UCLA researchers in the Department of Molecular and Medical Pharmacology have uncovered a novel therapeutic target for Glioblastoma leveraging an extensive lipidomic and transcriptomic database.
BACKGROUND: Glioblastoma (GBM) is a fast-growing and aggressive brain tumor. The National Brain Tumor Society predicted that over 14,000 people in the United States received a GBM diagnosis in 2023. GBM’s account for an estimated 50% of all primary malignant brain tumors and survival is poor, with only a 40% survival rate after the first year of diagnosis and 17% in the second year. GBMs are difficult to treat due to the localization of the tumors within the brain, the limited capacity of the brain to repair itself and malignant cells migrating to adjacent brain tissue, among other factors. In GBM cells, the lipid metabolism is altered in order to meet the energy needs of the rapid cancer cell proliferation. This has been linked to specific mutations of genes that reprogram GBM cellular lipid metabolism. A thorough understanding of the lipid metabolic profiles of GBM is needed to search for promising therapeutic targets.
INNOVATION: UCLA researchers led by Dr. David Nathanson obtained GBM patient tumor tissues and profiled their lipidomics and transcriptomics. Researchers identified a genetic alteration of a gene that encodes for control of cell cycle and cell fate pathways in regulating lipid compositions. When this gene was deleted (deletion occurs in 60% of patients with GBM), there was an increase in basal lipid peroxidation and this sensitized GBM cells to induction of ferroptosis, a type of programmed cell death. These studies provide proof of concept that inducing lipid peroxidation-mediated GBM cell death can be accomplished effectively via a critical ferroptosis target.
POTENTIAL APPLICATIONS:
- This work provides the foundation for developing a brain penetrant small molecule to induce lipid peroxidation-mediated GBM cell death.
- This work provides novel pharmacological targets for GBM related ferroptosis.
ADVANTAGES:
- The lipidomics and transcriptomics data set will enable investigation into novel genetic influences on GBM lipid metabolism.
- This work combines preclinical and clinical tumor samples.
DEVELOPMENT-TO-DATE: The cell culture and xenograft findings of the researchers were proved with clinically relevant samples.
Related Papers (from the inventors only): Minami, J.K., et al. CDKN2A deletion remodels lipid metabolism to prime glioblastoma for ferroptosis. 2023. Cancer Cell. 41, 1048-1060.