Glioblastoma, Brain metastasis,MRI Brain The doctor pointed out the location of the brain tumor on the computer screen.
Credit: Tonpor Kasa/Getty Images

A study published in Cancer Cell found that glioblastomas (GBM) involving a deletion in the CDKN2A gene make them more vulnerable to killing. Researchers at the UCLA Jonsson Comprehensive Cancer Center found that deletion of the CDKNA gene—which is present in about 60% of glioblastoma tumors—changes the way lipids are distributed in cancer cells, increasing the likelihood they could be targeted and destroyed by targeted therapies.

The team collected and analyzed lipidomic, transcriptomic, and genomic data from 156 molecularly diverse GBM tumors, including 84 human glioblastoma tumors, 42 human cell lines, and 30 mouse GBM models.

“We identified CDKN2A deletion remodels the GBM lipidome, notably redistributing oxidizable polyunsaturated fatty acids into distinct lipid compartments,” the authors write in their paper. Notably, CDKN2A deletion remodeled lipid composition similarly in the human brain, as a xenograft in the mouse brain, and when grown in cell cultures with CDKN2A deletion, indicating that this metabolic vulnerability could be a target of therapy in glioblastoma patients.

Further, the investigators discovered that CDKN2A-deleted GBMs process fats differently than those with the CDKN2A gene. They selectively prime tumors for ferroptosis—a form of regulated cell death characterized by the accumulation of iron, and the production of reactive oxygen species that attack and damage lipids. Ferroptosis is triggered by the depletion of molecules that protect cells from oxidative damage, particularly lipids, and is an emerging therapeutic target in several cancers.

The researchers evaluated a drug that induces ferroptosis by inhibiting GPX4, an enzyme that protects against lipid peroxidation. They observed that glioblastoma cells with the genetic alteration in CDKN2A were highly susceptible to cell death, while the glioblastoma cells that did not have the genetic alteration were insensitive to GPX4 inhibition.

“We discovered that CDKN2A may be a key regulator of cancer cell metabolism, which has never before been shown in the context of cancer, even though it is deleted in other types of cancer,” said co-senior author David Nathanson, associate professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.

The team’s results provide proof-of-concept evidence that GPX4 may be a relevant therapeutic target for a large, genetically stratified subset of patients with GBM, those with CDKN2A-deletion. While there are currently no pharmacological GPX4 inhibitors suitable for use in the brain the team believes these new results provide a strong rationale for developing brain-penetrant small molecules that induce GBM cell death via inhibition of GPX4 or other ferroptotic targets.

The database of the 156 glioblastoma samples that the investigators analyzed is available to researchers worldwide; the team has also expanded the number of samples in the database to more than 500.

“This dataset will enable investigations into the genetic influences on GBM lipid metabolism and potential impacts of the tumor environment,” the authors write, encouraging others to use it to uncover other potential therapeutically actionable treatments for glioblastoma.

Also of Interest