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 have worked with Affymetrix to beta-test the DMET chip that contains 1,936 genetic variations in 231 drug disposition genes, and have established a clinical trial where patients treated at the NCI will be genotyped with the DMET chip to explore potential links between these genes and outcomes from several cancer therapies. 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. The histone deacetylase inhibitor belinostat is eliminated through glucuronidation by UGT1A1. Polymorphisms that reduce UGT1A1 function could result in increased belinostat exposure and toxicities. We wanted to determine which single-nucleotide polymorphisms alter belinostat exposure and toxicity. In a phase 1 trial (belinostat over 48 hours in combination with cisplatin and etoposide), belinostat (400, 500, 600, or 800 mg/m(2) /24 h, 48-hour continuous infusion) was administered to patients with cancer in combination with cisplatin and etoposide (n = 25). Patients were genotyped for UGT1A1 variants associated with reduced function: UGT1A1*6, UGT1A1*28, and UGT1A1*60. End points were associations between UGT1A1 genotype and belinostat pharmacokinetics (PK), toxicities, and global protein lysine acetylation (AcK). Belinostat AUC was increased (P = .003), and t1/2 increased (P = .0009) in UGT1A1*28 and UGT1A1*60 carriers who received more than 400 mg/m(2) /24 h. The incidence of grades 3-4 thrombocytopenia (P = .0081) was associated with UGT1A1 polymorphisms. The US Food and Drug Administration-approved package insert recommends dose adjustment of belinostat for UGT1A1*28. However, our data suggest dose adjustment is also necessary for UGT1A1*60. UGT1A1 polymorphisms were associated with increased systemic belinostat exposure, increased AcK, and increased incidence of toxicities, particularly at doses 400 mg/m(2) /24 h. We provided PG analyses for the phase II trial of docetaxel, bevacizumab, lenalidomide, and prednisone in patients with metastatic castration-resistant prostate cancer. Inter-individual variation in the gene expression and plasma levels of VEGF has been attributed to single nucleotide polymorphisms (SNPs) in the VEGF gene; therefore, the VEGF -634G C SNP (rs2010963) was evaluated in 54 patients as it has been associated with a more aggressive phenotype of prostate cancer, altered-VEGF binding affinity, bevacizumab toxicity, and altered response to thalidomide-based therapy. Cereblon (encoded by CRBN) is considered to be the target of lenalidomide and SNPs in CRBN (rs1714327GC, rs1705814TC, and rs1672753GA) have been associated with lenalidomide efficacy. Twenty-four patients were found to have at least one VEGF -634 C allele (CC or CG), while 30 patients were carriers of the GG genotype. The median TTP for patients with the C allele (CC or CG) was 15.5 months, compared with 22.2 months for patients without the C allele (GG; P=0.014 unadjusted; P=0.027 adjusted). According to a multivariate Cox analysis, after univariate analyses had shown that albumin (2.4-3.4 g/DL vs 3.5 g/DL) and Halabi predicted survival were the only clinical factors to consider for inclusion in modeling the VEGF -634 C allele retained its significance (P 0.009, HR 0.41; 95% CI for HR 0.21-0.80) after adjusting for albumin (P=0.006; HR 0.28; 95% CI for HR 0.19-0.76). Univariate analysis of overall survival (OS) also favored patients who had the VEGF -634G (CG or GG) allele, with median OS of 25.7 vs 17.3 months (P=0.037 unadjusted; P=0.073 adjusted), although significance was not retained for CC or CG vs GG (P=0.19), with medians of 26.2 vs 23.2 months. Cox model analysis for OS failed to show an association of the VEGF-634 C allele when other clinical factors were taken into consideration. None of the CRBN SNPs were associated with TTP or OS. We conducted the PG 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 drug therapy. Single nucleotide polymorphism analysis of XRCC1 280H, R194W, and Q399R was done. XRCC1 DNA polymorphisms were not related to PFS. Exploratory correlative studies indicate that CEC and IL-8 changes may be predictive for response to therapy and prognostic in recurrent platinum-sensitive OvCa, requiring prospective validation.
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