基于BCL10的活化型弥漫性大B细胞淋巴瘤靶向治疗的研究

项目名称： 基于BCL10的活化型弥漫性大B细胞淋巴瘤靶向治疗的研究

项目编号： No.81473245

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 杨成华

作者单位： 中国科学院上海生命科学研究院

项目金额： 89万元

中文摘要： 活化型弥漫性大B细胞淋巴瘤（ABC-DLBCL）对传统的化疗药物有强烈的耐药性，目前尚无有效治疗方法。研究发现CARMA1-BCL10-MALT1 （CBM）复合体在介导NF-κB活化、促进ABC-DLBCL生长中有关键作用。前期我们发现CBM活化后组装成蛋白纤维，为NF-κB活化提供了中心支架平台，其中BCL10是CBM蛋白纤维结构的核心，其聚合能力是实现CBM功能的关键。据此，我们提出假说：BCL10是治疗ABC-DLBCL的有效靶点。本项目将在前期研究基础上通过高通量筛选针对BCL10聚合能力的小分子抑制剂，在细胞水平上研究此抑制剂对NF-κB信号通路和ABC-DLBCL细胞生长的影响，并在小鼠异体移植模型体内检验其对ABC-DLBC肿瘤生长的作用，阐明其作用机制。该研究将揭示对BCL10聚合能力的抑制是治疗ABC-DLBCL的有效策略，并为ABC-DLBCL提供新颖有效的治疗方法。

中文关键词： 抗肿瘤；抗肿瘤药物；分子靶向治疗；分子机制；淋巴瘤

英文摘要： Activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL) is the most chemotherapy resistant and clinical challenging subtype of DLBCL. Currently there is no effective therapy for ABC-DLBCL. Studies have shown that the CARMA1-BCL10-MALT1 complex (the CBM complex) plays a key role in mediating NF-KB activation and promoting aberrant cell proliferation and growth in ABC-DLBCL. Previously, we have unraveled that upon signal stimulation, the CBM complex assembles into a helical filamentous structure, which provides a central scaffold for the recruitment, aggregation and activation of downstream signaling components that result in NF-κB activation. BCL10 polymerizes and forms the core of the filament. The polymerization function of BCL10 is critical for the function of the CBM complex and could serve as potential therapeutic target to modulate the function of CBM complex and NF-κB signaling. Therefore, we hypothesize that inhibition of BCL10 polymerization is an effective method for the treatment of ABC-DLBCL. In this project, we plan to identify BCL10 inhibitors that could block the polymerization function of BCL10 through high throughput screening, evaluate their impact on NF-κB activity and the growth of ABC-DLBCL cells, explore their efficacy in inhibiting the growth of ABC-DLBCL tumors in xenotransplanted mouse model, and elucidate their mechanisms of action. This project will elucidate that inhibiting the polymerization function of BCL10 is an effective method to treat ABC-DLBCL, and provide new therapeutic directions for the treatment of ABC-DLBCL.

英文关键词： Cancer therapy;anti-cancer drug;molecular targeted therapy;molecular mechanism;lymphoma