A Cell-Based Assay to Find Inhibitors of Chronic Active B-Cell Receptor Signaling

描述（由申请人提供）：候选人和前同事最近发现，弥漫性大B细胞淋巴瘤（DLBCL）的活化B细胞（ABC）亚型的某些细胞系对标准治疗反应较差，依赖于B细胞受体（BCR）激活经典NF：B通路和其他对其生存至关重要的通路。该应用程序的主要目标是与分子库探针生产中心网络（MLPCN）合作，使用MLPCN已经建立的基于细胞的初步测定，以找到称为“慢性活性BCR信号传导”（CABS）的这一过程的小分子抑制剂。该测定将在CABS依赖性细胞系中进行，并与反筛选和二级测定组合，将用于鉴定CABS的抑制剂，所述抑制剂可被优化以用作其知之甚少的机制的化学探针，以及用于药物开发作为针对ABC-DLBCL的靶向疗法的候选物。 拟议的项目将是申请人先前关于NF：B通路如何在ABC-DLBCL中被组成性激活的研究的延续，以确定增加特异性的潜在治疗靶点。寻找CABS的化学探针将推进申请人的直接职业目标，即进一步发现这一途径，并成为一名独立的研究者。为药物开发寻找严肃的候选药物将推进申请人将其研究成果扩展到临床竞技场的长期目标，这与他最近加入的一个擅长新疗法开发和临床测试的部门保持一致。 公共卫生相关性：许多不同类型的癌症依赖于特定的和异常激活的生物学途径，这些途径的抑制剂有可能提供高效的靶向治疗，减少副作用。当在癌细胞系中发现关键途径时，可以对该细胞系进行工程改造，以方便地“报告”该途径的活性水平，从而用于筛选该途径抑制剂的大型化合物库。该项目将使用这种方法来寻找一种对标准治疗反应较差的B细胞（淋巴瘤）癌症中激活的关键途径的抑制剂，帮助研究这种途径，并可能为靶向治疗的开发提供候选药物。

DESCRIPTION (provided by applicant): Certain cell lines of the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), which responds poorly to standard therapy, have recently been discovered by the candidate and former colleagues to rely on the B-cell receptor (BCR) for activation of the canonical NF:B pathway and other pathways essential for their survival. The principal goal of the application is to collaborate with the Molecular Libraries Probe Production Centers Network (MLPCN), using a cell-based primary assay already established by the MLPCN, to find small-molecule inhibitors of this process termed "chronic active BCR signaling" (CABS). The assay will be performed in a CABS-dependent line, and in combination with counterscreens and secondary assays, will be used to identify inhibitors of CABS that can be optimized to serve as chemical probes of its poorly- understood mechanisms, and candidates for drug development as targeted therapy against ABC-DLBCL. The proposed project would be a continuation of the applicant's previous investigations into how the NF:B pathway is constitutively activated in ABC-DLBCL, identifying potential therapeutic targets of increasing specificity. Finding chemical probes of CABS would advance the applicant's immediate career goals of making further discoveries about this pathway, and becoming established as an independent investigator. Finding serious candidates for drug development would advance the applicant's long-term goals of extending his research findings into the clinical arena, in keeping with his having recently joined a department which excels in the development and clinical testing of new therapies. PUBLIC HEALTH RELEVANCE: Many different types of cancer depend on specific and abnormally-activated biological pathways, and inhibitors of these pathways have the potential to provide highly effective targeted therapies with reduced side effects. When a critical pathway is found in a cancer cell line, the line can be engineered to conveniently "report" on that pathway's activity level, and thus be used to screen large libraries of chemical compounds for inhibitors of the pathway. This project will use this approach to find inhibitors of a critical pathway activated in one type of cancer of B cells (lymphomas) that responds poorly to standard therapy, helping in studies of this pathway and possibly providing candidates for development as targeted therapy.