Our laboratory has a strong interest in pharmacogenetics. We have been active in studying how germline genetic variants can alter pharmacokinetics, response, and toxicity of various anticancer agents, thereby contributing to interindividual variation in clinical outcomes in therapies with an already narrow therapeutic window. We have established a molecular link between these polymorphisms and their phenotype as it relates to drug treatment. Most of our work has been focused on genetic variations in drug metabolism and transporting candidate genes such as ABCB1 (P-glycoprotein, MDR1), ABCG2 (BCRP), SLCO1B3 (OATP1B3, OATP8), CYP3A4, CYP3A5, CYP1B1, CYP2C19, CYP2D6, UGT1A1, UGT1A9 and several others. Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such, they are involved in physiology, development of disease, drug pharmacokinetics, and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable interindividual variation in physiology and pharmacotherapy. Thus, we are interested in studying how inherited variants in transporters are associated with disease etiology, disease state, and the pharmacological treatment of diseases. We are also interested in non-candidate gene approaches where large numbers of polymorphisms are explored to establish a relationship with clinical outcome, and experiments are conducted to validate potential causative alleles resulting from exploratory scanning. We have worked with Affymetrix to beta-test the DMET chip that contains 1,256 genetic variations in 170 drug disposition genes, and are currently establishing a clinical trial where patients treated at the NCI will be genotyped with the DMET chip to explore potential links between these genes and various treatments of several cancers. We are currently making progress in validating the results from the initial DMET chip experiments. While many of these studies have been conducted in order to explain some of the genetic influence on pharmacokinetic variability, we also have a strong interest in clarifying genetic markers of pharmacodynamics and therapeutic outcome of several major anticancer agents since this field has been rather poorly studied. We conducted the pharmacogenetics analysis of a study evaluating olaparib (O), a polyADPribose polymerase (PARP) inhibitor, and cediranib (C), a VEGF receptor (VEGFR)1-3 inhibitor together had greater activity than O alone in women with recurrent platinum-sensitive ovarian cancer (OvCa). The objective of this study is to identify potential lead biomarker candidates for response to O + C in the setting of a multi-institutional phase II study of O with and without C in recurrent platinum-sensitive OvCa. Single nucleotide polymorphism analysis of XRCC1 280H, R194W, and Q399R was done. XRCC1 DNA polymorphisms were not related to PFS. Our exploratory correlative studies indicate that CEC and IL-8 changes may be predictive for response to O + C and prognostic in recurrent platinum-sensitive OvCa, requiring prospective validation. We provided PGx support for a phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors. Pharmacogenomic expression of specific DNA repair genes were evaluated. In a collaborative effort with the FDA, we also examined the PK and pharmacogenetics of clopidogrel. We assessed the effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 metabolizers and found that quadrupling the usual clopidogrel dose might be necessary to overcome the effect of poor CYP2C19 metabolism. We further found that the CYP2C19*17 variant is not independently associated with clopidogrel response and that the observed effect of this variant is due to linkage disequilibrium with the CYP2C19*2 loss-of-function variant. Moreover, we participated in a multi-institutional study of outcomes after pediatric heart transplantation evaluating the candidate gene polymorphism of ABCC2. The study concluded that ABCC2 rs717620 polymorphisms should be included in any expanded pharmacogenomic analysis of outcomes after pediatric heart transplantation.
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