Exploiting metabolic pathways used by glioblastoma cells to halt tumour growth

Wednesday 4 January 2017

A team at The Scripps Research Institute, USA, have been able to identify a cellular pathway used by glioblastoma (GBM) tumours to allow them to survive, that could be exploited therapeutically to halt tumour growth.

The study, led by Dr Paul Mischel, found that GBM cells import vast amounts of a molecule called cholesterol to produce energy, allowing them to thrive and demonstrated that the mechanisms that they use to do so can be targeted by a small drug-like molecule called LXR-623.

In a recent interview with Oncology Times, Dr Mischel explained the importance of this research and how it might suggest a new approach to the development of cancer therapies.

“We know more about the mutations that cause this disease than those, perhaps, of any other cancer. But, so far, we haven't been able to use that information for the benefit of patients.

“One reason is that the drugs that target those mutations have a difficult time crossing the blood-brain barrier and hardly make it into the tumor. We'd been thinking about this problem and wanted to essentially flip it on its head, approaching it by looking not at the oncogenes themselves but at how oncogenes change the way normal, unmutated enzymes are used by the cell.

“Cancer cells rely heavily on some of those changes for survival, which is why they're referred to as oncogene-induced co-dependencies."

When normal cells get enough cholesterol, they stop producing it, stop taking it and start pumping it back out of the cell. However Dr Mischel's research has found that GBM cells have no off switch for this mechanism and keep eating up the cholesterol, enabling them to produce high levels of energy to survive.

The team have shown that disrupting cholesterol import by GBM cells using LXR-623 caused dramatic cancer cell death and shrank tumors significantly in animal models.

Dr Mischel's research also highlighted that the dependency of the tumour on this specific metabolic pathway to import cholesterol seemed to be present in the vast majority of GBM tumours, as well as in other cancers that have spread to the brain.

In his interview, Dr Mischel expresses the importance of re-examining and repurposing drugs that have failed in trials for other diseases.

Part of the message of this paper is that drugs that come from outside the cancer therapy pipeline and even drugs that might have failed in the clinic could turn out to be very useful for cancer patients, including brain cancer patients."

“As we've shown in this paper, the CNS side effects of an experimental cardiovascular disease drug may actually turn out to be a benefit in brain cancer therapy because it suggests the drug is actually getting in there.

“This would mean really re-examining and repurposing drugs that have failed in trials for other indications."