Amino Acid Transport and the Biology of Human Gliomas

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This proposal has the objective to develop a rational treatment approach for patients with malignant glial-derived brain tumors (glioma). Gliomas and are among the most difficult cancers to treat and typical symptoms include intractable headaches and epileptic seizures. These seizures arise from tumor associated "peritumoral" brain and are particularly common in low grade gliomas where up to 90% of patients present with "peritumoral epilepsy" that is often refractory to effective treatment. The central hypothesis developed from the previous funding cycle of this grant posits that seizures are caused by the release of glutamate from gliomas into the peritumoral brain, causing abnormal neuronal glutamate receptor activation in the peritumoral region, and, over time, glutamate causes excitotoxic neuronal loss thereby vacating space for tumor expansion. It is hypothesized that glutamate is released as an obligatory by-product of cystine uptake into tumor cells via the system xc- cystine-glutamate exchanger. This transporter can be pharmacologically inhibited using Sulfasalazine, a clinically approved drug for the treatment of inflammatory bowl disorder (Crohn's). This proposal will perform preclinical studies aimed at demonstrating a mechanistic link between system xc- activity, peritumoral seizures and tumor growth. If successful, these studies will support the future clinical use of sulfasalazine to treat patients with malignant glioma who are in desperate need for better more effective treatments.