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Diacylglycerol Kinase Alpha Is a Critical Signaling Node and Novel Therapeutic Target in Glioblastoma and Other Cancers

Dominguez, Charli
Thesis/Dissertation; Online
Dominguez, Charli
Purow, Benjamin
While Diacylglycerol kinase alpha (DGKα) has been linked to several signaling pathways related to cancer cell biology, it has been neglected as a target for cancer therapy. The attenuation of DGKα activity via DGKα-targeting siRNA and small-molecule inhibitors, R59022 and R59949, induced caspase-mediated apoptosis in glioblastoma cells and in other cancers, but lacked toxicity in non-cancerous cells. We determined that mTOR and HIF-1α are key targets of DGKα inhibition, in addition to its regulation of other oncogenes. DGKa regulates mTOR transcription via a unique pathway involving cyclic AMP. Lastly, we showed efficacy of DGKα inhibition with shRNA or a small-molecule agent in glioblastoma and melanoma xenograft treatment models, with growth delay and decreased vascularity. Subsequently, the inhibition of the DGKα product PA was investigated as a therapeutic target as well. Combination inhibition of the three PA synthetic pathways was significantly toxic to glioblastoma cells and other cancers, but lacked toxicity in non-cancerous cells. We showed that triple drug combination to inhibit the production of PA has a synergistic effect when compared to either single or double drug combinations. We believe that PA is a promising single target with high impact on cancer biology that can provide a novel approach for treatment-resistant cancers. Lastly, we identified and begun to investigate a compound, ritanserin, that is structurally similar to DGKα small-molecule inhibitors. We have preliminarily shown ritanserin to be toxic to GBM cells, safe in non-cancerous cells and to have an inhibitory affect on DGKα activity that is comparable to R59022 and R59949. This study establishes DGKα as a central signaling hub and a promising therapeutic target in the treatment of cancer, sets the foundation for PA as a potential single target, and begins to investigate ritanserin as a promising compound with potential for quick advancement to clinical trials for cancer therapy.
University of Virginia, Department of Neuroscience, PHD, 2013
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