Cell Line Panel Profiling for Discovery of Multiple Myeloma Therapeutics

项目摘要 多发性骨髓瘤的遗传和转录组成是特别异质的，有几个 癌基因常规突变和多种染色体畸变在不同的组合中注意到。的 这种疾病的异质性使得不可能鉴定单一细胞模型或“理想”患者 可以用于药物发现活动。为了说明患者在表征新的 最近的趋势是在大量已建立的细胞系上测试化合物， 并联这些小组提供了必要的遗传广度，并已被证明是高度 信息量大。然而，由于后勤和复杂性，这种强大的方法的效用是有限的 与并行运行许多细胞系实验相关。增加的细胞系数量 执行这些筛选所需的成本、人力和时间。这限制了可用于检测的测定类型。 进行，也大大减少了可以分析的化合物的数量，严重限制了 这种方法的影响。在第一阶段SBIR提案中，我们概述了这些问题的解决方案， 一种新的基于细胞的测定平台的实现，该平台将实验读数与 细胞系所提出的分析平台利用Primont的CellCode多路复用技术， 具有独特荧光特征的细胞群，使得多个细胞系可以在单个管中组合 同时分析。使用这种技术，可以用 从一个样品中获得多个端点，大大减少了所需的时间和资源， 同时增加从每个细胞系获得的信息量。成功者， 这些研究的完成将为多发性骨髓瘤建立一种新的药物发现工具， 多种多样的遗传多样性，并保持药物所有阶段所需的通量 发现过程。

Project Summary The genetic and transcriptional makeup of Multiple Myeloma is particularly heterogeneous, with several oncogenes routinely mutated and multiple chromosomal aberrations noted in different combinations. The heterogeneous nature of this disease makes it impossible to identify a single cellular model or "ideal" patient that could be utilized in a drug discovery campaign. To account for patient diversity in characterizing new anti-cancer drugs, a recent trend has been to test compounds on large panels of established cell lines in parallel. These panels provide the necessary genetic breadth and have been shown to be highly informative. However the utility of this powerful approach is limited due to the logistics and complications associated with running many cell line experiments in parallel. The increased number of cell lines multiplies the cost, manpower, and time required to perform these screens. This limits the types of assays that can be performed and also dramatically reduces the numbers of compounds that can be profiled, severely limiting the impact of this approach. In this Phase I SBIR proposal we outline a solution to these problems with the implementation of a novel cell-based assay platform that multiplexes experimental readouts with libraries of cell lines. The proposed assay platform exploits Primity's CellCode multiplexing technology which labels cell populations with unique fluorescent signatures such that multiple cell lines can be combined in a single tube and analyzed simultaneously. Using this technology, panels of up to 40 cell lines can be assayed with multiple end-points from a single sample, dramatically reducing the time and resources required - while simultaneously increasing the amount of information obtained from each cell line. Thus, the successful completion of these studies will establish a novel drug discovery tool for multiple myeloma that accounts for a wide variety of genetic diversity and maintains the throughput necessary for all phases of the drug discovery process.