Metabolic Processes in Glioblastoma: Innovative Treatments for Brain Cancer

Scientists at UCLA have discovered that a modified CDKN2A gene alters the distribution of lipids within cancer cells, rendering them more susceptible to drug treatment in laboratory settings.

The researchers demonstrated that the absence of the CDKN2A gene causes tumor cells to process polyunsaturated fatty acids (PUFAs) in a way that makes them more vulnerable to ferroptosis, a controlled cell death mechanism dependent on iron and the accumulation of lipid peroxides. By using compounds like ML210 and RSL3, which induce ferroptosis and inhibit glutathione peroxidase (GPX4), they found that glioblastoma cells with the gene alteration were highly responsive to cell death, while those without it were largely resistant. Given that around 60 percent of GBM patients possess this mutation, targeting this “ferroptosis pathway” could offer a promising and critical target for future drugs capable of crossing the blood-brain barrier (BBB).

In their study published in Cancer Cell, the UCLA team analyzed a collection of 84 GBM tumor samples, 29 orthotopic xenografts, and 43 GBM-derived cell cultures. Their aim was to identify a “therapeutically exploitable link between a recurring molecular lesion and altered lipid metabolism in GBM.”

They found that the deletion of CDKN2A remodels the GBM lipidome, leading to the redistribution of oxidizable polyunsaturated fatty acids into specific lipid compartments, displaying higher lipid peroxidation. Based on their theory that gene-altered samples with increased basal lipid peroxidation would be sensitized to ferroptosis induction, they treated them with RSL3 or ML210 and observed pronounced cell death. In contrast, cancer samples without the genetic mutation remained largely unresponsive to both compounds.

Metabolic Processes in Glioblastoma – The researchers concluded that their results provide proof-of-concept evidence that GPX4 may serve as a relevant therapeutic target for a genetically stratified subset of GBM patients. They called for further exploration of methods to deliver GPX4 inhibitors across the BBB, taking advantage of the identified ferroptosis pathway, as the current lack of brain-penetrating GPX4 inhibitors poses a challenge.

Additionally, the UCLA study indicated a second potential approach to combat GBM: disrupting cancers with specific diets. Their data showed that CDKN2A-deleted cancer cells alter the type of lipids used to build cellular membranes, which could be exploited to kill tumors. The researchers suggested that prescribing special diets containing “wrong” lipids might enhance susceptibility to therapy or reduce tumor growth.

Furthermore, the UCLA team expanded their research database to include over 500 cancer samples, making it accessible to scientists worldwide. Their goal is to identify more connections between cancer-fighting genes and specific lipids used in brain cancer, potentially paving the way for further treatment advancements.

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