in mice, they examined its effect on glioblastoma tumors derived from human patients that were implanted in mice. This study suggests that LXR-623 could offer a viable pharmacological therapy for glioblastoma patients.

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Paul S. Mischel et al. An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers. Cancer Cell, 2016. DOI: 10.1016/j.ccell.2016.09.008