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Targeted therapy to disrupt aberrant Glutamate release from Glioma, Harald Sontheimer, PhD
October 7, 2016 @ 9:50 am - 10:15 am
Harald Sontheimer, PhD, Professor/Director, of the VTCRI Center for Glial Biology in Health, Disease and Cancer; I.D. Wilson Chair, Executive Director, School of Neuroscience, Virginia Tech College of Science
Glutamate (Glu) has emerged as an important molecule in glioma biology: Glu increases to toxic concentrations in peritumoral tissue causing excitotoxicity, edema, peritumoral seizures, enhanced tumor growth and tumor invasion. Glu is released via a cystine-glutamate exchanger called “system Xc” (SXC), which supplies cystine for the production of the cellular antioxidant glutathione (GSH) that protects cells from stressors including free radicals and temozolomide (TMZ) chemotherapy whereby SXC-mediated GSH production confers resistance to programmed cell death. Here we show that the catalytic subunit of the SXC transporter, encoded by the SLC7A11 gene, is highly expressed in ~54% of glioma patients, yet lacking or poorly expressed in all others. Tumor from patients with high SLC7A11 expression assiduously release Glu, causing seizures and excitotoxicity when implanted into mice, while tumors with low SLC7A11 expression show neither excitotoxicity nor seizures. In a clinical pilot trial we show that only tumors that express SLC7A11 respond to the SXC inhibitor Sulfasalazine (SAS) with attenuated Glu release. Further analysis as to whether SLC7A11 expressing tumor differ genetically revealed that the expression of SLC7A11 is regulated by p53 acting as transcriptional suppressor. Loss or mutation of p53, which is common among many gliomas and leads to aberrant SLC7A11 expression resulting in tumors with enhanced GSH that evade programmed cell death and kill surrounding neurons by glutamate neurotoxicity. This suggests that p53 expression status can be used as a proxy for SLC7A11 expression and it associated morbidity. These studies are significant and clinically important as they explore have the potential to use p53 to predict tumor response to personalized treatments for many glioma patients.