Quantitative Analysis of Cell Death Pathways in Cancer

由Peter Sorger教授领导的这个项目的总体目标是，用精确的分子术语描述， 哺乳动物细胞暴露于小分子后调节细胞凋亡发生的机制 和生物疗法。从一种细胞类型到下一种细胞类型以及从一个细胞到下一个细胞类型的变化将是 特别关注，最终目标是开发预测患者对治疗的特异性反应的方法。 作为一种手段，创造机制，概率，整合和预测的理解细胞凋亡，我们将 收集关于半胱天冬酶活化动力学的群体水平和单细胞数据， 分析一系列描述哺乳动物细胞死亡关键步骤的数学模型。我们将重点 主要是对现有的和研究中的抗癌药物，但也希望检查代理，改变 炎症和免疫反应。我们选择治疗剂的指导原则是：（i） 常规药物在癌症标准治疗中的应用以及开发改善临床疗效的可能性 方案（如紫杉烷类）（ii）药物反应中患者间差异的程度和伴随的困难 （iii）新药物的潜力， 临床前和临床研究（例如ABT-737）证实，显著改善结局。四 具体目标将涉及：（1）预测和机制分析的途径控制 配体作用下细胞线粒体外膜通透性和效应caspase激活 （2）直接比较细胞与细胞之间的时间和概率变化， 克隆细胞群成员之间和不同肿瘤细胞系之间的细胞死亡（3）实验 微管毒物紫杉醇和Bcl 2诱导的内源性细胞凋亡的模型驱动分析 抑制剂ABT 737和联合使用化疗药物对不同癌细胞单细胞分析 线（4）发展和应用的方法，有丝分裂和细胞凋亡的活体成像在癌症中， 在小鼠体内。这些目标的成功不仅会影响细胞凋亡的研究，而且会影响一般的 癌症生物学和化疗药物的使用

The overall goal of this project, led by Prof. Peter Sorger, isto delineate, in precise molecular terms, the mechanisms that regulate the onset of apoptosis in mammalian cells following exposure to small molecule and biological therapeutics. Variation from one cell type to the next and one cell to the next will be an area of particular focus, with the eventual goal of developing means to predict patient-specific responses to therapy. As a means to create mechanistic, probabilistic, integrative and predictive understanding of apoptosis we will collect population-level and single-cell data on caspase activation kinetics and construct, calibrate and analyze a series of mathematical models that describe key steps in mammalian cell death. We will focus largely on existing and investigational anti-cancer drugs, but also expect to examine agents that alter inflammatory and immune responses. Our selection of therapeutic agents is guided by (i) the importance of conventional agents in standard of care cancer treatment and the possibility of developing improved clinical protocols (e.g. taxanes) (ii) the extent of patient-patient variation in drug response and the attendant difficulty of identifying patients who might benefit from a particular treatment (iii) the potential of new agents to significantly improve outcomes as demonstrated by pre-clinical and clinical studies (e.g. ABT-737). Four specific aims will be pursued involving (1) predictive and mechanistic analysis of pathways controlling mitochondrial outer membrane permeablization and effector caspase activation in cells exposed to ligands that trigger extrinisic apoptosis (2) direct comparison of cell-to-cell variation in the timing and probability of cell death among members of a clonal cell population and between different tumor cell lines (3) experimental and model-driven analysis of intrinsic apoptosis induced by the microtubule poison paclitaxel and the Bcl2 inhibitor ABT737 and single-cell analysis of chemotherapeutics used in combination on diverse cancer cell lines (4) development and application of methods for intravital imaging of mitosis and apoptosis in cancer in situ in the mouse. Success with these aims will impact not only the study of apoptosis, but also general cancer biology and the use of chemotherapeutic drugs