A metabolic process in cancer cells could unlock a possible treatment for glioblastoma in about 60% of patients

Good news! Cancer is history (soon)!

"A study l... has found that targeting a metabolic process in people with a specific genetic mutation could help treat glioblastoma, an aggressive brain cancer.

The genetic alteration — a deletion in a gene called CDKN2A — is present in about 60% of people who have glioblastoma. The mutation causes changes in the way lipids are distributed in cancer cells, which in turn makes the cancer cells vulnerable to being destroyed. ...

They found that the gene rewires lipid metabolism to work in a different way than cells without that genetic alteration. And when the CDKN2A gene is missing, the way cancer cells process fats makes them more vulnerable to cell death, or ferroptosis.

The team then used a drug that targets this process and found 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 the drug. ..."

From the highlights and abstract:

"Highlights

...

Unbiased multi-omic analysis identifies CDKN2A as a regulator of lipid metabolism

• CDKN2A deletion reduces oxidizable PUFA sequestration into lipid droplets

• GBMs with CDKN2A deletion are susceptible to lipid peroxidation and ferroptosis

Summary

Malignant tumors exhibit heterogeneous metabolic reprogramming, hindering the identification of translatable vulnerabilities for metabolism-targeted therapy. How molecular alterations in tumors promote metabolic diversity and distinct targetable dependencies remains poorly defined. Here we create a resource consisting of lipidomic, transcriptomic, and genomic data from 156 molecularly diverse glioblastoma (GBM) tumors and derivative models. Through integrated analysis of the GBM lipidome with molecular datasets, we identify CDKN2A deletion remodels the GBM lipidome, notably redistributing oxidizable polyunsaturated fatty acids into distinct lipid compartments. Consequently, CDKN2A-deleted GBMs display higher lipid peroxidation, selectively priming tumors for ferroptosis. Together, this study presents a molecular and lipidomic resource of clinical and preclinical GBM specimens, which we leverage to detect a therapeutically exploitable link between a recurring molecular lesion and altered lipid metabolism in GBM."

A metabolic process in cancer cells could unlock a possible treatment for glioblastoma | UCLA UCLA-led study could lead to new strategy for treating aggressive brain cancer

CDKN2A deletion remodels lipid metabolism to prime glioblastoma for ferroptosis (open access)

Graphical abstract