Amino Acid Transport and the Biology of Human Gliomas

本提案的目的是为恶性胶质源性脑肿瘤（胶质瘤）患者制定合理的治疗方法。神经胶质瘤是最难治疗的癌症之一，典型的症状包括顽固性头痛和癫痫发作。这些癫痫发作由肿瘤相关的“瘤周”脑引起，并且在低级别胶质瘤中特别常见，其中高达90%的患者存在“瘤周癫痫”，这通常难以有效治疗。从该资助的上一个资助周期发展而来的中心假设假定癫痫发作是由胶质瘤释放谷氨酸到瘤周脑中引起的，导致瘤周区域神经元谷氨酸受体激活异常，随着时间的推移，谷氨酸导致兴奋性毒性神经元丢失，从而为肿瘤扩张腾出空间。假设谷氨酸作为胱氨酸摄取的强制性副产物通过系统xc-胱氨酸-谷氨酸交换剂释放到肿瘤细胞中。这种转运蛋白可以使用柳氮磺胺吡啶（一种临床批准用于治疗炎性肠病（克罗恩病）的药物）来抑制。该提案将进行临床前研究，旨在证明系统xc-活性，肿瘤周围癫痫发作和肿瘤生长之间的机制联系。如果成功，这些研究将支持柳氮磺胺吡啶未来的临床应用，以治疗恶性胶质瘤患者谁是迫切需要更好的更有效的治疗。

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.