胶质母细胞瘤（GBM）是神经系统发病率、复发率和死亡率最高的原发性恶性肿瘤。目前临床上缺乏GBM的治疗靶点，亦缺乏相应的靶向药物。因此，对GBM治疗靶点及相应靶向药物的发现迫在眉睫。我们的生物信息学分析和实验数据显示SPHK1在GBM中高表达，并与患者的预后不良和低生存率密切相关；过表达SPHK1可以增加肿瘤细胞侵袭、转移和克隆形成。我们初步以SPHK1为靶点虚拟筛选出了5个得分值大于其天然配体的化合物。我们认为SPHK1是GBM潜在治疗靶点，其抑制剂是治疗GBM的有效药物。本研究将从SPHK1的功能、作用机制和甲基化表达调控三个方面确认SPHK1为GBM潜在治疗靶点。并采用虚拟筛选结合高通量筛选模型筛选效力高、特异性强的SPHK1抑制剂。本课题的研究对确立SPHK1为GBM药物靶点及GBM的临床治疗具有重要的指导意义。

Glioblastoma multiforme (GBM) is the most challenging primary malignant tumor in the central nervous system with high morbidity, mortality, and recurrence rate. Currently, its drug targets and corresponding drugs are lacking in the clinical practice. Therefore, it is urgent to develop drug targets and corresponding drugs for GBM. Our bioinformatics analyses and experimental data showed that the elevated level of SPHK1 was observed in GBM patients, which was strongly correlated with poor prognosis and reduced overall survival; overexpression of SPHK1 also promoted the tumor cell invasion, metastasis, and clone formation. Using virtual screening, we preliminary screened out five small molecules whose scores were higher than the natural ligand of SPHK1. Based on these results, we propose SPHK1 as a potential therapeutic target of GBM and the application of its inhibitors could be effective drugs for the treatment of GBM. In this study, we will investigate the functions, mechanisms and methylation regulation of SPHK1 to confirm that it is a potential therapeutic target of GBM. Furthermore, we will identify inhibitors targeting SPHK1 using virtual screening followed by high throughput drug screening. It is necessary and important to identify SPHK1 as a potential drug target and guide the treatment of GBM.