Wolfgang Sadee, Dr.rer.nat.

Felts Mercer Professor of Medicine and Pharmacology
Chair, Department of Pharmacology
Professor of Pharmacy, Psychiatry and Medical Genetics
Director, OSU Program in Pharmacogenomics
5078 Graves Hall
333 W. 10th Avenue
Columbus, OH 43210
Phone: (614) 292-1597
Fax: (614) 292-7232
Email: wolfgang.sadee@osumc.edu

Curriculum Vitae

Research Interests

Pharmacogenetics-Pharmacogenomics
Research conducted in the OSU Program in Pharmacogenomics aims at finding biomarkers that guide effective treatment of individual patients.  We assume that genetic differences among individuals play a significant role in determining treatment outcomes.  In the emerging era of personalized medicine, use of genetic information has vast promise in reducing toxicity and improving efficacy of drug therapy.  This applies to drugs already in routine use and to novel drugs emerging from the discovery pipeline.  While the potential of pharmacogenomics is great, translation into clinical practice has been slow.

Main hurdles in rapid implementation include the complexity of human genetics - we often do not know the impact of a gene variant on disease or therapy outcome in patients.  The Sadee laboratory has developed a novel approach to finding genetic variations in key genes already know to play a significant role - either as drug targets or as disease risk factors.  We have applied this approach to >60 candidate genes implicated in CNs disorders, cancer, cardiovascular disease, and inflammation and autoimmune disorders, including multiple sclerosis, and in drug metabolism.  This has led to discoveries of genetic variants in key genes affecting biogenic amine activity - such as serotonin and dopamine, involved in depression, psychosis, cognition and memory, autism, neurodegenerative disorders, and drug addiction.  These discoveries are all the more surprising as some of these key genes had already been under intense study elsewhere.

We have already taken these newly discovered genetic markers into clinical trials, finding unexpectedly strong association in some cases, and raising the hope for the development of viable biomarkers.

We are currently initiating a series of clinical collabortions, addressing the following medical needs and searching for potential biomarkers/drug targets:  cancer (e.g., colon, lung, breast), hypertension and myocardial infarction, CNS disorders, including drug addiction, and HIV/AIDS.

Current Projects

Susceptibility genes in drug addiction. We use human autopsy brain tissues from large tissue repositories to discover and study genetic variants affecting gene expression and mRNA processing - possibly main genetic causes of human phenotypic variability.  Measuring allelic mRNA expression imbalance (AEI) provides us with a quantitative measure of cis-acting factors andpermits gene scanning to locate the responsible genetic and epigentic factors.  We have discovered novel frequent functional polymorphisms in key genes, even though these gene had already been intensely studied by numerous laboratories.  The relevance of these polymorphisms in drug addiction is currently under investigation.

We also search for polymorphisms in candidate genes involved in cardiovascular disorders, using large genotype association studies and AEI analysis in human heart tissues from transplant patients.  This has revealed a novel promoter SNP in ACE-1 that affects gene expression and is frequent in African Americans.  First clinical association analyses has revealed a significant link to outcomes in hypertensive patients (INVEST cohort, collaboration with Dr. J. Johnson, Gainesville).

We have established large genotyping panels targeting drug metabolism and transport, and genes involved in cancer biology.  These tools, in combination with AEI analysis, are being applied to chemotherapy trials of leukemias, and to colon cancer subjects.  The goal is to identify biomarkers that can guide personalized treatment regimen.

We employ mRNA and microRNA profiling in transformed tissues and compare expression pattern with cytotoxic potencies of anticancer drugs (chemogenomics).  We take advantage of the NCI60 panel of cell lines used for drug discovery at the NCI, with > 60,0000 chemicals tested for potency.  Correlations between gene expression and compound potencies lead to discovery of novel drug targets and promising drug candidate for cancer chemotherapy.  Also, we study mechanisms of chemoresistance this approach.  Our results have identified a series of genes invovled in chemoresistance.  Moreover, we have demonstrated that the regulatory microNAs play a pervasive role in chemoresistance and -sensitivity.

Recent Publications

Wang D, Chen H, Momary KM, Cavallari LH, Johnson JA, Sadee W. (2008) Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement.  Blood 112:1013-1021.

Blower PE, Chung JH, Verducci JS, Lin S, Park JK, Dai Z, Liu CG, Schmittgen TD, Reinhold WC, Croce CM, Weinstein JN, Sadee W. (2008) microRNAs modulate the chemosensitivity of tumor cells. Molec Cancer Therap 7:1-9.

Besecker B, Bao S, Bohacova B, Papp A, Sadee W, Knoell D. (2008) The human zinc transporter SLC39A8 (Zip8) is critical in zinc-mediated cytoprotection in lung epithelia.  Amer J Physiol Lung Cell Mol Physiol 294:L1127-L1136.

Dai Z, Papp AC, Wang D, Hample H, Sadee W. (2008) Genotyping panel for assessing response to cancer chemotherapy.  BMC Medical Genomics 1:24. http://www.biomedcentral.com/1755-8794/1/24.

Blower PE, Verducci JS, Lin S, Zhou J, Chung JH, Dia Z, Liu CG, Reinhold W, Lorenzi PL, Kaldjian EP, Croce CM, Weinstein JN, Sadee W. (2007) MicroRNA expression profiles for the NCI-60 cancer cell panel.  Mol Cancer Ther 6:1483-1491.

Liu R, Blower PE, Pham AN, Fang J, Dai Z, Wise C, Green B, Teitel CH, Ning B, Ling W, Lyn-Cook BD, Kadlubar FF, Sadee W, Huang Y. (2007) Cystine-glutamate transporter SLC7A11 mediates resistance to geldanamycin but not to 17-AAG.  Molec Pharmacol 72:1637-1646.

Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R, Lee MLT, Xiao T, Papp A, Wang D, Sadee W. (2007) Novel polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory.  Proc Natl Acad Sci USA 104:20552-20557.

Lim JE, Pinsonneault J, Sadee W, Saffen D. (2007) Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons.  Molec Psychiatry 23:491-501.

Dai Z, Sadee W, Blower P. (2007) Chemogenomics of sensitivity and resistance to anticancer drugs.  Curr Pharmacogenom 5:11-19.

Wang D, Sun X, Sadee W. (2007) Different effects of opioid antagonists on mu, delta, and kappa opioid receptors with and without agonist pretreatment.  J Pharmacol Exp Ther 321:544-552.

Dai Z, Huang Y, Sadee W, Blower W. (2007) Chemoinformatics analysis identifies cytotoxic compounds susceptible to chemoresistance mediated by glutathione and cystine/glutamate transport system ^x-c.  J Med Chem 15:1896-1906.

Beitelshees AL, Gong Y, Wang D, Schork NJ, Cooper-DeHoff RM, Langaee TY, Shriver MD, Sadee W, Pepine CJ, Johnson JA. (2007) KCNMB1 genotype influences response to verapamil SR and adverse outcomes in the INternational VErapamil SR/Trandolapril STudy (INVEST).  Pharmacogen Genomics 17:719-729.

Huang Y, Blower PE, Dai Z, Moon H, Fang J, Sadee W. (2007) Chemogenomic analysis identifies geldanamycins as substrates and inhibitors of ABCB1.  Pharm Res 24:1702-1712.

Cao X, Fang L, Gibbs S, Huang Y, Dai Z, Wen P, Zheng X, Sadee W, Sun D. (2007) Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia.  Cancer Chemother Pharmacol 59:495-505. 

Dai Z, Barbacioru C, Huang Y, Sadee W. (2006) Prediction of anticancer drug potency from expression of genes involved in growth factor signaling.  Pharm Res 23:337-349.

Anderle P, Nielsen CU, Pinsonneault P, Lindskov Krog P, Brodin B, Sadee W. (2006) Genetic variants of the human dipeptide transporter PEPT1.  J Pharmacol Exp Ther 316:636-646.

Lim J-E, Papp A, Pinsonneault J, Sadee W, Saffen D. (2006) Allelic expression of serotonin transporter (SERT) mRNA in human pons: Lack of correlation with the polymorphisms SERTLPR.  Molec Psychiatry 11:649-662.

Kresja C, Rogge M, Sadee W. (2006) Protein therapeutics - New applications for pharmacogenetics.  Nature Rev Drug Disc 5:507-521.

Wang D, Papp AC, Binkley PF, Johnson JA, Sadee W. (2006) Highly variable mRNA expression and splicing of L-type voltage-dependent calcium channel alpha subunit 1C (CACNA1C) in human heart tissues.  Pharmacogen Genomics 16:735-745.

Wang Y, Dai Z, Sadee W, Hancock WS. (2006) Proteomic profiling of cancer cell line EKVX treated with the combination of a chemotherapeutic drug and a small molecule inhibitor.  Mol Pharmaceut 3:566-578.

Pinsonneault JK, Papp AC, Sadee W. (2006) Allelic mRNA expression of X-linked monoamine oxidase A (MAOA) in human brain:  Dissection of epigenetic and genetic factors.  Hum Molec Genet 15:2636-2649.

Sadee W, Wang D, Bilsky EJ. (2005) Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities.  Life Sci 76:1427-1437.

Johnson AD, Wang D, Sadee W. (2005) Polymorphisms affecting gene regulation and mRNA processing:  Broad implications for pharmacogenetics.  Pharmacol Ther 106:19-38.

Huang Y, Blower PE, Yang C, Barbacioru C, Dai Z, Zhang Y, Xiao JJ, Chan KK, Sadee W. (2005)  Correlating gene expression with chemical scaffolds of cytotoxic agents: Ellipticines as substrates and inhibitors of MDR1.  Pharmacogenomics 5:112-125.

Becker JD, Arnold A, Berkeley KJ, Blaustein JD, Eckel L, Hampson E, Herman JP, Mart S, Sadee W, Taylor J, Young E. (2005) Strategies and methdos for research on sex differences in brain and behavior.  Endocrinology 146:1650-1673. 

Xiao JJ, Foraker AB, Swaan PW, Liu S, Huang Y, Dai Z, Chen J, Sadee W, Byrd J, Marcucci G, Chan KK. (2005) Efflux of depsipeptide FK228 (FR091228, NSC-630176) is mediated by both P-glycoprotein and MRP1.  J Pharmacol Exp Ther 313:268-276.

Raehal KM, Lowery JJ, Ghamidipati CM, Paolino RM, Wang D, Sadee W, Bilsky EJ. (2005)  In vivo characterization of 6(beta)-naltrexol, an opioid ligand with less inverse agonist activity compared to naltrexone and naloxone in opioid dependent mice.  J Pharmacol Exp Ther 313:1150-1162.

Frank NY, Margaryan A, Schatton T, Huang Y, Waaga-Gasser AM, Gasser M, Sayegh MH, Sadee W, Frank MH. (2005) ABCB5-Medicated doxorubicin transport and chemoresistance in human malignant melanoma.  Cancer Res 65:4320-4333.

Wang D, Sun X, Bohn LM, Sadee W. (2005) Opioid receptor homo- and hetero- dimerization in living cells by quantitative bioluminescence resonance energy transfer.  Molec Pharmacol 67:2173-2184.

Huang Y, Dai Z, Barbacioru C, Sadee W. (2005) Cystine/glutamate transporter SLC7A11 in cancer chemosensitivity and -resistance.  Cancer Res 65:7446-7454.

Sadee W. (2005) Pharmacogenomics: Harbinger for the era of personalized medicine?  Molec Interventions 5:140-143.

Sadee W, Dai Z. (2005) Pharmacogenetics/genomics and personalized medicine.  Hum Mol Genet 14:R207-R214.

Wang D, Johnson AD, Papp A, Kroetz DL, Sadee W. (2005) Multidrug resistance polypeptide 1 (MDR1, ABCB1) Variant 3435C>T affects mRNA stability.  Pharmacogen Genomics 15:693-704.

Zhang Y, Wang D, Johnson AD, Papp AC, Sadee W. (2005) Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G.  J Biol Chem 280:32618-32624.