Grant: Project Grant

An important class of cancer therapeutics known as anti-mitotics are front line therapies for several cancers including breast and lung. However, the success of these drugs is limited by their toxicity and the development of drug resistance. The efficacy of these drugs is dependent on their ability to inhibit the cell cycle during the process of cell division called mitosis. Treating cells with anti-mitotic drugs usually results in cells becoming arrested in mitosis, however, cancer cells can often "slip" through this mitotic arrest and continue to grow. Such slippage leads to cells with unstable genomes that promotes selection for even more aggressive cancer phenotypes. Recently, we demonstrated that combining the anti-mitotic drug, taxol, with drugs that inhibit the protein eIF4A may have clinical application in cancers that are otherwise resistant to taxol. We have shown that taxol displays synergy with inhibitors of eIF4A to promote cancer cells to die during mitotic arrest rather than slip. eIF4A is a regulator of mRNA translation and In this proposal we will further examine the molecular mechanisms through which eIF4A affects cell fate during mitotic arrest and explore how this knowledge can be exploited therapeutically.