Vanderbilt University researchers have discovered a “backdoor” approach to blocking an enzyme that fuels the growth of glioblastoma, the most common and most fatal form of brain cancer.
Their finding in cell culture, published Jan. 10 in the Journal of Biological Chemistry, could lead to more effective treatments for the cancer, and with fewer serious side effects.
“This paper represents more than three years of work, and I believe in time it will be viewed as a landmark finding,” said H. Alex Brown, Ph.D., the Bixler-Johnson-Mayes Professor of Pharmacology and co-senior author with Craig Lindsley, Ph.D., the William K. Warren Jr. Professor of Medicine.
Ronald Bruntz, graduate student in Brown’s lab, is first author on the current paper, and Harry Taylor, Ph.D., former instructor in Medicine at Vanderbilt, contributed to the research.
Their approach, blocking the enzyme phospholipase D (PLD) with compounds they invented, can shrink tumors in mice. If further studies are successful, Lindsley said he hopes a drug company will license the small molecules and “do the sponsored research to get (them) to … the clinic.”
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, said Lindsley, co-director of the Vanderbilt Center for Neuroscience Drug Discovery.
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.
They 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 by the Vanderbilt researchers, including the original finding that PLD inhibitors block invasiveness of breast cancer cells, published in Nature Chemical Biology in 2009.
In two recent papers published in collaboration with a group at Case Western Reserve University, 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 said.
Brown, associate director of the Vanderbilt Institute of Chemical Biology, and Lindsley, director of the Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, have collaborated on several projects. In 2011 they were honored by their Vanderbilt colleagues with an Academic Enterprise Faculty Award for Outstanding Contributions to Research.
The study was supported in part by National Institutes of Health grants ES013125 and MH084659, and by the James S. McDonnell Foundation.
