Researchers break chain of biochemical events that brain cancer cells use to evade therapy

In their quest to find and exploit vulnerabilities in the natural armor that protects malignant brain tumors from destruction, researchers have found a way to decrease the cells resistance to therapies that are designed to trigger cell death. The findings resulted from laboratory experiments conducted at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute and are based on the manipulation of a series of intricate biochemical events taking place within brain tumor cells.

"We have described and are exploiting a biochemical pathway to make brain cancers much more sensitive to common therapeutic agents that cause a natural process of cell death called apoptosis," said John S. Yu, M.D., co-director of the Comprehensive Brain Tumor Program at the Institute, adding that the researchers are applying for Food and Drug Administration approval to translate their findings into patient clinical trials as soon as possible.

Although most types of cells can be dismantled and cleared by apoptosis a "programmed" and necessary cell death mechanism gliomas and other cancer cells have genes that enable them to thwart apoptosis and continue to grow unchecked even when subjected to therapies that are designed to initiate or enhance apoptosis.

One such therapy, which Institute researchers have studied and are developing, centers on a protein called TRAIL (tumor necrosis factor related apoptosis inducing ligand). TRAIL has been shown to cause cell death in several types of cancers, with negligible damage to normal cells. The new findings should increase the effectiveness of TRAIL and other agents that trigger a "caspase cascade" a specific biochemical chain reaction resulting in cell death.

In the normal process of apoptosis, the enzymes caspase-8 and caspase-9 activate caspase-3, which initiates cell breakdown, leading to cell death. In gliomas, however, several proteins that modulate these enzymes are overexpressed, resulting in down-regula

Contact: Sandy Van
Cedars-Sinai Medical Center

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