Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation

描述(由申请者提供)：该计划项目的长期目标是以精确的数量术语了解单个癌细胞和肿瘤如何对药物治疗做出反应，从靶向接触到诱导细胞凋亡再到最终的肿瘤消退。这将通过改进药物反应的预测和合理设计组合疗法，并通过确定更好的未来药物的靶点来改善患者护理。我们将在两类触发癌细胞凋亡的药物、抗有丝分裂药物和靶向凋亡诱导剂(包括TRAIL和ABT737)的背景下解决这一目标。实验将在细胞培养和小鼠肿瘤中进行。我们的目标是了解细胞对这些药物的反应：(I)根据特定蛋白质和其他生物分子之间的相互作用来解释细胞表型的机制；(Ii)应用质量作用动力学和其他数学形式来定量地应用质量作用动力学和其他数学形式来根据相互作用的蛋白质的个体生物化学知识来预测整体的行为；(Iii)以概率的方式解释不同细胞对药物的反应的差异性，以及伴随而来的可能性，即只有一小部分肿瘤细胞会因化疗药物的治疗而停止或死亡(Iv)后基因组分析不同的细胞系(以及最终的患者(V)假设药物反应的决定因素是多因素的，必须研究多条相互作用的途径，而不是单一的基因或蛋白质。我们将在四个计划特定目标中解决这些目标：在目标1中，我们将确定在抗有丝分裂药物和ABT737反应中调节MOMP的分子机制。在目标2中，我们将调查细胞对抗有丝分裂药物和靶向的凋亡诱导剂反应变化的原因。在目标3中，我们将使用活体成像和其他方法，询问细胞培养和小鼠肿瘤的药物反应在多大程度上是相同的。在目标4中，我们将寻求几种方法，将目标1-3中的机械性理解转化为更好的病人护理。

DESCRIPTION (provided by applicant): The long-term goal of this Program Project is to understand, in precise quantitative terms, how individual cancer cells and tumors respond to drug treatment, from target engagement to induction of apoptosis to eventual tumor regression. This will improve patient care by allowing improved prediction of drug responses and rational design of combination therapies, and by identifying targets for better future drugs. We will address this goal in the context of two drug classes that trigger apoptosis in cancer cells, anti-mitotic drugs, and targeted apoptosis inducers, including TRAIL and ABT737. Experiments will be performed in cell culture and mouse tumors. We aim for an understanding of the cellular response to these drugs that is (i) mechanistic in explaining cellular phenotypes in terms of interactions among specific proteins and other bio-molecules (ii) quantitative in applying mass-action kinetics and other mathematical formalisms to predicting the behavior of ensembles of interacting proteins from knowledge of their individual biochemistry (iii) probabilistic in accounting for the variability from one cell to the next in responses to drugs with the attendant likelihood that only a fraction of tumor cells will arrest or die in response to treatment with a chemotherapeutic drug (iv) post-genomic in analyzing diverse cell lines (and ultimately patient samples) with knowledge of their genetic differences and with the possibility of applying powerful knock-out/in and RNAi strategies to alter genotype (v) integrative in assuming that determinants of drug response are multi-factorial and that multiple interacting pathways rather than single genes or proteins must be studied. We will address these goals in four Program Specific Aims: In aim 1 we will determine the molecular mechanisms that regulate MOMP in response to anti-mitotic drugs and ABT737. In aim 2 we will investigate the causes of variation in cell responses to anti-mitotics and targeted inducers of apoptosis. In aim 3 we will ask to what extent drug responses are the same in cell culture and mouse tumors, using intravital imaging and other methods. In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care.