Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation

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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.