COLUMBUS, Ohio – A new study suggests that blocking cancer cells' access to cholesterol may offer a new strategy for treating glioblastoma, the most common and deadly form of brain cancer, and perhaps other malignancies. The potential treatment could be appropriate for tumors with a hyperactive PI3K signaling pathway, which accounts for up to 90 percent of glioblastomas cases.
Researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) and at UCLA's Jonsson Comprehensive Cancer Center who led the study discovered that the hyperactive signaling pathway is linked to cholesterol metabolism, and that inhibiting this pathway leads to the death of glioblastoma cells in an animal model.
he findings are published in the journal Cancer Discovery.
"Our research shows that the tumor cells depend on large amounts of cholesterol for growth and survival, and that pharmacologically depriving tumor cells of cholesterol may offer a novel therapeutic strategy to treat glioblastoma," says first author and researcher Dr. Deliang Guo, assistant professor of radiation oncology at the OSUCCC – James.
"This study uncovers a mechanism that links a common oncogene with altered cell metabolism, and it potentially offers a strategy for blocking that mechanism and causing specific tumor-cell death without significant toxicity," says principal investigator Dr. Paul S. Mischel, professor of pathology at UCLA's Jonsson Cancer Center and an adjunct professor of radiation oncology at the OSUCCC – James.
"Overall, our findings suggest that the development of drugs to target this pathway may lead to significantly more effective treatments for patients with this lethal form of brain cancer."
Glioblastomas strike about 18,500 Americans annually and kill nearly 13,000 of them. Glioblastoma multiforme is the most common and lethal form of the malignancy, with an average survival of 15 months after diagnosis. The tumors are difficult to surgically remove because malignant cells invade surrounding brain tissue.
In addition, genetic differences leave some glioblastoma cells in the tumor resistant to chemo- and radiation therapy, the researchers say.
"Some glioblastomas respond well to treatment initially when the therapy-sensitive cells are killed, but the tumor then returns relatively quickly as the therapy-resistant cells proliferate," says co-author Dr. Arnab Chakravarti, chair and professor of Radiation Oncology and co-director of the OSUCCC – James Brain Tumor Program.
"Because glioblastomas are among the most treatment-resistant of cancers, new therapeutic strategies are urgently needed," says Chakravarti.
The study used tumor-cell lines, cells from patients and an animal model. Key technical findings include the following:
- In nearly 50 percent of glioblastomas, a mutation called EGFRvIII hyperactivates the PI3K signaling pathway and a master transcriptional regulator called SREBP-1.
- Activating this pathway upregulates the low-density lipoprotein (LDL) receptor and promotes LDL uptake, enabling tumor cells to import large amounts of cholesterol that feed tumor-cell growth and survival.
- Pharmacological activation of the nuclear Liver X Receptor leads to the loss of LDL receptors and to upregulation of the ABCA1 protein pump, which transports cholesterol out of the malignant cells. Together, these actions starve tumor cells of cholesterol, causing their death.
"Because this pathway is activated in other types of cancer, this work may have significant implications for a broad range of cancer types," Mischel says.
Journal
Cancer Discovery