This mutation occurring in 60% of glioblastoma patients may be key to a novel cure

Scientists discover that a mutation in the gene CDKN2A makes cancer cells more vulnerable to being eliminated. 
Sade Agard
Representional image of magnetic resonance imaging showing glioblastoma in the brain.
Representional image of magnetic resonance imaging showing glioblastoma in the brain.

Tonpor Kasa/iStock 

The aggressive brain cancer glioblastoma can be treated by focusing on a metabolic pathway present in around 60 percent of patients with the disease, according to a new study published in Cancer Cell on May 25.

A mutation in a gene called CDKN2A induces changes in the distribution of lipids in cancer cells, which makes the cancer cells more open to being eliminated. The finding could lead to therapies that directly target that vulnerability.

Is glioblastoma curable? 

Glioblastomas are deadly brain tumors with rapid growth, and few effective treatments are currently available. Only approximately 5 percent of patients with glioblastoma survive more than five years after their diagnosis, and the average lifespan of someone diagnosed with a brain tumor is about 12 to 15 months. 

Disrupting cancer cells' ability to use energy and nutrients to grow, thrive, and infiltrate healthy cells is thought to be one of the keys to developing novel, efficient therapies.

In the latest study, researchers examined data from 84 glioblastoma tumors, 42 human cell lines, and 30 mouse models of glioblastoma to look for potential trends in how the cancer cells digest fats that would suggest they could be vulnerable to medication. 

They uncovered discrepancies with CDKN2A — the gene frequently altered in glioblastoma patients.

CDKN2A: A never-before-seen cancer cell regulator

They discovered that the gene rewires lipid metabolism to operate differently in affected cells than in unaffected ones. Additionally, how cancer cells handle lipids renders them more susceptible to cell death, or ferroptosis, when the CDKN2A gene is absent.

The scientists subsequently utilized a drug that targets this pathway. They found that glioblastoma cells with the CDKN2A genetic change were far more likely to experience cell death than those without the alteration.

"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 David Nathanson in a press release, co-senior author of the study at UCLA.

"Importantly, we found that CDKN2A deletion rewires lipid metabolism not just in our models but also in tumors from glioblastoma patients. This indicates that this metabolic vulnerability could one day be a target of therapy in glioblastoma patients." 

Nathanson reasoned that while there is no existing drug that could penetrate the brain to target the process studied by his team, their findings provide a strong rationale for developing one.

Another significant component of the research, according to co-senior author Steven Bensinger, is that it may provide new insight into how nutrition and other lifestyle choices may affect the course of cancer and how well patients respond to treatment.

"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," Bensinger concluded.