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

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。

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.