The fight against glioblastoma, one of the deadliest brain cancers, may have received a big boost thanks to a team of researchers at UCLA’s Jonsson Comprehensive Cancer Center. In a new study published September 15 in Cancer Discovery, senior author Dr. Paul Mischel, a Jonsson Cancer Center researcher and a professor of pathology and laboratory medicine and of molecular and medicinal pharmacology, and his colleagues discovered that blocking cholesterol uptake into glioma cells can potently kill cancer cell lines and malignant tumors in mice. This novel finding potentially offers a more effective treatment strategy for patients with glioblastomas that have become resistant to traditional chemo and radiotherapies.

According to the study, nearly half of all glioblastoma patients have cancers driven by a mutated oncogene—the epidermal growth factor receptor (EGFR). Cancers harboring EGFR mutations are consequently able to hi-jack normal cholesterol regulatory mechanisms by upregulating the low-density lipoprotein (LDL) receptor as part of their survival pathways. The result is the ability to pump copious amounts of cholesterol into cells needed for cell membrane synthesis, energy, and tumor cell growth.

Therefore, Mischel and his colleagues hypothesized that targeting the LDL receptor for destruction could result in strong anti-tumor activity against glioblastoma. They showed that a drug that activates the nuclear liver X receptor, a critical regulator of intracellular cholesterol that ensures appropriately balanced levels, degraded the LDL receptor in tumor cells bearing EGFR mutations, potently killing the cancerous tumors in mice.

"This study suggests a potential therapeutic strategy to treat glioblastoma and potentially a broader range of cancer types," Mischel said.

In a previous study, Mischel showed that inhibiting fatty acid synthesis in brain cancer cells may offer an additional option to treat those with mutated EGFR. Rapidly dividing cancer cells also require fatty acids to form new membranes and provide energy for the cells. Mischel and his team found the same cell signaling pathway is at work in fatty acid synthesis and the import of cholesterol into cancer cells.

"That was a surprise here, this ghastly trick of the cancer cells," Mischel said. "The same mutation is coordinately regulating both the cholesterol and fatty acid synthesis mechanisms."

Going forward, Mischel and his colleagues will do more pre-clinical studies that could lead to clinical trials of drugs that activate the liver X receptor.

UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2011, the center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 of the last 12 years.

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