This proposal represents the scientific accomplishments, contributions to the NIH Pharmacogenetics Research Network (PGRN), and plans for our Pharmacogenetics of Anticancer Agents Research (PAAR) Group. The PAAR Group includes a multidisciplinary team of investigators from the University of Chicago (UC), St. Jude Children's Research Hospital (SJCRH), MD Anderson Cancer Center, and the University of Pittsburgh. The PAAR Group will continue to be chaired by Mark Ratain (UC), a medical oncologist, and vice-chaired by Mary Rolling (SJCRH), a molecular and clinical pharmacologist. The Group is governed by an Executive Committee of nine senior investigators. Our goal is to improve the efficacy of anticancer drugs by elucidating the impact and mechanisms of germ line polymorphisms affecting the pharmacokinetics and pharmacodynamics of anticancer agents.
Our aims i nclude: (1) To enhance pharmacogenetic knowledge and deposition in PharmGKB through (a) identification of new polymorphisms in drug metabolizing enzymes, transporters, or targets relevant to anticancer agents, (b) detailed analysis of the haplotypic structure and population diversity of important candidate genes, (c) determination of the association between newly discovered and previously identified polymorphisms and haplotypes (genotype) and variability in toxicity and/or response to anticancer agents (phenotype), and (d) collaboration and interaction with other PGRN investigators and the NCI-funded Cooperative Groups;(2) To create shared resources of value for other PGRN investigators and users of PharmGKB;and (3) To demonstrate the clinical utility of pharmacogenetic knowledge. Over the past funding period, the group has demonstrated substantial productivity as evidenced by >54 publications and over 229 publicly-available PharmGKB deposits. Our scientific plans include a consistent phenotype-to-genotype approach and are organized around four Projects (childhood leukemia, colorectal cancer, CYP3A and related genes, cellular susceptibility), two Platforms (Whole Genome and Deep Re-sequencing), and five Cores (Administrative, Study Design and Data Analysis, Molecular Genetics, Liver Tissue, Cell Line). Our objective is to define how genetic variability impacts phenotypic variability in anticancer drug response, with the long-term aspiration that individualization of therapy, based on genomics, will improve efficacy and decrease adverse effects of anticancer agents.
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