Pharmacogenomics of a Cytidine Analogue, Gemcitabine

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DESCRIPTION (provided by applicant): This proposal represents an application for an NCI Transition Career Development Award (K22) on behalf of Liewei Wang, M.D.-Ph.D. Dr. Wang has laboratory-based Cancer Research training in pharmacogenomics -- with an emphasis on the pharmacogenomics of purine antimetabolites such as 6-mercaptopurine. The applicant initiated her independent research career approximately a year ago, and this proposal builds on her training in Cancer Research to focus on pharmacogenomic studies of the pyrimidine antineoplastic antimetabolite, gemcitabine. The proposed studies will take advantage of the outstanding environment at the Mayo Clinic and a series of NIH-Mayo initiatives, including the NIH Comprehensive Cancer Center, the NIH Pharmacogenetics Research Network (PGRN) grant and the NIH Pancreatic Cancer SPORE. The applicant proposes to utilize a "Human Variation Panel" cell line model system that expresses virtually all of the genes encoding proteins that participate in "the gemcitabine pathway", i.e., drug transport, metabolism, activation and targets. This Human Variation Panel consists of 203 cell lines obtained from three different ethnic groups. The applicant has obtained in-depth resequencing data for these genes in all 203 cell lines, as well as basal gene expression array data and genome-wide SNP data. She has also generated gemcitabine cytotoxicity data for the cell lines that will make it possible to perform both gemcitabine pathway-based and genome-wide SNP pharmacogenomic genotype-phenotype association analyses. Hypotheses generated with this model system will then be tested using DNA samples from patients with pancreatic cancer who were treated with gemcitabine, and candidate genes/SNPs identified with the cell lines and/or patient samples will be characterized functionally in the laboratory. These studies will not only utilize modern statistical genetic and high throughput genomic techniques to test the hypothesis that genetic variation in germline DNA might contribute to gemcitabine sensitivity and/or resistance, but will also serve to build on the applicant's training in Cancer Research to make it possible for her to gain additional training in statistical genetics with Dr. Daniel Schaid as her Mentor. Therefore, the proposed studies will provide an ideal "Transition Career Development" path to extend her pharmacogenomic studies of antineoplastic drugs and to make it possible for her to submit a future R01 Cancer Research grant.