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

描述（由申请人提供）：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，对标准治疗反应不佳，最近被候选人和前同事发现依赖B细胞受体（BCR）激活典型的NF:B途径和其他对其生存至关重要的途径。该应用程序的主要目标是与分子文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级试验，寻找这一过程的小分子抑制剂，称为“慢性活性BCR信号传导”（CABS）。该检测将在CABS依赖的细胞系中进行，并与反筛和二次检测相结合，将用于识别CABS抑制剂，这些抑制剂可以被优化为其尚不清楚的机制的化学探针，以及用于针对ABC-DLBCL的靶向治疗药物开发的候选药物。拟议的项目将是申请人先前研究NF:B通路如何在ABC-DLBCL中组成性激活的延续，以确定增加特异性的潜在治疗靶点。发现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。找到药物开发的重要候选药物将推进申请人将其研究成果扩展到临床领域的长期目标，与他最近加入的一个擅长新疗法开发和临床试验的部门保持一致。

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.