恶性脑胶质瘤的有效药物研发缓慢，且受限于血脑屏障的阻碍。已经发现，经化学结构改进得到的新型倍半萜内酯类药物ACT001能高效通过血脑屏障，具有多靶点肿瘤抑制作用，并选择性抑制胶质瘤干细胞（GSCs）。在前期工作基础上，本项目将在体内外实验中研究ACT001对Notch、NF-κB及STAT3通路的多靶点抑制，发现对GSCs靶向作用机理，并证明ACT001对不同亚型的GSCs均有抑制作用；观察ACT001抑制肿瘤微环境中炎症与免疫调节的关键信号NF-κB及STAT3活性和重要免疫抑制分子的表达，逆转肿瘤免疫抑制。在体内实验中，通过小鼠GL261原位种植模型和人源性肿瘤原位种植模型，观察ACT001对在体肿瘤的杀伤作用，并在小鼠GL261原位种植模型中重点分析ACT001对GSCs及其免疫抑制性微环境的双重靶向作用。本项目将为恶性胶质瘤干细胞治疗及改善免疫抑制性微环境的单药靶向治疗提供新的策略

The research of effective drugs for the treatment of malignant glioma develops very slowly, which are limited by the blood brain barrier (BBB) as well. It has been found that ACT001, an agent of guaianolide sesquiterpene lactone, is able to penetrate BBB with high efficiency and selectively inhibit glioma stem cells (GSCs) by targeting multiple signaling molecules, which is chemically synthesized based on parthenolide. Based upon preliminary study, we plan to investigate the potential mechanism of ACT001 against GSCs by inhibition of Notch, NF-κB and STAT3 signaling pathways, and further confirm that ACT001 might target effectively to different subtype of GSCs both in vitro and in vivo. The study will also focus on how ACT001 inhibites NF-κB and STAT3 signaling as well as key immune suppressive factors to reverse the tumor induced immune suppression in the tumor microenviroment. In orthotopic model of GL261 and patient-derived tumor xenograft model, anti-tumor effect will be dynamically observed after ACT001 treatment, and targeting effects of ACT001 both to GSCs and immune suppressive microenviroment will be analyzed especially in orthotopic model of GL261. This study is expected to supply the new strategy for the simultanmously targeting GSCs and immune suppressive microenviroment by a single medication.