PTEN-PI3K/Akt细胞信号传导通路与美罗华单抗耐药的关系和机制研究

The rituximab can justiably be described as the most effective, successful, and widely used therapeutic monoclonal antibody for non-Hodgkin lymphoma (NHL) developed to date. Nonetheless, as with any antineoplastic agent, the effectiveness of rituximab is ultimately limited in part by the development of treatment resistance. Despite wide-spread clinical use, the mechanisms by which tumor cells resist rituximab-mediated destruction remain unclear. PTEN , as a new tumor suppressor gene, can exert its tumor suppression effect through suppress PI3K/Akt pathway. 1) We propose to evaluate the association between PTEN and PIK3CA with efficacy of rituximab therapy in non-Hodgkin lymphoma by detecting the expression levels of PTEN and PIK3CA mutations in lymphoma tissues treated with rituximab effectively or ineffectively. 2) At the same time, we design to study the expression levels of PTEN and relevant target factors in the PI3K/Akt pathway in lymphoma cells resistant to rituximab to explore the mechanism of rituximab resistance in vitro. 3) Furthermore, we plan to study the role of PTEN-PI3K/Akt pathway in the rituximab resistance by establishing the model of rituximab-resistant lymphoma mouse in vivo. This study aims to provide a basic theory on rituximab resistance and find a new marker to predicate the effectiveness of rituximab.

美罗华对非霍奇金淋巴瘤单药治疗或联合化疗目前在世界范围被认为是最成功的生物治疗方式之一，但经过长期治疗后发现约半数以上病人可产生耐药。目前对于美罗华单抗耐药机制和耐药逆转方法的探索尚处于初步阶段。PTEN作为一种新的肿瘤抑制基因通过抑制其下游PI3K/AKT信号转导通路在肿瘤生长抑制、诱导凋亡、逆转耐药等多方面发挥重要的作用。本课题拟通过：1）检测CD20+ B细胞淋巴瘤患者使用美罗华后复发或有效时肿瘤组织内PTEN表达情况和PIK3CA突变情况，分析二者与美罗华耐药的关系；2）体外细胞实验研究PTEN-PI3K/Akt信号通路在美罗华耐药中的作用及机制；3）构建美罗华耐药的淋巴瘤小鼠模型，通过体内动物实验进一步验证PTEN-PI3K/Akt信号通路在美罗华耐药中的作用，为探索美罗华耐药机制和逆转美罗华耐药提供理论基础，同时有希望发现新的能够预测美罗华单抗疗效的生物学指标。

美罗华对非霍奇金淋巴瘤单药治疗或联合化疗目前在世界范围被认为是最成功的生物治疗方式之一，但经过长期治疗后发现约半数以上病人可产生耐药。目前对于美罗华单抗耐药机制和耐药逆转方法的探索尚处于初步阶段。PTEN作为一种新的肿瘤抑制基因通过抑制其下游PI3K/AKT信号转导通路在肿瘤生长抑制、诱导凋亡、逆转耐药等多方面发挥重要的作用。本课题通过：1）对CD20+B细胞淋巴瘤患者使用美罗华后耐药或有效者共48例进行免疫组化检测，分析了患者肿瘤组织内PTEN, p-Akt和Ki-67蛋白的表达情况及其临床病理学特征和意义；2）进一步检测以上组织内PTEN表达情况和PIK3CA突变情况，分析二者与美罗华耐药的关系；3）成功筛选出3种不同恶性程度B细胞淋巴瘤的美罗华耐药细胞（Raji-R，DOHH2-R以及LY-8-R），为系列研究美罗华耐药机制提供了基础；4）体外实验验证了PTEN-PI3K/Akt信号通路在美罗华耐药中的作用，为探索美罗华耐药机制和逆转美罗华耐药提供理论基础,同时发现了新的能够预测美罗华单抗疗效的生物学指标。