Keeping cholesterol from brain tumors may improve survival rates

Cholesterol may be the key in fighting brain cancer, a team of international researchers have found that the absence of cholesterol in the brain kills tumors cells and led the mouse models into remission. The findings were published Oct. 13 in the journal Cancer Cell.

Glioblastomas (GBMs), a common and deadly form of brain cancer, comes with an average survival rate of just 14 months.

"Researchers have been thinking about ways to deal with this problem," said Paul S. Mischel, MD, a member of the Ludwig Cancer Research branch at UC San Diego and professor at the UC San Diego School of Medicine Department of Pathology. "We have been challenged by the fact that GBMs are among the most genomically well characterized forms of cancer, with clear evidence of targetable driver oncogene mutations but this information has yet to benefit patients, at least in part, because the drugs designed to target these oncogenes have difficulty accessing their targets in the brain. We have been trying to find an alternative way to use this information to develop more effective treatments."

The team discovered that GBM cells cannot produce cholesterol on their own, rather taking in necessary amounts needed from astrocyte brain cells. By suppressing the oxysterols, GBM cells make the liver X receptors (LXR) inactive.

"So when normal cells get enough cholesterol, they stop making it, stop taking it up and start pumping it out," said Mischel. "We found that in GBM cells, this mechanism is completely disrupted. They're like parasites of the brain's normal cholesterol system. They steal cholesterol and don't have an off switch. They just keep gobbling the stuff up."

In tests conducted on mice, the team used the experimental metabolic drug LXR-623 to reactive the LXRs. The drug yielded positive results, was able to bind to LXRs, restarted the production of oxysterols and reduced the amount of cholesterol. GBMs were unable to suck up the cholesterol, leading to cell death and tumor regression.

"Disrupting cholesterol import by GBM cells caused dramatic cancer cell death and shrank tumors significantly, prolonging the survival of the mice," said Mischel. "The strategy worked with every single GBM tumor we looked at and even on other types of tumors that had metastasized to the brain. LXR-623 also had minimal effect on astrocytes or other tissues of the body."