Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation

抗有丝分裂和细胞凋亡调节的机制药理学

• 批准号: 8470471
• 负责人: Timothy J Mitchison
• 金额: $ 169.15万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470471
• 关键词: Accounting; Address; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Promoter; Apoptosis Regulator; Apoptotic; Behavior; Binding; Biochemical; Biochemistry; Biological Assay; Biological Markers; Bystander Effect; Cancer cell line; Cause of Death; Cell Culture Techniques; Cell Cycle; Cell Cycle Progression; Cell Cycle Stage; Cell Death; Cell Line; Cell division; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Classification; Clinic; Clinical; Combined Modality Therapy; Complement; Complex; Confusion; Cultured Cells; Cyclin B; Cytolysis; Cytotoxic agent; Data; Development; Disease; Drops; Drug Combinations; Drug Targeting; Drug usage; Drug-sensitive; Engineering; Environment; Event; Family; Future; Gene Expression; Gene Mutation; Genes; Genetic; Genomics; Genotype; Goals; Hour; Human; Human Genome; Image; Individual; Induction of Apoptosis; Investigation; Kinetics; Knock-out; Knowledge; Label; Lead; Leukocytes; Life; Ligands; Link; Literature; Malignant Neoplasms; Maps; Measurement; Methods; Microtubules; Mitosis; Mitotic; Mitotic spindle; Modeling; Molecular; Molecular Profiling; Monitor; Motor; Mus; Neurons; Outcome; Outer Mitochondrial Membrane; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Positioning Attribute; Probability; Process; Protein Family; Protein Kinase; Proteins; RNA Interference; Regulation; Reporter; Resistance; Resources; Role; S-Phase Fraction; Sampling; Signal Transduction; Small Interfering RNA; TNF gene; TNFSF10 gene; Technology; Testing; Time; Training; Translating; Variant; Work; base; cancer care; cancer cell; cell behavior; cell killing; chemotherapy; combat; cytotoxic; design; drug mechanism; drug sensitivity; gene interaction; genetic regulatory protein; imaging modality; improved; insight; interest; intravital imaging; killings; mathematical model; neoplastic cell; neurotoxicity; novel; optical imaging; programs; research study; response; screening; skills; small molecule; tool; tumor; tumor xenograft

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.

描述（由申请人提供）：该计划项目的长期目标是以精确的定量术语了解个体癌细胞和肿瘤如何对药物治疗作出反应，从靶向参与到诱导凋亡到最终的肿瘤消退。这将通过改进药物反应的预测和合理设计联合治疗，以及通过确定更好的未来药物的靶点来改善患者护理。我们将在两类药物的背景下解决这一目标，这些药物触发癌细胞凋亡，抗有丝分裂药物和靶向凋亡诱导剂，包括TRAIL和ABT 737。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，即（i）在特定蛋白质和其他生物分子之间的相互作用方面解释细胞表型的机制（ii）在应用质量作用动力学和其他数学形式主义来预测相互作用蛋白质集合的行为时的定量（iii）在解释对药物的反应中从一个细胞到下一个细胞的变异性时的概率性，伴随的可能性是只有一小部分肿瘤细胞将响应于用化疗药物的治疗而停滞或死亡（iv）在分析不同细胞系时的后基因组（以及最终的患者样品）具有其遗传差异的知识，并且具有应用强大的敲除/敲入和RNAi策略来改变基因型的可能性（v）整合假设药物反应的决定因素是多因素的，并且必须研究多个相互作用的途径而不是单个基因或蛋白质。我们将在四个项目具体目标中解决这些目标：在目标1中，我们将确定调节MOMP响应抗有丝分裂药物和ABT 737的分子机制。在目标2中，我们将研究细胞对抗有丝分裂药和靶向凋亡诱导剂的反应变化的原因。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中药物反应的相同程度。在目标4中，我们将寻求几种方法，将目标1-3中的机械理解转化为改善患者护理。