Vaults as New Targets for Modulating Tumor Response

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Vaults are highly conserved cytoplasmic ribonucleoprotein particles believed to be involved in nuclearcytoplasmic transport. The aim of present proposal is to investigate the mechanism of vault-mediated multidrug resistance (MDR) to establish the particle as a direct target for development of anti-vault therapeutics. MDR is a common mechanism used by tumor cells exposed to chemotherapy to escape death. In order to develop the next generation of cancer therapies it will be necessary to understand the mechanisms responsible for MDR. Drug resistance can be accomplished by induction of transport-associated proteins such as P- glycoprotein, multidrug resistance protein, and breast cancer resistance protein, alterations in the essential nuclear enzymes, DNA topoisomerases, and induction of lung resistance-related protein (LRP), identified as the major vault protein (MVP). A number of approaches will be used including expression of anti-MVP ribozymes, perturbation of nuclear transport of drugs and effects of impaired vault function on tumor development and resistance. If the reduction of vault levels in cancer cells is able to prevent or revert the development of MDR that develops in response of chemotherapy, it would open up a new areas of vault research leading to the development of anti-vault modulators.