新型AKT/STAT3双靶点抑制剂诱导胶质母细胞瘤凋亡的作用与机制

Glioblastoma multiforme (GBM) is the most common form of malignant brain cancer in adults. Patients with GBM have a uniformly poor prognosis, with a median survival of 12 to 15 months. Thus, there is an urgent need for the development of novel targeted therapeutics. EGFR/AKT is the most frequently mutated oncogenetic pathway in GBM. AKT is the key molecular of the pathway, which regulates the malignant proliferation of tumor. Furthermore, STAT3 is required for maintenance of the self-renewal potency in GBM stem cells. Thus, the simultaneous targeting of AKT and STAT3 oncogenic pathways might both inhibit proliferation of GBM and tumor stem cells. We develop a novel dual inhibitor of AKT and STAT3, MS-052, which could inhibit activity of targeted protein and induce apoptosis of GBM cells. In this project, we will further investigate the effects of MS-052 on GBM cell proliferation, apoptosis and self-renewal of stem cells both in vitro and in vivo. We will elucidate the mechanisms of simultaneous targeting AKT and STAT3 and regulating the signal pathway by MS-052. This study may offer novel targeted drugs for GBM treatment.

胶质母细胞瘤是最常见的成人恶性脑肿瘤，患者平均生存期仅为12-15个月。研发治疗胶质母细胞瘤的新药是亟待解决的难题。EGFR/AKT是胶质母细胞瘤突变频率最高的致癌通路，AKT激酶是通路下游的关键分子，调控肿瘤恶性增殖。而STAT3活性是维持胶质母细胞瘤干细胞自我更新能力所必需的信号。因此，联合靶向AKT和STAT3既能抑制胶质母细胞瘤的恶性增殖，又能清除肿瘤干细胞。我们前期通过筛选，获得原创AKT/STAT3双靶点抑制剂MS-052，初步证明其可直接抑制靶蛋白活性，并诱导胶质母细胞瘤凋亡。本项目拟进一步研究MS-052在细胞和动物模型中对胶质母细胞瘤增殖、凋亡和干细胞自我更新能力的影响；阐明MS-052同时靶向AKT/STAT3的作用模式及调控信号途径的机制。项目完成，可为设计、优化AKT/STAT3双靶点抑制剂提供实验基础，有望为治疗胶质母细胞瘤提供具有自主知识产权的靶向药物。

胶质母细胞瘤是最常见的成人恶性脑肿瘤，患者平均生存期仅为12-15个月。研发治疗胶质母细胞瘤的新药是亟待解决的难题。EGFR/AKT信号是胶质母细胞瘤突变频率最高的致癌通路，AKT激酶是通路下游的关键分子，调控肿瘤恶性增殖。而STAT3活性是维持胶质母细胞瘤干细胞自我更新能力所必需的信号。因此，同时抑制AKT和STAT3既能抑制胶质母细胞瘤的恶性增殖，又能清除肿瘤干细胞。本项目研究了小分子化合物MS-052调控脑胶质瘤细胞增殖与胶质瘤干细胞干性维持的作用与机制，评价了MS-052对胶质母细胞瘤的治疗效果。研究结果如下所示：1）小分子抑制剂MS-052可显著抑制胶质母细胞瘤细胞增殖、侵袭与迁移能力；2）MS-052通过调控细胞周期G1期相关蛋白的表达进而将胶质母细胞瘤细胞周期进程阻滞于G1期，且诱导了细胞凋亡；3）MS-052能显著抑制AKT磷酸化，进而抑制AKT/mTOR信号通路下游核心蛋白的磷酸化；4）该小分子抑制剂可抑制STAT3蛋白的磷酸化与入核，进而抑制STAT3下游调控蛋白c-jun，Cyclin D1，Bcl-xl和p65的表达；5）体内实验表明，与未治疗组相比MS-052治疗组显著抑制原位GBM移植瘤的生长，延长了荷瘤鼠的中位生存期；6）MS-052能显著抑制胶质母细胞瘤干细胞增殖、神经球形成与自我更新能力；7）在胶质瘤干细胞中MS-052同样阻滞细胞周期进程于G1期，并诱导肿瘤干细胞凋亡。综上可知，小分子抑制剂MS-052能同时阻断AKT与STAT3信号通路抑制胶质母细胞瘤细胞增殖与干细胞自我更新能力。该研究结果有助于加深对胶质母细胞瘤发病的认识，小分子抑制剂MS-052的研发可为治疗胶质母细胞瘤提供新思路。

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