PI3Kδ选择性抑制剂581在急性B淋巴细胞白血病中的抗肿瘤作用及机制研究

项目名称： PI3Kδ选择性抑制剂581在急性B淋巴细胞白血病中的抗肿瘤作用及机制研究

项目编号： No.81503109

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张希

作者单位： 中国科学院上海药物研究所

项目金额： 17.9万元

中文摘要： 白血病是造血系统最常见的一种恶性肿瘤，多发于儿童与青少年。目前，针对B细胞白血病重要分子的靶向治疗成为新的治疗策略。PI3Kδ已被证实是治疗B细胞白血病的一个高效靶点。CAL-101作为首个获批上市的选择性PI3Kδ抑制剂，尽管在临床上表现出良好的治疗效果，但是仍存在一些问题：此类抑制剂的结构类型相对局限，适应症范围相对狭小，抗肿瘤作用机制有待完善，尚未发现和确认能够预测疗效的生物标志物。因此发现和研究新结构、新作用模式的PI3Kδ抑制剂对解决上述问题显得尤为重要。本课题将以本实验室新发现的全新结构的PI3Kδ选择性抑制剂581系列化合物为研究对象，研究其与PI3Kδ的作用模式，阐释其抗肿瘤的生物学效应，通过比较人原代B-ALL细胞对其敏感性的不同来寻找和验证可以指示疗效的生物标志物及其敏感响应的分子机制，为新一代PI3Kδ抑制剂的开发提供理论依据，指导其临床合理用药。

中文关键词： PI3Kdelta抑制剂；急性B淋巴白血病；抗肿瘤；靶向治疗；分子机制

英文摘要： Leukemia is one of the most common hematopoietic malignancies. It is prevalent in children and young adults. Molecular targeted therapies based on mechanistic study become the new strategy. PI3Kδ, which is largely enriched in the hematopoietic system, has been identified as an efficient antitumor target. CAL-101, the first approved PI3Kδ selective inhibitor, has shown good activity against chronic lymphocytic leukemia. However, the inhibitor structure is relatively limited, the range of indications is comparatively narrow, and the mechanism remains unclear. Additionally, the predictive biomarker(s) has not been reported. Therefore, the discovery and study of novel PI3Kδ inhibitors with new structures and binding modes with PI3Kδ is particularly important to solve the aforementioned problems. Our study intends to use PI3Kδ-specific inhibitor 581, which has new structure, to study its antitumor efficiency and mechanisms. By comparing the sensitivity of multiple primary pediatric B-ALL cells to PI3Kδ-specific inhibitor 581, we expect to find and identify a biomarker(s). This approach could result in better performance and more active antitumor drugs, and lay the foundation for their clinical application.

英文关键词： PI3Kdelta Inhibitors;B-cell Acute Lymphoblastic Leukemia;Antitumor;Targeted therapy;Molecular Mechanisms