Chromosome instability drives cancers to a state of aneuploidy which, in turn, is thought to drive mutations that lead to tumorigenesis. The broad goal of this project is to understand how alterations in microtubule dynamics lead to chromosome instability. Specifically, we have preliminary data indicating that increased microtubule polymerization rates, which serve as a readout for changes in regulation of microtubule dynamics, are correlated with chromosome instability. Furthermore, the lesions that result in increased microtubule dynamics are not always predictable based on established signaling pathways. We have developed a relatively simple visual assay for lesions that lead to increased microtubule polymerization rates. We have also found that microtubule polymerization rates can be rescued and restored to normal levels by experimental alterations in regulatory molecules, some of which are known to be manageable by small molecule inhibitors. We hypothesize that chromosome instability deriving from changes in microtubule dynamics represents a subclass of neoplastic alterations that could be preferentially responsive to certain classes of therapeutics. Our approach is to screen for genes whose loss leads to increased microtubule polymerization rates. The screens will be performed at the Quellos High Throughput Screening Core at the University of Washington. Initially we will use an established transformed cell line which serves as a model system for chromosome instability because it stably maintains a consistent ploidy. We will then confirm hits in primary human cells. These genes will represent good candidates for therapeutic drugs. Finally, new therapies may be discovered by screening for revertants using the ChemBridge corporation library of 115,000 small molecules available at the Quellos High Throughput Screening Core at the Institute for Stem Cell and Regenerative Medicine at the University of Washington.
Segregation of chromosomes with perfect fidelity is critically dependent on dynamic polymers within the cell called microtubules and drugs that alter microtubule dynamics have proven to be potent as anti-cancer therapies. However, the acquisition of resistance to first-line therapeutics is a problem in refractory cancers that this study seeks to solve via a novel screen to develop a molecular profile of tumor cells exhibiting altered microtubule dynamics enabling the identification of new targets for cancer therapies which are specifically effective against cancers with chromosome instability deriving from altered microtubule behavior.
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