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
Pharmacogenetics-Pharmacogenomics of drug receptors and transporters, Genetics of drug addiction, other CNS disorders, cardiovascular diseases, and cancer. Chemogenomics and anticancer drug discovery.
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.
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.
Duan W, Gao L, Zhao W, Leon M, Sadee W, Webb A, Resnick K, Wu X, Ramaswamy B, Cohn De, Shapiro C, Andreassen PR, Otterson GA, Villalona-Calero MA. (2012) Assessment of FANCD2 nuclear foci formation in paraffin-embedded tumors: a potential patient-enrichment strategy for treatment with DNA interstrand crosslinking agents. Transl Res doi:pii: S1931-5244(12)00330-1. 10.1016/j.trsl.2012.09.003. [Epub ahead of print].
Azad Ak, Sadee W, Schlesinger LS. (2012) Innate immune gene polymorphisms in tuberculosis. Infect Immun 80:3343-3359.
Kitzmiller JP, Embi PJ, Manickam K, Sweet KM, Phelps MA, Jackson RD, Marsh CB, Sadee W. (2012) Program in pharmacogenomics at the Ohio State University Medical Center. Pharmacogenomics 13:751-756.
Papp AC, Pinsonneault JK, Wang D, Newman LC, Gong Y, Johnson JA, Pepine CJ, Kumari M, Hingorani AD, Talmud PJ, Shah S, Humphries SE, Sadee W. (2012) Cholesteryl ester transfer protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk. PLos One 7:e31930.
Barrie ES, Smith RM, Sanford JC, Sadee W. (2012). mRNA transcript diversity creates new opportunities for pharmacological intervention. Mol Pharmacol 81:620-630.
Yancey-Wrona J, Dallaire B, Bilsky E, Bath, B, Burkart J, Webster L, Magiera D, Yang X, Phelps M, Sadee W. (2011) 6ß-Naltrexol, a peripherally selective opioid antagonist that inhibits morphine-induced slowing of gastrointestinal transit: an exploratory study. Pain Med 12:1727-1737.
Wang D, Para MF, Koleta SL, Sadee W. Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity. Pharmacogenet Genomics 21:652-664.
Sadee W. (2011) Pharmacogenomic biomarkers: validation needed for both the molecular genetic mechanism and clinical effect. Pharmacogenomics 12:675-680.
Sadee W. (2011) Genomics and personalized medicine. Int J Pharm [Epub ahead of print].
Pinsonneault JK, Han DD, Burdick KE, Kataki M, Bertolino A, Malhotra AK, Gu HH, Sadee W. (2011) Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacology 36:1644-1655.
Kitzmiller JP, Groen DK, Phelps MA, Sadee W. (2011) Pharmacogenomic testing: relevance in medical practice: why drugs work in some patients but not in others. Cleve Clin J Med 78:243-257.
Sadee W, Wang D, Papp AC, Pinsonneault JK, Smith RM, Moyer RA, Johnson AD. (2011) Pharmacogenomics of the RNA world: structural RNA poloymorphisms in drug therapy. Clin Pharmacol Ther 89:355:365.
Moyer RA, Wang D, Papp AC, Smith RM, Duque L, Mash DC, Sadee W. (2011) Iontronic polymorphisms affecting alternative splicing of human dopamine D2 receptor are associated with cocaine abuse. Neuropsychopharmacology 36;753-762.
Smith RM, Sadee W. (2011) Synaptic signaling and aberrant RNA splicing in autism spectrum disorders. Front Synaptic Neurosci 26;3:1.
Smith RM, Alachkar H, Papp AC, Wang D, Mash DC, Wang JC, Bierut LJ, Sadee W. (2011) Nicotinic a5 receptor subunit mRNA expression is associated with distant 5' upstream polymorphisms. Eur J Hum Genet 19:76-83.
Ni W, Ji J, Dai Z, Papp A, Johnson AJ, Ahn S, Farley KL, LIn TS, Dalton JT, Li X, Jarjoura D, Byrd JC, Sadee W, Grever MR, Phelps MA. (2010) Flavopiridol pharmacogenetics: clinical and functional evidence for the role of SLCO1B1/OATP1B1 in flavopiridol disposition. PLoS One 5:e13792.
Atkinson EJ, McDonnell SK, Witte JS, Crawford DC, Fan Y, Fridley B, Li D, Li L, Rodin A, Sadee W, Speed T, Weiss ST, Yang J, Yerges L, Schaid DJ. (2010) Conference scene: lessons learned from the 5th statistical analysis workshop of the pharmacogenetics research network. Pharmacogenomics 11:297-303.
Wang H, Karikomi M, Naidu S, Rajmohan R, Caserta E, Chen HZ, Rawahneh M, Moffitt J, Stephens JA, Fernandez SA, Weinstein M, Wang D, Sadee W, La Perle K, Stromberg P, Rosol TJ, Eng C, Ostrowski MC, Leone G. (2010) Allele-specific tumor spectrum in pten knockin mice. Proc Natl Acad Sci USA 107:5142-5147.
Wang D, Guo Y, Wrighton SA,Cooke GE, Sadee W. (2010) Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J Apr 13 [Epub ahead of print].
Yancey-Wrona JE, Raymond TJ, Mercer HK, Sadee W, Bilsky EJ. (2009) 6beta-naltrexol preferentially antagonizes opioid effects on gastrointestinal transit compared to antinociception in mice. Life Sci 85:413-420.
Bekaii-Saab T, Markowitz J, Prescott N, Sadee W, Heerema N, Wei L, Dia Z, Papp A, Campbell A, Culler K, Balint C, O'Neil B, Lee RM, Zalupski M, Dancey J, Chen H, Grever M, Eng C, Villalona-Calero M. (2009) A multi-institutional phase II study of the efficacy and tolerability of a lapatinib in patients with advanced hepatocellular carcinomas. Clin Cancer Res 15:5895-5901.
Roe BE, Tilley MR, Gu HH, Beversdorf DQ, Sadee W, Haab TC, Papp AC. (2009) Financial and psychological risk attitudes associated with two single nucleotide polymorphisms in the nicotine receptor (CHRNA4) gene. PLoS 4:36704.
Pham AN, Wang J, Fang J, Gao X, Zhang Y, Blower PE, Sadee W, Huang Y. (2009) Pharmacogenomics approach reveals MRP1 (ABCC1)-mediated resistance to geldanamycins. Pharm Res 26:936-945.
Bertolino A, Fazio L, Di Giorgio A, Blasi G, Romano R, Taurisano P, Caforio G, Sinibaldi L, Ursini G, Popolizio T, Tirotta E, Papp A, Dallapiccola B, Borrelli E, Sadee W. (2009) Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans. J Neurosci 29:1224-1234.
Bertolino A, Fazio L, Caforio G, Blasi G, Rampino A, Romano R, Di Giorgio A, Taurisano P, Papp A, Pinsonneault J, Wang D, Nardini M, Popolizio T, Sadee W. (2009) Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. Brain 132(pt2):417-425.
John AD, Gong Y, Wang D, Langaee TY, Shin J, Cooper-DeHoff RM, Schork NJ, Binkley P, Pepine CJ, Johnson JA, Sadee W. (2009) Promoter polymorphisms in ACE (angiotensin-I converting enzyme) associated with clinical outcomes in hypertension. Clin Pharmacol Ther 85:336-44.
Alachkar H, Kataki M, Scharre DW, Papp A, Sadee W. (2008) Allelic mRNA expression of sortilin-1 (SORL 1) mRNA in Alzheimer's autopsy brain tissue. Neurosci Lett 448:120-124.
Xu LH, Zheng H, Sedmak DD, Sadee W. (2008) The reemerging concept of personalized health care. Personalized Med 5:457-469.
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.
Johnson AD, Zhang Y, Papp AC, Pinsonneault JK, Lim J-E, Saffen D, Daiz Z, Wang D, Sadee W. (2008) Polymorphisms affecting gene transcription and mRNA processing in pharmacogenetic candidate genes: detection through allelic imbalance in human target tissues. Pharmacogen Genom 18:781-791
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.
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.
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.