Researchers have found a potential strategy for fighting glioblastoma by blocking the uptake of large amounts of cholesterol into brain cancer cells.
The study, which appeared in Cancer Discovery, used cell lines, mouse models, and analysis of tissue from patients with brain cancer.1 Researchers from Jonsson Comprehensive Cancer Center at the University of California at Los Angeles attempted to uncover 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 brain cancer cells. Specifically, EGFRvIII upregulates its cellular receptor, the low-density lipoprotein (LDL) receptor, promoting rapid growth and survival.
Lead author Paul Mischel, MD, adds that the mutant EGFR “hijacks” the system, enabling cancer cells to import large amounts of cholesterol through the LDL receptor. For that reason, he and colleagues concluded that the LDL receptor is a potential drug target. They showed that a drug that activates the nuclear liver X receptor, which is a critical regulator of intracellular cholesterol, destroyed the LDL receptor in tumor cells bearing EGFR mutations, killing cancerous tumors in mice.
The findings could potentially help 45% of patients with glioblastoma whose cancers are driven by mutated EGFR. In addition, because EGFR is mutated in other cancers, the findings may have implications for these tumors well.
The researchers are working on more preclinical studies that could lead to clinical trials of drugs that activate the liver X receptor. Dr. Mischel adds that because glioblastoma is highly resistant to chemotherapy and radiation, new treatments are necessary.