INHIBITORS OF THE PLD2-AKT SIGNALING COMPLEX REVEAL A METABOLIC VULNERABILITY IN GLIOBLASTOMAS
Led by H Alex Brown at Vanderbilt University Medical Center
This proposal seeks to develop a novel therapeutic approach targeting the complex between phospholipase D (PLD) and Akt kinase in the treatment glioblastomas. Our group has developed novel small molecule isoenzymes selective inhibitors against PLD. In characterizing the mechanism of action of these inhibitors, we have discovered that dissociation of the complex has profound effects on the cell survival pathway and intracellular metabolites of the ATP biosynthesis pathways. While this observation is potentially relevant to most cancers due to changes in metabolism known as the Warburg effect, we have observed that these effects are particularly pronounced in glioblastomas. This may represent an Achilles Heel in the cell survival pathway of gliomas. The one year proposal seeks to identify the step in glycolysis that is most profoundly effected in disruption of the PLD2-Akt complex and optimize existing compounds for pharmacological intervention. If confirmed we will target these pathways for therapeutic intervention and take advantage of this phosphatidic acid addiction in glioblastomas to kill the cells while leaving pten-wild type, normal cells intact.
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