The primary aim of this proposal is to create a Research Group focused on the pharmacogenetics of anticancer agents (PAAR Group). The PAAR Group includes investigators from the University of Chicago (UC), St. Jude Children's Research Hospital (SJCRH), Tulane University, and the University of Pittsburgh. The PAAR Group will be chaired by Mark Ratain, Chairman, Committee on Clinical Pharmacology at UC, and a medical oncologist. The Vice-Chair will be Mary Relling, a molecular and clinical pharmacologist at SJCRH. The Group will be governed by an Executive Committee of six senior investigators. The scope of the Group's activities will include both pharmacokinetic and pharmacodynamic polymorphisms affecting response to anticancer agents.
The aims of the proposal are: 1) To create a mulitdisciplinary, collaborative, and comprehensive Pharmacogenetics of Anticancer Agents Research Group (PAAR Group) with the capabilities to identify and evaluate polymorphisms in drug metabolizing enzymes, transporters, or targets relevant to anticancer agents. 2) To identify new polymorphisms in drug metabolizing enzymes, transporters, or targets relevant to anticancer agents. 3) To determine the association between new and previously identified polymorphisms (genotype) and variability in toxicity and/or response to anticancer agents (phenotype). 4) To define the population diversity of polymorphisms of clinical interest. 5) To create shared resources of value to other Research Groups in the Pharmacogenetic Research Network. The initial focus of the Group's activities will be on a class of drugs called topoisomerase inhibitors, widely used in both hematologic malignancies and solid tumors. The Group will utilize a consistent general research scheme, including four decision levels. Projects will require approval by the Executive Committee to progress to the next decision level. These levels are: DL1, evaluation of phenotypic variability; DL2, evaluation of genotypic variability and collection of preliminary data to support genotypic-phenotypic concordance; DL3, demonstration in preclinical model of genotypic-phenotypic concordance; DL4, prospective clinical studies of genotypic-phenotypic concordance and population diversity studies. The Group proposes four projects for the first year, involving UGT (DL4), CYP3A4 (DL4), carboxylesterases (DL1), and MLL (a gene involved in topoisomerase inhibitor-induced leukemogenesis) (DL2). A fifth project evaluating cellular susceptibility to topoisomerase inhibitors (DL1) will begin in year 2. Three core facilities are proposed: Molecular Genetics (includes sub-Core focused on gene array technology at Tulane), Liver Bank (includes sub-Core to acquire livers at Pittsburgh), and Lymphoblastoid Cell Line. The Group investigators will interact extensively in most of the proposed projects and core facilities. The PAAR Group will participate in the NIGMS Pharmacogenetic Research Network, and agrees to abide by the recommendations of the Network Steering Committee. The PAAR Group will maintain a pharmacogenetic database, and release its data to the Network Database Group on request.
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