Researchers have discovered a new way to block an enzyme that fuels the growth of glioblastoma, the most common and most fatal form of brain cancer.
The findings in cell culture show this backdoor approach could lead to more effective treatments for the cancer, with fewer serious side effects.
A new study published in the Journal of Biological Chemistry, shows that blocking the enzyme phospholipase D (PLD) with newly invented compounds can shrink tumors in mice.
The compounds are the first isoenzyme-selective inhibitors of PLD, which has been implicated in multiple human cancers, including breast, renal, gastric, and colorectal.
PLD regulates the oncogenic enzyme called Akt, which is important in cancer cell growth, proliferation, metabolism, and survival.
Because there are several “isoenzymes,” also called “isoforms,” of Akt throughout the body, blocking Akt directly causes serious side effects, including an exaggerated immune response and diabetic symptoms, says Craig Lindsley, professor of medicine and co-director of the Center for Neuroscience Drug Discovery at Vanderbilt University.
It’s a complicated story, and that’s why cancer is so difficult to treat. The researchers found that the form of Akt most associated with tumor growth is activated by another chemical, phosphatidic acid, which in turn is produced by a form of PLD called PLD2.
Researchers discovered that Akt kinase functions as a “coincidence detector” for the formation of phosphatidylinositol (3,4,5)P3 and phosphatidic acid to modulate autophagy, a form of programmed cell death. When PLD2 is blocked by a small molecule that attaches to an allosteric, or secondary, binding site on the enzyme, phosphatidic acid is not generated, Akt is not activated, and the cells die—without causing side effects elsewhere in the body.
This discovery builds upon previous work, including the original finding that PLD inhibitors block invasiveness of breast cancer cells, published in Nature Chemical Biology in 2009.
In two recent papers, they also showed that PLD is essential to the transformative activity of the oncogenic FAM83B/EGFR pathway.
“The fact that you can now modulate the one isoform of Akt that’s responsible for these really difficult-to-treat tumors indirectly with molecules that get into the CNS (central nervous system) very quickly is pretty cool,” Lindsley says.
The National Institutes of Health and the James S. McDonnell Foundation supported the research.
Source: Vanderbilt University