PIK3CA,PIK3CB双重抑制联合利妥昔单抗在DLBCL靶向治疗中的作用及机制研究

弥漫大B细胞淋巴瘤（Diffuse Large B Cell Lymphoma, DLBCL）是最常见的淋巴造血系统恶性肿瘤，其侵袭性强、预后差且异质性高。R-CHOP是其临床一线治疗方案，但发现其对部分个体治疗效果不佳。我们前期发现，DLBCL中PIK3CA，PIK3CB存在基因拷贝数变异且与预后差有统计学相关性，提示PIK3CA/B的基因拷贝数变异在DLBCL治疗中起着重要作用，但其作用及机制未知。本研究拟分析DLBCL患者中PIK3CA/B的拷贝数变异与治疗效果的相关性；拟运用PIK3CA抑制剂BYL719及PIK3CB抑制剂TGX-221联合利妥昔单抗在体外DLBCL细胞系水平及体内裸鼠皮下荷瘤实验，观察双重抑制PIK3CA,PIK3CB在靶向治疗DLBCL中的作用；以阐明其在DLBCL治疗中的作用及相关机制，最终为DLBCL的新疗法提供理论依据。

Diffuse Large B Cell Lymphoma (DLBCL) is most frequent malignancy in hemotopoietic lymph system, which is characterized by strong invasion and poor prognosis. DLBCL has greater heterogeneity in clinical manifestation as well as histological morphology whose first–line clinical treatment is R-CHOP approach. It was however found that R-CHOP therapy was not necessarily effective to all patients with DLBCL. In our previous study, we found that there existed copying number variation (CNV) in PIK3CA and PIK3CB, two catalytic subunits of PI3K and there were significant association between CNV of PIK3CA and PIK3CB and poorer prognosis, suggesting that both PIK3CA and PIK3CB may play an important role in the carcinogenesis of DLBCL. However, the relevant role and underlying mechanism remain elusive. In our present study, we propose that dual inhibition of PIK3CA and PIK3CB in combination of Rituximab could effectively suppress therapy the DLBCL. Therefore, to support the proposal with evidence, we are going to statistically analyze the correlation between CNV of PIK3CA/B and therapeutic effect; and to observe the potential therapy of dual inhition of PIK3CA/B using BYL719 and TGX-221, specific inhibitor of PIK3CA and PIK3CB respectively, in combination with Rituximab, a well-used clinical injection on the xenograft mouse model of DLBCL; and to establish the transgenic DLBCL cell lines whose PIK3CA/B was ectopically expressed (stably knockdown or over-expression). With those cell model, we are going to observe the interaction between PIK3CA and PIK3CB, and molecular changes of downstream targets of PIKCA/B.