Jatinder Lamba, Ph.D., M.Sc.
Experimental and Clinical Pharmacology
University of Minnesota Institute of Human Genetics
Zoology, Botany, Chemistry, Panjab University, Chandigarh, India, 1992
Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India, 1994
“Pharmacogenetics of CYP2C19 in North Indians,” Postgraduate Institute of Medical Education and Research, Chandigarh, India, 2000
University of Minnesota
College of Pharmacy
Department of Experimental and Clinical Pharmacology
7-115 Weaver-Densford Hall
308 Harvard St. SE
Minneapolis, MN 55455
→ Learn more about Dr. Lamba's work by reading International Innovation-Healthcare's "Paths to Precise Prescriptions" (PDF)
2000- 2006, Postdoctoral Research Associate, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
2006- 2008, Research Associate, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
July 2008 – Present, Assistant professor, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota
RESEARCH FOCUS AREAS:
Pharmacogenomics of Anticancer Drugs: Includes pathway directed pharmacogenomics approach to study inter-patient variation in drug response to chemotherapeutic agents as nucleoside analogs, platinating agents (funded by Minnesota state partnership funds) monoclonal antibodies etc.
One of the main ongoing projects funded by NCI is focused on pharmacogenomics of cytarabine in childhood leukemia. Cytarabine is mainstay of AML chemotherapy, it itself is inactive and requires activation inside the cell by multiple phosphorylation steps.An uptake transporter hENT1 is crucial for ara-C uptake into the cell where it is, ara-C phosphorylation by deoxycytidine kinase (DCK) is the rate-limiting step in ara-C activation . The resulting ara-C monophosphate (ara-CMP) is then further phosphorylated by pyrimidine kinases to the active 5’-triphosphate derivative, ara-CTP. Conversely, the enzyme 5’-nucleotidase (NT5C2) can dephosphorylate ara-CMP back to ara-C, while ara-C and ara-CMP can both be converted into the inactive forms, ara-U or ara-UMP, by the action of the enzymes cytidine deaminase (CDA) and deoxycytidylate deaminase (DCTD), respectively. DNA incorporation of ara-CTP in place of deoxycytidine triphosphate (dCTP) results in chain termination, blocking DNA and RNA synthesis and causing leukemic cell death, which in turn is associated with therapeutic response of ara-C. Thus genetic variation in key genes in the ara-C metabolic pathway can influence inter-patient variability in intracellular ara-CTP concentrations and sensitivity to ara-C. Our lab This NCI funded project focuses on understanding genetic variants in the key candidate genes involved in the metabolic activation of ara-C, as well as pharmacodynamic targets of ara-C, providing an opportunity to identify patients at increased risk of adverse reactions or decreased likelihood of response, based upon their genetic profile, which in future could help in dose optimization to reduce drug toxicity without compromising efficacy. The pharmacogenetic studies on ara-C would also be equally applicable to other nucleoside analogs such as gemcitabine, decitabine, clofarabine, etc. that are metabolized by the same pathway.
Pharmacogenomics of drug metabolism: This collaborative project with Dr. Vishal Lamba involves understanding factors contributing to inter-individual differences in drug metabolism.
Pathway Driven Pharmacogenomics, University of Minnesota Alliance (PUMA)
PUMA is a coordinated effort by a group of University of Minnesota researchers with expertise in multiple disciplines to advance understanding of the role played by pharmacogenomics in explaining the inter-individual variation observed in therapeutic response and outcome and treatment related toxicity. The long term goal is to move pharmacogenetic testing into the clinical setting to improve safety and efficacy of drug therapy. PUMA is an affiliate member of the national organization Pharmacogenetics Research Network (PGRN).
The overall objective and goal of my research work is to identify comprehensive panels of potentially functional and clinically relevant genetic polymorphisms in pharmacokinetic (ADME) and pharmacodynamic pathways important for the treatment in childhood leukemia. My long term goal is to move pharmacogenetic testing into the clinical setting to improve safety and efficacy of drug therapy. To accomplish this, we have developed a focused, productive, and independent program in pharmacogenomics research. My research spans preclinical basic research comprising the discovery phase to translational/clinical phase in patient populations. The former focuses on use of cell lines from different ethnic groups that are part of international HAPMAP project as a model for pharmacogenomic discovery. My lab has established 180 HAPMAP cell lines in my lab that are also available to other investigators for collaborative projects. The translational phase involves patient oriented research to determine the clinical impact of basic research/pharmacogenomic findings. We have successful collaborations with clinical investigators in hematology-oncology at St. Jude Children’s Research Hospital, Masonic Cancer Center at UMN, Fred-Hutchinson Cancer Center, Mayo Clinic as well as with multiple cooperative groups such as Children’s Oncology Group (COG) and Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL).
1. Jatinder Lamba*, Kristine R. Crews, Stanley B Pounds, Xueyuan Cao, Varsha Gandhi, William Plunkett, Bassem Razzouk, Vishal Lamba, Fred Behm, Shayrn Baker, Susana C Raimondi, Dario Campana, Ching-Hon Pui, James Downing, Jeffrey Rubnitz, and Raul C Ribeiro. Integrative analysis of genome-wide gene expression profiles with multiple pharmacological and clinical phenotypes predicts cytarabine response in childhood acute myeloid leukemia. (In Press Pharmacogenomics)
2. Wilke, R, Hua x, Denny J, Roden D, McCarty C, Davis R, Skaar T, Lamba J, Savova, G. The Emerging role of Electronic Medical Records in Pharmacogenomics (In Press: Clinical Pharmacology and Therapeutics)
3. Thorn CF, Lamba JK, Lamba V, Klein TE, Altman RB. PharmGKB summary: very important pharmacogene information for CYP2B6. Pharmacogenet Genomics. 2010 Aug; 20(8):520-3.
4. Chaudhary AS, Urban TJ, Lamba JK, Birnbaum AK, Remmel RP, Subramanian M, Strom S, You JH, Kasperaviciute D, Catarino CB, Radtke RA, Sisodiya SM, Goldstein DB, Schuetz EG. CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin auto-induction of clearance and maintenance dose. J Pharmacol Exp Ther. 2010;332(2):599-611.
5. Lamba JK*. Genetic factors influencing cytarabine therapy. Pharmacogenomics. 2009 Oct;10(10):1657-74.
6. Pounds S, Cheng C, Cao X, Crews KR, Plunkett W, Gandhi V, Rubnitz J, Ribeiro RC, Downing JR, Lamba J. PROMISE: a tool to identify genomic features with a specific biologically interesting pattern of associations with multiple endpoint variables. Bioinformatics, 2009:25 (16):2013-9.
7. Hartford, CM, Duan S, Delaney SM, Mi S, Kistner EO, Lamba JK, Huang RS, Dolan ME. Population specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity. Blood. 2009 Mar 5;113(10):2145-53.
8. Lamba JK*, Pounds S, Cao X, Downing JR, Campana D, Ribeiro RC, Pui C-H and Rubnitz J. Coding polymorphisms in CD33 and response to gemtuzumab ozogamicin in pediatric patients with AML: a pilot study. Leukemia 2009 ;23(2):402-4.
9. Roberts PJ, Rollins KD, Kashuba AD, Paine MF, Nelsen AC, Williams EE, Moran C, Lamba JK, Schuetz EG, Hawke RL. The Influence of CYP3A5 Genotype on Dexamethasone Induction of CYP3A Activity in African Americans. Drug Metab Dispos. 2008 May 19.
10. Poonkuzhali B, Lamba J, Strom S, Sparreboom A, Thummel K, Watkins P, Schuetz E.Association of breast cancer resistance protein/ABCG2 phenotypes and novel promoter and intron 1 single nucleotide polymorphisms. Drug Metab Dispos. 2008 Apr;36(4):780-95.
11. Lamba JK* Pharmacogenetics of the constitutive androstane receptor. Pharmacogenomics. 2008 Jan;9(1):71-83.
12. Isoherranen N, Ludington SR, Givens RC, Lamba JK, Pusek SN, Dees EC, Blough DK, Iwanaga K, Hawke RL, Schuetz . The influence of CYP3A5 expression on the extent of hepatic CYP3A inhibition is substrate-dependent: an in vitro-in vivo evaluation. Drug Metab Dispos. 2008 Jan;36(1):146-54.
13. Lamba J, Lamba V, Strom S, Venkataramanan R, Schuetz E. Novel SNPs in the Promoter and Intron 1 of Human PXR/NR1I2 and Their Association with CYP3A4 Expression. Drug Metab Dispos. 2008 Jan;36(1):169-81.
14. Altman RB, Benowitz N, Gurwitz D, Lunshof J, Relling M, Lamba J, Wieben E, Mooney S, Giacomini K, Weiss S, Johnson JA, McLeod H, Flockhart D, Weinshilboum R, Shuldiner AR, Roden D, Krauss RM, Ratain M. Genetic nondiscrimination legislation: a critical prerequisite for pharmacogenomics data sharing. Pharmacogenomics. 2007 May;8(5):519
15. Vyas PM, Roychowdhury S, Khan FD, Prisinzano TE, Lamba JK, Schuetz EG, Blaisdell J, Goldstein JA, Munson KL, Hines RN, Svensson C. Enzyme-mediated protein haptenation of dapsone and sulfamethoxaozle in human keratinocytes - 1. Expression and role of cytochromes P450. J Pharmacol Exp Ther. 2006 Oct;319(1):488-96,2006.
16. Lamba JK*, Crews K, Pounds S, Schuetz E, Gresham J, Gandhi V, Plunkett W, Rubnitz J, Ribeiro R. Pharmacogenetics of Deoxycytidine kinase: identification and characterization of novel genetic variants. J Pharmacol Exp Ther. 2007 Dec;323(3):935-45.
17. Anderson PL, Lamba J, Aquilante CL, Schuetz E, Fletcher CV. Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: A pilot study. J Acquir Immune Defic Syndr. 42(4):441-449, 2006.
18. Lamba JK, Chen X, Lan L-B, Kim JW, Relling MV, Kazuto K, Strom S, Sun D, Schuetz JD, Schuetz EG. Analysis of CYP3A copy number variations in DNA from normal and neoplastic human liver and in ethnically diverse populations. Pharmacogenetics and Genomics 16:415-427, 2006.
19. Lamba JK, Lamba V, Strom S, Schuetz EG. Effect of MDR polymorphism on CYP3A4 inductive phenotype. Clin Pharmacol Ther 79:325-338, 2006.
20. Song P, Lamba JK, Zhang L, Schuetz E, Shukla N, Meibohm B, Yates CR. G2677T and C3435T genotype and haplotype are associated with hepatic ABCB1 (MDR1) expression. J Clin Pharmacol 46:373-379, 2006.
21. Mouly SJ, Matheny C, Paine MF, Smith G, Lamba J, Lamba V, Pusek SN, Schuetz EG, Stewart PW, Watkins PB. Variation in oral clearance of saquinavir is predicted by CYP3A5*1 genotype but not by enterocyte content of cytochrome P450 3A5. Clin Pharmacol Ther 78:605-618, 2005.
22. Zheng H, Schuetz EG, Zeevi, A, Zhang J, McCurry K, webber S, Iacono A, Lamba J, Burckart G. Sequential analysis of tacrolimus dosing in adult lung transplant patients with ABCB1 haplotypes. J Clin Pharmacol 45(4):404-410, 2005.
23. Lamba JK, Lamba V, Schuetz EG. Genetic Variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. Curr Drug Metabolism 6:369-383, 2005.
24. Zheng HX, Zeevi A, McCurry K, Schuetz E, Webber S, Ristich J, Zhang J, Iacono A, Dauber J, McDade K, Zaldonis D, Lamba J, Burckart GJ. The impact of pharmacogenomic factors on acute persistent rejection in adult lung transplant patients. Transpl Immunol 14(1):37-42, 2005
25. Lamba JK, Lamba V, Yasuda K, Thompson E, DiRienzo A, Strom S, Schuetz EG. Expression of Constitutive androstane receptor splice variants in human tissues and their functional consequences. J Pharmacol Exp Ther (311)811-821, 2004.
26. Zheng HX, Webber SA, Zeevi A, Schuetz E, Zhang J, Lamba J, Boyle GJ, Wilson JW, Burckart GJ. The impact of pharmacogenomic factors on steroid dependency in pediatric heart transplant patients using logistic regression analysis. Pediatr Transplant 8(6):551-557, 2004.
27. Schuetz EG, Relling MV, Kishi S, Yang W, Das S, Chen P, Cook EH, Rosner GL, Pui CH, Blanco JG, Edick MJ, Hancock ML, Winick NJ, Dervieux T, Amylon MD, Bash RO, Behm FG, Camitta BM, Raimondi SC, Goh BC, Lee SC, Wang LZ, Fan L, Guo JY, Lamba J, Lim R, Lim HL, Ong AB, Lee HS, Kuehl P, Zhang J, Lin Y, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS. PharmGKB update: II. CYP3A5, cytochrome P450, family 3, subfamily A, polypeptide 5. Pharmacol Rev 56(2):159, 2004.
28. Lamba V, Yasuda K, Lamba J, Assem M, Davila J, Strom S, Schuetz E. PXR (NR1I2): Splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators. Toxicol Appl Pharmacol (199)251-265, 2004.
29. Zheng H, Zeevi A, Schuetz E, Lamba J, McCurry K, Griffith BP, Webber S, Ristich J, Dauber J, Iacono A, Grgurich W, Zaldonis D, McDade K, Zhang J, Burckart GJ. Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. J Clin Pharmacol 44(2):135-140, 2004.
30. Zheng H, Zeevi A, McCurry K, Schuetz E, Webber S, Ristich J, Zhang J, Iacono A, Dauber J, McDade K, Zaldonis D, Lamba J, Burckart G. MDR1 EXON26 genotype predicts treatment-resistant rejection in lung transplant patients as assessed by logistic regression analysis. Hum Immunol 64(10 Suppl):S42, 2003.
31. Lamba V, Lamba J, Yasuda K, Strom S, Davila J, Hancock ML, Fackenthal JD, Rogan PK, Ring B, Wrighton SA, Schuetz EG. Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J Pharmacol Exp Ther 307(3):906-922, 2003.
32. Givens RC, Lin YS, Dowling AL, Thummel KE, Lamba JK, Schuetz EG, Stewart PW, Watkins PB. CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. J Appl Physiol 95(3):1297-1300, 2003.
33. Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Bowman P, Boyle G, Law Y, Miller S, Lamba J, Burckart GJ. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR gene polymorphisms. Am J Transplant 3(4):477-483, 2003.
34. Kadlubar FF, Berkowitz GS, Delongchamp RR, Wang C, Green BL, Tang G, Lamba J, Schuetz E, Wolff MS. CYP3A4*1B variant is related to the onset of puberty, a known risk factor for the development of breast cancer. Cancer Epidemiol Biomarkers Prev 12(4):327-331, 2003.
35. Zamber CP, Lamba JK, Yasuda K, Farnum J, Thummel K, Schuetz JD, Schuetz EG. Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. Pharmacogenetics 13(1):19-28, 2003.
36. Lamba JK, Adachi M, Sun D, Tammur J, Schuetz EG, Allikmets R, Schuetz JD. Nonsense mediated decay down-regulates conserved alternatively spliced ABCC4 transcripts bearing nonsense codons. Hum Mol Genet 12(2):99-109, 2003.
37. Goh BC, Lee SC, Wang LZ, Fan L, Guo JY, Lamba J, Schuetz E, Lim R, Lim HL, Ong AB, Lee HS. Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J Clin Oncol 20(17):3683-3690, 2002.
38. Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Lamba J, Bowman P, Burckart GJ. The MDR1 polymorphisms at exons 21 and 26 predict steroid weaning in pediatric heart transplant patients. Hum Immunol 63(9):765-770, 2002.
39. Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 54(10):1271-1294, 2002.
40. Lin YS, Dowling AL, Quigley SD, Farin FM, Zhang J, Lamba J, Schuetz EG, Thummel KE. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol 62(1):162-172, 2002.
41. Lamba JK, Lin YS, Thummel K, Daly A, Watkins PB, Strom S, Zhang J, Schuetz EG. Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. Pharmacogenetics 12(2):121-132, 2002.
42. Lamba JK, Dhiman RK, Singh R, Kohli KK. Correlation between omeprazole hydroxylase and CYP2C19 genotype in North Indians. Eur J Clin Pharmacol 57(9):649-652, 2001.
43. Schuetz EG, Strom S, Yasuda K, Lecureur V, Assem M, Brimer C, Lamba J, Kim RB, Ramachandran V, Komoroski BJ, Venkataramanan R, Cai H, Sinal CJ, Gonzalez FJ, Schuetz JD. Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem 276(42):39411-39418, 2001.
44. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27(4):383-391, 2001.
45. Lamba JK, Dhiman RK, Kohli KK. CYP2C19 genetic mutations in North Indians. Clin Pharmacol Ther 68(3):328-335, 2000.
46. Lamba V, Lamba JK, Dilawari JB, Kohli KK. Genetic polymorphism of CYP2D6 in North Indian subjects. Eur J Clin Pharmacol 54(9-10):787-791, 1998.
47. Lamba JK, Dhiman RK, Kohli KK. Genetic polymorphism of the hepatic cytochrome P450 2C19 in north Indian subjects. Clin Pharmacol Ther 63(4):422-427, 1998.
48. Lamba JK and Schuetz E. Chapter 9. Genetic variants of xenobiotic Receptors and their implications in drug metabolism and pharmacogenetics. Book Title: Nuclear receptors in Drug Metabolism.