DESCRIPTION (provided by applicant): Cancer chemotherapy can significantly improve patient outcomes but is often limited by toxicity. The long term goal of the proposed pharmacogenomic studies is to identify genetic predictors of drug toxicity that can be used to achieve maximal therapeutic benefit with minimal toxicity. This proposal is focused on microtubule targeting agent-induced sensory peripheral neuropathy, a dose-limiting toxicity associated with these widely used chemotherapy agents. We have recently identified several common genetic variants associated with paclitaxel-induced sensory peripheral neuropathy through a genome-wide association study. The studies proposed here will extend these findings and test the central hypothesis that both common and rare variants contribute to interindividual variability in microtubule targeting agent toxicity. The studies in aim 1 will identify rare varians in novel genes associated with microtubule targeting agent-induced sensory peripheral neuropathy. Sequencing of exomes and selected regulatory regions of 622 DNA samples from subjects enrolled in a Phase III trial of microtubule targeting agents in advanced breast cancer (CALGB 40502) will be performed and novel genes identified that are associated with drug-induced sensory peripheral neuropathy. The results from aim 1 and from our earlier genome-wide association study will be replicated in aim 2. Replication samples will come from three clinical trials testing paclitaxel in the treatment of early stage and advanced breast cancer and from the BioVU resource at Vanderbilt University. Finally, aim 3 will be functional genomics studies to characterize the effect of novel genes identified in our earlier genome-wide association study on neuronal and Schwann cell function. Specifically, neurite extension assays, cell shape and cellular signaling will be used to screen for the most biologically relevant genes identified in our genomic studies. Identification and validation of genetic predictors of this toxiity will advance the long term goal of these studies to use biomarkers for the identification of patients at increased risk of chemotherapy-induced sensory peripheral neuropathy and to develop targeted therapies to prevent or treat this toxicity.
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