Our laboratory has a strong interest in pharmacogenetics. We have integrated pharmacogenetics/pharmacogenomics (PG) research in our drug development efforts to evaluate the impact of genetic variants on drug metabolism, PK, response and toxicity as well as to understand the contribution of inter-individual 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 were involved with implementing the pharmacogenomics program at the NIH Clinical Center. In the first phase, we implemented genotyping for HLA-A and HLA-B gene variations with clinical decision support (CDS) for abacavir, carbamazepine, and allopurinol. In the second phase, we implemented genotyping for drug-metabolizing enzymes and transporters: SLCO1B1 for CDS of simvastatin and TPMT for CDS of mercaptopurine, azathioprine, and thioguanine. We recently published a review to describe the implementation process, which involves clinical, laboratory, informatics, and policy decisions pertinent to the NIH CC. We have established a clinical trial where patients treated at the NCI will be genotyped with the Drug Metabolizing Enzymes and Transporters (DMET) platform (which ascertains 1931 genotypes in 235 genes) to explore potential links between these genes and outcomes from several cancer therapies. While many 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 have studied the pharmacogenetics assessments of many anticancer agents including recently mithramycin, belinostat, docetaxel/lenalidomide/bevacizumab combination, olaparib/carboplatin combination, carfilzomib, azathioprine, and abiraterone. Pharmacogenetics studies have identified several allelic variants with the potential to reduce toxicity and improve treatment outcome. This study was designed to determine if such findings are reproducible in a heterogenous population of patients with lung cancer undergoing therapy with paclitaxel. We designed a prospective multi-institutional study that recruited patients (n=103) receiving paclitaxel therapy with a 5-year follow up. All patients were genotyped using the DMET chip. Initial screening revealed eleven variants that are associated with progression-free survival (PFS). Of these, seven variants in ABCB11 (rs4148768), ABCC3 (rs1051640), ABCG1 (rs1541290), CYP8B1 (rs735320), NR3C1 (rs6169), FMO6P (rs7889839), and GSTM3 (rs7483) were associated with paclitaxel PFS in a multivariate analysis accounting for clinical covariates. Multivariate analysis revealed four SNPs in VKORC1 (rs2884737), SLC22A14 (rs4679028), GSTA2 (rs6577), and DCK (rs4643786) were associated with paclitaxel toxicities. With the exception of a variant in VKORC1, the present study did not find the same genetic outcome associations of other published research on pharmacogenetics variants that affect paclitaxel outcomes. This finding suggests that prior pharmacogenomics research findings may not be reproduced in the most frequently-diagnosed malignancy, lung cancer. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: ABCB4 (multidrug resistance 3) rs2302387 and ABCB11 [bile salt export pump (BSEP)] rs4668115 reduce transporter expression and were associated with grade 3 transaminitis developing 24 hours after the third infusion of mithramycin. In this study we characterized the mechanism of mithramycin-induced acute transaminitis and found that mithramycin not only altered farnesoid X receptor (FXR) and small heterodimer partner gene expression but also inhibited bile acid binding to FXR, resulting in deregulation of cellular bile homeostasis. Two novel single-nucleotide polymorphisms in bile flow transporters are associated with mithramycin-induced liver function test elevations, and the present results are the rationale for a genotype-directed clinical trial using mithramycin in patients with thoracic malignancies. Differences in drug metabolism associated with UGT1A1 polymorphism could result in individualized local response to hepatic chemoembolization with irinotecan-eluting beads (DEBIRI) or predictable toxicities. Five patients with inoperable hepatic metastases from colorectal or anal malignancies treated with DEBIRI were assessed for UGT1A1 mutations. No difference in area under the curve (AUC) for SN38 in normal liver and tumor tissue samples was noted with variant or wild-type UBT1A1 (P = .16 and P = .05, respectively). Plasma SN-38 AUC was significantly lower in wild-type compared to variant patients (P 0.0001). UGT1A1 genotype may not be predictive of hematologic toxicity after DEBIRI.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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McCrea, Edel M; Lee, Daniel K; Sissung, Tristan M et al. (2018) Precision medicine applications in prostate cancer. Ther Adv Med Oncol 10:1758835918776920
Green, Dionna J; Duong, Son Q; Burckart, Gilbert J et al. (2018) Association Between Thiopurine S-Methyltransferase (TPMT) Genetic Variants and Infection in Pediatric Heart Transplant Recipients Treated With Azathioprine: A Multi-Institutional Analysis. J Pediatr Pharmacol Ther 23:106-110
Alyamani, Mohammad; Emamekhoo, Hamid; Park, Sunho et al. (2018) HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer. J Clin Invest 128:3333-3340
Sissung, Tristan M; Peer, Cody J; Korde, Neha et al. (2017) Carfilzomib and lenalidomide response related to VEGF and VEGFR2 germline polymorphisms. Cancer Chemother Pharmacol 80:217-221
Sissung, Tristan M; McKeeby, Jon W; Patel, Jharana et al. (2017) Pharmacogenomics Implementation at the National Institutes of Health Clinical Center. J Clin Pharmacol 57 Suppl 10:S67-S77
Backman, Joshua D; O'Connell, Jeffrey R; Tanner, Keith et al. (2017) Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response. Pharmacogenet Genomics 27:159-163
Hauke Jr, Ralph J; Sissung, Tristan M; Figg, William D (2017) Discussing the predictive, prognostic, and therapeutic value of germline DNA-repair gene mutations in metastatic prostate cancer patients. Cancer Biol Ther :1-2
Goey, Andrew K L; Sissung, Tristan M; Peer, Cody J et al. (2016) Effects of UGT1A1 genotype on the pharmacokinetics, pharmacodynamics, and toxicities of belinostat administered by 48-hour continuous infusion in patients with cancer. J Clin Pharmacol 56:461-73
Schmidt, Keith T; Chau, Cindy H; Price, Douglas K et al. (2016) Precision Oncology Medicine: The Clinical Relevance of Patient-Specific Biomarkers Used to Optimize Cancer Treatment. J Clin Pharmacol 56:1484-1499
Peer, Cody J; Goey, Andrew K L; Sissung, Tristan M et al. (2016) UGT1A1 genotype-dependent dose adjustment of belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation. J Clin Pharmacol 56:450-60

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