Clinical Pharmacogenetics

Our laboratory has a strong interest in clinical pharmacogenetics. We have integrated pharmacogenetics and pharmacogenomics (PG) research in our drug development efforts to evaluate the impact of genetic variants on drug metabolism, pharmacokinetics (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. Given the importance of pharmacogenomics in precision medicine, we are actively involved with implementing the pharmacogenomics program at the NIH Clinical Center. 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 PK, 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 inter-individual 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. 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. In the past, we have genotyped patients 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. In the current fiscal year, we have transitioned over to the updated Pharmacoscan platform, which interrogates 4627 variants in 1191 ADME genes. It also detects 4389 ancestry informative markers, 239 gender markers, 7116 human leukocyte antigen markers, and 1484 killer cell immunoglobulin-like receptor markers. We have studied the PG assessments of many anticancer agents including recently mithramycin, belinostat, docetaxel/lenalidomide/bevacizumab combination, olaparib/carboplatin combination, carfilzomib, azathioprine, abiraterone, and paclitaxel. In a phase II trial of cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma, we found that VEGF genotypes (1498CT and. 634CG) were associated with hypophosphatemia - one of the common grade 3-4 toxicities of cabozantinib in the study. We recently conducted a pharmacogenetic analysis in patients on a recent phase I clinical trial to investigate zotiraciclib combined with temozolomide in recurrent glioblastoma and anaplastic astrocytoma. Zotiraciclib is metabolized by CYP1A2 and CYP3A4; from the pharmacoscan results, we identified a single-nucleotide change in gene coding CYP1A2 (CYP1A2 5347TC; rs2470890). This SNP is also associated with a significant difference in zotiraciclib pharmacokinetics (higher AUCinf value) in a cohort of 13 patients. This PK/PG analysis identified a polymorphism that potentially alters the PK of zotiraciclib, suggesting further investigations are warranted for a genotype-guided dosing to reduce the toxicities. Cancers of the colon are commonly treated with fluoropyrimidines, which often cause severe toxicities in patients with certain variants in DPYD. Moderate to strong evidence indicates that ten genetic variants in DPYD are associated with a reduction in the rate of fluoropyrimidine metabolism, and at least 17 other DPYD genotypes may reduce DPYD function. Several of these variants are observed in specific racial populations, and understanding of genetic variability in specific racial populations will be crucial for future reductions in fluoropyrimidine toxicity. We present a case report of an African-American patient who underwent FOLFOX therapy for a colorectal malignancy who developed profound pancytopenia during treatment. Pharmacoscan analysis identified the patient with the DPYD Y186C variant (rs115232898), an uncommon allele (minor allele frequency (MAF) = 0.032 in African-Americans) that causes a 46% decrease in the DPYD-mediated fluoropyrimidine metabolic rate. The patient was also heterozygous for a SNP in the 3' untranslated region of DPYD (rs12132152), an uncommon variant (MAF = 0.0061 in African-Americans) that has also been associated with fluorouracil toxicity. The severe pancytopenia and high fluorouracil plasma concentration this patient experienced is likely a function of uncommon genetic variants that affect DPYD metabolism. The present data adds to emerging evidence that the Y186C variant is important in patients with African origins who are receiving 5-FU, and future studies should evaluate the consequences of rs12132152 on interindividual variation of DPYD function and its clinical effects on fluoropyrimidine therapy. While over ten-thousand phase I studies are published in oncology, fewer than 1% of these studies stratify patients based on genetic variants that influence pharmacology. Pharmacogenetics-based patient stratification can improve the success of clinical trials by identifying responsive patients who have less potential to develop toxicity; however, the scientific limits imposed by phase I study designs reduce the potential for these studies to make conclusions. We compiled all phase I studies in oncology with pharmacogenetics endpoints (n = 84), evaluating toxicity (n = 42), response or PFS (n = 32), and pharmacokinetics (n = 40). Most of these studies focus on a limited number of agent classes: Topoisomerase inhibitors, antimetabolites, and anti-angiogenesis agents. Eight genotype-directed phase I studies were identified. Phase I studies consist of homogeneous populations with a variety of comorbidities, prior therapies, racial backgrounds, and other factors that confound statistical analysis of pharmacogenetics. Taken together, phase I studies analyzed herein treated small numbers of patients (median, 95% CI = 28, 24-31), evaluated few variants that are known to change phenotype, and provided little justification of pharmacogenetics hypotheses. Future studies should account for these factors during study design to optimize the success of phase I studies and to answer important scientific questions.