September 20, 2011
Targeting Cholesterol to Fight Brain Cancer
(Ivanhoe Newswire) — Glioblastoma is the most common brain malignancy and one of the most lethal of all cancers, killing most victims within 12-15 months of diagnosis. It is also one of the most chemotherapy-radiation resistant cancers. Researchers found that by blocking brain cancer cells from getting large amounts of cholesterol they could provide a new strategy to battle glioblastoma, according to this study.
The study, done in cells lines, mouse models and analysis of tissue from brain cancer patients, uncovered a novel mechanism by which the most commonly activated oncogene, the mutated epidermal growth factor receptor (EGFR), overcomes normal cell regulatory mechanisms to feed large amounts of cholesterol to the brain cancer cells, Dr. Paul Mischel, a professor of pathology and laboratory medicine and molecular and medical pharmacology, a Jonsson Cancer Center researcher and senior author of the study, was quoted as saying.
The study shows that EGFRvIII, common in glioblastoma, promotes the uptake of cholesterol into cancer cells by up-regulating its cellular receptor, the LDL receptor, promoting rapid tumor growth and survival.
There are at least three ways by which cells normally tightly control their cholesterol levels - synthesis, import and efflux, or pumping out the cholesterol, Mischel said.
"Our study found that the mutant EGFR hijacks this system, enabling cancer cells to import large amounts of cholesterol through the LDL receptor," Mischel said. "This study identifies the LDL receptor as a key regulator of cancer cell growth and survival, and as a potential drug target."
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.
About 45 percent of glioblastoma patients have cancers driven by mutated EGFR, so the findings have the potential to help almost half of those diagnosed with this aggressive malignancy.
"This study suggests a potential therapeutic strategy to treat glioblastoma, and potentially a broader range of cancer types," Mischel said.
"This study uncovers a novel and potentially therapeutically targetable tumor cell growth and survival pathway, which could result in more effective treatments for patients," Mischel said.
SOURCE: Cancer Discovery, September 15, 2011