Clinical Pharmacogenetics

Our laboratory has a strong interest in clinical pharmacogenetics. We have integrated pharmacogenetics/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 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. 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. The PharmacoScan pharmacogenomics platform screens for variation in genes that affect drug absorption, distribution, metabolism, elimination (ADME), immune adverse reactions and targets. The platform 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. Using such PGx platforms like Pharmacoscan, we have studied the PG assessments of many anticancer agents using including recently mithramycin, belinostat, docetaxel/lenalidomide/bevacizumab combination, olaparib/carboplatin combination, carfilzomib, azathioprine, abiraterone, paclitaxel, cabozantinib, and zotiraciclib. Gonadotropin-releasing hormone 2 (GNRH2) is a poorly-studied peptide hormone that is widely distributed in the central nervous system and expressed in peripheral tissues of mammals. The non-synonymous rs6051545 variant in GNRH2 (A16V) has been linked to higher serum testosterone concentrations. This study investigated whether the A16V variant is associated with altered androgen-deprivation therapy (ADT) progression-free survival (PFS) and overall survival (OS). We examined the expression of GNRH2 in prostate tissue microarrays comprising normal tissue, prostatic hyperplasia, and prostate cancer using immunofluorescence. We also evaluated the GNRH2 genotype in 131 patients with prostate cancer who received ADT and compared PFS and OS between the variant and wild-type genotypes. GNRH2 was detected in all prostate tissues, although expression did not vary with Gleason grade or disease stage. The GNRH2 A16V genotype was not associated with PFS or OS; however, univariate and multivariate analyses revealed Gleason score and definitive local therapy were each associated with PFS, whereas age and Gleason score were associated with OS. GNRH2 is expressed in normal, hyperplastic, and neoplastic prostate tissues; the A16V variant is not related to treatment outcome or survival.