Metabolic process in glioblastoma could unlock new treatments

Targeting a gene-altered metabolic process in glioblastoma (GBM) could unlock new ways of treating the deadly brain cancer.

Researchers at UCLA say the alteration in the CDKN2A gene changes the way that lipids are distributed in cancer cells – making them more vulnerable to drug treatment in vitro.

They demonstrate that the way tumour cells process polyunsaturated fatty acids (PUFAs) when the CDKN2A gene is missing makes them more vulnerable to ferroptosis - a regulated cell death mechanism defined by a dependence on iron, and by the accumulation of lipid peroxides. Using the current ferroptosis inducing- and glutathione peroxidase (GPX4) inhibiting compounds ML210 and RSL3, they found glioblastoma cells with the genetic alteration were highly susceptible to cell death, while those without it were largely insensitive. As about 60 per cent of GBM patients have the mutation, this ‘ferroptosis pathway’ could provide a viable and important target for a future drug capable of crossing the blood brain barrier (BBB).

Writing in Cancer Cell, the UCLA team report that they compiled a collection of 84 GBM tumour samples, 29 orthotopic xenografts, and 43 GBM-derived cell cultures - with the aim of finding “a therapeutically exploitable link between a recurring molecular lesion and altered lipid metabolism in GBM.”

They found that CDKN2A deletion remodels the GBM lipidome, “notably redistributing oxidizable polyunsaturated fatty acids into distinct lipid compartments” displaying higher lipid peroxidation. Having theorised that the gene-altered samples with increased basal lipid peroxidation would be sensitised to the induction of ferroptosis, they treated them with RSL3 or ML210 and found that both “resulted in pronounced cell death”. Meanwhile, cancer samples without the genetic mutation remained “largely insensitive to both compounds”. 

“Our results provide proof-of-concept evidence that GPX4 may be a relevant therapeutic target for a large, genetically stratified subset of patients with GBM,” the researchers concluded.

They urged others to take up the challenge of designing a method that delivers GPX4 inhibitors across the BBB, and take advantage of the ferroptosis pathway they have identified – noting the paucity of treatments for the “universally lethal” cancer, whose sufferers typically have a post-diagnosis lifespan of just 12-15 months.

“There are currently no pharmacological GPX4 inhibitors suitable for use in the brain,” the UCLA team wrote.

“Our findings provide a strong rationale for developing brain-penetrant small molecules that induce lipid peroxidation-mediated GBM cell death via inhibition of GPX4 or other ferroptotic targets.”

As well as demonstrating the potential for targeting glioblastoma with drugs, the UCLA study also suggested a second potential avenue of attack: disrupting cancers with special diets.

“Our data indicates that CDKN2A-deleted cancer cells shift the type of lipids used to build their cellular membranes, and that this difference can be exploited to kill tumors,” said co-senior author Steven Bensinger.

“This opens up the exciting possibility that prescribing special diets containing the 'wrong' lipids could make them more susceptible to therapy or reduce tumor growth.”

The UCLA team has now expanded the database used in the research to more than 500 cancer samples, and made it available to scientists worldwide. By doing this, they hope to identify more relationships between cancer-fighting genes and specific lipids used by brain cancer.