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overview
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The Dolan lab is focused on improving the quality of life of cancer patients through the identification of genetic variants associated with risk for severe and persistent toxicities following chemotherapy (i.e. peripheral neuropathy, ototoxicity, tinnitus), particularly in children and young adults whose adverse sequelae could persist throughout their lifetimes. To this end, they perform clinical genome wide association studies to identify genetic variants associated with toxicity in patients following chemotherapy and determine whether there is shared genetic architecture with idiopathic forms of these traits. They develop preclinical models to elucidate the biochemical and cellular impact of genes identified in clinical studies of chemotherapeutic toxicity. Their approach integrates multiple large datasets including: genetic variation, gene expression, miRNA, modified cytosine, transcription factor levels and chemotherapeutic induced pharmacologic traits. Her laboratory made the seminal observation that chemotherapeutic-induced cytotoxicity is a heritable trait and that pharmacologic SNPs, identified through GWAS, are enriched in expression quantitative trait loci. More recently, her laboratory has developed an induced pluripotent stem cell derived neuronal cell model to evaluate genes contributing to chemotherapeutic-induced neuropathy, a common adverse event of multiple chemotherapeutic agents. They are creating a resource of human induced pluripotent stem cell derived neurons from well-phenotyped cancer survivors following treatment with paclitaxel, vincristine or cisplatin to be used to identify an in vitro toxicity readout that parallels the clinical phenotype. The models they are developing will have broad applicability for gaining insight on druggable targets to treat or prevent this devastating side effect of chemotherapy and providing an understanding of the genetic components and genes contributing to severe toxicity.
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