Brain tumor cells feed on cholesterol, and blocking their access to it may offer a new way of treating glioblastoma, the most deadly form of brain cancer, and perhaps other cancers too, say US researchers in a new study published online this week in the journal Cancer Discovery. The researchers propose the potential treatment could be effective for tumors with an over-active PI3K signaling pathway, which includes nearly 9 in 10 glioblastomas.

Lead investigator Dr Paul S. Mischel, professor of pathology at the Jonsson Cancer Centre at the University of California Los Angeles, told the media they discovered a mechanism that links a common cancer gene with altered cell metabolism, and blocking that mechanism offers a potential treatment that kills specific tumor cells without significant toxicity.

The chances of surviving a glioblastoma are not high: they strike about 18,500 Americans a year and kill nearly 13,000 of them. The most common and deadly form is glioblastoma multiforme, the average survival is about 15 months after diagnosis.

Because the cancer cells invade surrounding brain tissue, the tumors are extremely hard to remove with surgery. And to make matters worse, some people have genes that cause some of the cancer cells to become resistant to chemo- and radio-therapy.

Co-author Dr Arnab Chakravarti, chair and professor of Radiation Oncology at Ohio State University Comprehensive Cancer Centre (OSUCCC), said we urgently need new ways to treat this resistant cancer:

“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,” said Chakravarti.

The researchers used tumor cell lines, as well as cells from patients and an animal model. Their key findings include:

  • In nearly half of glioblastomas, a gene variant known as EGFRvIII hyperactivates the PI3K signaling pathway and a master transcriptional regulator called SREBP-1.

  • When this pathway switches on, it increases the activity of the low-density lipoprotein (LDL) receptor which increases LDL uptake, allowing tumor cells to import the large amounts of cholesterol they need for growth and survival.

  • Activating another receptor with drugs, the nuclear Liver X Receptor, reduces the number of LDL receptors, which in turn switches on the ABCA1 protein pump, a major regulator of cellular cholesterol, causing it to transport cholesterol out of the cancer cells.

  • It is the combination of these actions that starves the tumor cells of their much-needed cholesterol, without which they eventually die off.

First author and researcher Dr Deliang Guo, also at the OSUCCC said their study shows that tumor cells need large amounts of cholesterol for growth and survival, and “pharmacologically depriving tumor cells of cholesterol may offer a novel therapeutic strategy to treat glioblastoma”.

“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,” said Mischel.

And because the pathway involved is not confined to glioblastoma, he added that this method may “have significant implications for a broad range of cancer types”.

Written by Catharine Paddock PhD