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 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. 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. DMET The anticancer agent docetaxel exhibits significant inter-individual variation in its pharmacokinetic and toxicity profile. Thalidomide is an active anticancer agent and also exhibits wide pharmacologic variation. Past pharmacogenetic research has not explained this variation. Patients with prostate cancer enrolled in a randomized phase II trial using docetaxel and thalidomide versus docetaxel alone were genotyped using the Affymetrix DMET 1.0 platform, which tests for 1,256 genetic variations in 170 drug disposition genes. Genetic polymorphisms were analyzed for associations with clinical response and toxicity. Ten SNPs in three genes were potentially associated with response to therapy: PPAR&#948;, SULT1C2, and CHST3. Eleven SNPs in eight genes were associated with toxicities to treatment: SPG7, CHST3, CYP2D6, NAT2, ABCC6, ATP7A, CYP4B1, and SLC10A2. Genotyping results between DMET and direct sequencing showed greater than 96% concordance. These findings highlight the role that non-CYP450 metabolizing enzymes and transporters may play in the pharmacology of docetaxel and thalidomide. Genetics of Ethnic Disparities: ERCC1, ERCC2, XRCC1 and PARP1 Nucleotide excision repair (NER) and base excision repair (BER) pathways are DNA repair pathways that are important in carcinogenesis and in response to DNA-damaging chemotherapy. ERCC1 and ERCC2 are important molecular markers for NER;XRCC1 and PARP1 are important molecular markers for BER. Functional polymorphisms have been described that are associated with altered expression levels of these genes and with altered DNA repair capability. Our results showed that differences were observed between Americans of European descent and Americans of African descent in the allelic frequencies of the ERCC1 N118N polymorphism (P <0.000001). Differences were also observed between these two ethnic groups for ERCC2 K751Q (p=0.006675), XRCC1 R399Q (p<0.000001), and PARP1 V762A (p= 0.000001). To verify the functional implication, we introduced the variant allele into the open reading frame (ORF) clone of ERCC1 and assayed for platinum sensitivity of the transfected ERCC1 deficient UV-20 cell line. The cells transfected with the ERCC1 clone exhibited significant higher resistance to platinum-containing drugs, including cisplatin, carboplatin and oxaliplatin. However, the two alleles of ERCC1 N118N did not show a difference in terms of platinum sensitivity or ERCC1 protein expression level. We hypothesize that the polymorphisms in the intronic and/or regulatory regions of ERCC1 may contribute to its functional alteration. ABCB1 variants and QTc interval prolongation associated with the cyclic depsipeptide FK228. Romidepsin-induced QTc prolongation was compared with genotyping data from ABCB1 (1236C>T, 2677G>T/A, 3435C>T), CYP3A4*1B, CYP3A5*3C, SLCO1B3 (S112A), and ABCB1 diplotypes. Individuals carrying only wild-type alleles at ABCB1 had the greatest QTcBSB prolongation (22 ms;n=19) compared to those carrying increasing numbers of genetic variants at the three loci (12 ms;n=44), or those who were completely variant (3 ms;p=0.011;n=12). The strongest association with &#8710;QTcBMB was found within individuals carrying 2677GG (16 ms, n=15) and 2677GT (19 ms, n=18) genotypes, who had similar &#8710;QTcBMB values, while those carrying the 2677TT genotype had the lowest &#8710;QTcBMB (0 ms, n=6). No other genotypes within any other gene including SLCO1B3, CYP3A4*1B, and CYP3A5*3C were related to alterations in &#8710;QTcBSB. This analysis reveals that ABCB1 genetic variants may influence the QT-prolonging properties of romidepsin, and perhaps other ABCB1 substrates. NAT2 slow acetylation haplotypes are associated with the clinical outcome of thalidomide-based therapy. Several NAT2 alleles were found to be markers of poor prognosis following thalidomide-based therapy on the ATD (n = 49) and thalidomide trials (n = 45). The NAT2 282C>T (n = 87, p=0.0098), the 341T>C (n = 88, p=0.0016), the 481C>T (n = 89, p=0.0038), and the 803A>G (n = 89, p=0.0035), and the NAT2*5 haplotype (i.e. coinheritance of 341T>C and 481C>T;n = 34, p=0.0033). SNPs were all associated with survival following thalidomide alone, or in combination with bevacizumab and docetaxel. No relationship with overall survival was noted in men treated with suramin-based therapy (n = 52). Progression-free survival after intermittent thalidomide therapy was also related to the following NAT2 alleles: 282C>T (n = 32, p=0.028), 590G>A (n = 32, p=0.0037), and the NAT2*6 haplotype (i.e. coinheritance of 282C>T and 590G>A;n = 29, p=0.0015). No relationship with progression-free survival was noted in men participating on the same trial that were treated with placebo (n = 35), or men receiving androgen deprivation therapy without thalidomide (n = 57). Analysis of toxicities on the thalidomide D0 trial revealed that creatinine clearance was much lower in individuals carrying slow-metabolizing NAT2*5A variants (p=0.000001). Other notable relationships with toxicity and NAT2 alleles included leukopenia (p=0.00066), sensory neuropathy frequency (p=0.00052), and sedation (p=0.0001). Our experiments have shown that neither thalidomide, nor lenalidomide is metabolized by recombinant NAT2;therefore we hypothesize that creatinine clearance of thalidomide may be lower in patients with certain NAT2 variants thereby altering the plasma pharmacokinetics of the drug. NAT2 knockout mice will be used to test this hypothesis, and experiments are being planned.

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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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