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Grant Details

Grant Number: 5R01CA132946-05 Interpret this number
Primary Investigator: Lamba, Jatinder
Organization: University Of Minnesota
Project Title: Pharmacogenetics of Ara-C Metabolic Pathway
Fiscal Year: 2012
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Abstract

The nucleoside analog cytarabine (ara-C) has been the mainstay of acute myeloid leukemia (AML) chemotherapy for more than 40 years and is one of the most important drugs used to induce remission in patients with AML. A number of studies suggest that the intracellular concentration of its active metabolite, ara-CTP, varies widely among patients and in turn is associated with variability in clinical response. The objective of the current proposal is to determine the molecular basis of this variation in intracellular ara-CTP levels by identifying and evaluating the pharmacogenomic effect of genetic polymorphisms in key genes in the ara-C metabolic pathway, with the long-term goal of explaining the variability observed in treatment response and toxicity profile among AML patients receiving ara-C chemotherapy. The hypothesis of this research is that genetic polymorphisms in key genes in the ara-C metabolic pathway -specifically: deoxycytidine kinase (DCK, a rate limiting activating enzyme); 5'nucleotidase (NT5C2), deoxycytidine deaminase (CDA), and deoxycytidylate deaminase (DCTD) (3 main inactivating enzymes); human equilibrative nucleoside transporter (hENT1/ SLC29A1, ara-C uptake transporter); and ribonucleotide reductase (enzyme regulating intracellular dCTP pools, and consisting of RRM1 and RRM2 subunits) -form the molecular basis of the inter-patient variability observed in intracellular ara-CTP concentration and sensitivity to ara-C. This hypothesis is based on the observations that the above mentioned candidate genes have been shown by various in vitro and in vivo studies to be associated with the clinical response and/or sensitivity to ara-C and demonstrate a wide inter- patient variability in their expression. The specific aims of the proposed research are: 1) To identify and functionally characterize the coding genetic polymorphisms in key ara-C metabolic pathway genes in lymphoblast samples with European (CEPH) or African (YRI) ancestry; 2) To identify and characterize regulatory cis-genetic polymorphisms associated with mRNA expression of the candidate genes; and 3) To determine the association of functionally significant genetic polymorphisms in the candidate genes with clinical phenotypes such as candidate gene expression and ara-C sensitivity in diagnostic blasts, and intracellular ara- CTP levels and the extent of DNA synthesis inhibition in post ara-C treatment leukemic blasts from pediatric AML patients enrolled in the St. Jude AML2002 protocol. The use of CEPH and YRI samples will allow us to use HAPMAP genotype data and to study any ethnic differences in genotype frequencies and in candidate gene expression. The results from this study would also be applicable to other nucleoside analogs such as gemcitabine, decitabine, clofarabine, etc. that are metabolized by the same pathway. Understanding genetic variation in the key candidate genes involved in the metabolism of ara-C will provide us 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 on efficacy. Relevance Statement: Acute myeloid leukemia (AML) is the second most common childhood leukemia and has the worst outcome of all major childhood cancers. Ara-C is the main drug used in AML chemotherapy but the cellular levels of its active form, ara-CTP, vary widely among patients and in turn are associated with variability in clinical response to ara-C treatment. The proposed research seeks to explain this variability by studying the inherited genetic variation in key genes involved in ara-C metabolism and may, in future, help to optimize ara-C dosing based on patient genetics.

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Publications

SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours.
Authors: Khatri A, Williams BW, Fisher J, Brundage RC, Gurvich VJ, Lis LG, Skubitz KM, Dudek AZ, Greeno EW, Kratzke RA, Lamba JK, Kirstein MN
Source: Br J Cancer, 2014 Jan 21;110(2), p. 304-12.
EPub date: 2013 Dec 3.
PMID: 24300978
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RRM1 and RRM2 pharmacogenetics: association with phenotypes in HapMap cell lines and acute myeloid leukemia patients.
Authors: Cao X, Mitra AK, Pounds S, Crews KR, Gandhi V, Plunkett W, Dolan ME, Hartford C, Raimondi S, Campana D, Downing J, Rubnitz JE, Ribeiro RC, Lamba JK
Source: Pharmacogenomics, 2013 Sep;14(12), p. 1449-66.
PMID: 24024897
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Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients.
Authors: Gamazon ER, Lamba JK, Pounds S, Stark AL, Wheeler HE, Cao X, Im HK, Mitra AK, Rubnitz JE, Ribeiro RC, Raimondi S, Campana D, Crews KR, Wong SS, Welsh M, Hulur I, Gorsic L, Hartford CM, Zhang W, Cox NJ, Dolan ME
Source: Blood, 2013 May 23;121(21), p. 4366-76.
EPub date: 2013 Mar 28.
PMID: 23538338
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Clinical significance of CD33 nonsynonymous single-nucleotide polymorphisms in pediatric patients with acute myeloid leukemia treated with gemtuzumab-ozogamicin-containing chemotherapy.
Authors: Mortland L, Alonzo TA, Walter RB, Gerbing RB, Mitra AK, Pollard JA, Loken MR, Hirsch B, Raimondi S, Franklin J, Pounds S, Cao X, Rubnitz JE, Ribeiro RC, Gamis A, Meshinchi S, Lamba JK
Source: Clin Cancer Res, 2013 Mar 15;19(6), p. 1620-7.
EPub date: 2013 Feb 26.
PMID: 23444229
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Valproic acid pathway: pharmacokinetics and pharmacodynamics.
Authors: Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, Altman RB, Klein TE
Source: Pharmacogenet Genomics, 2013 Apr;23(4), p. 236-41.
PMID: 23407051
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Assessment of healthcare students' views on pharmacogenomics at the University of Minnesota.
Authors: Moen M, Lamba J
Source: Pharmacogenomics, 2012 Oct;13(13), p. 1537-45.
PMID: 23057552
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PharmGKB summary: zidovudine pathway.
Authors: Ghodke Y, Anderson PL, Sangkuhl K, Lamba J, Altman RB, Klein TE
Source: Pharmacogenet Genomics, 2012 Dec;22(12), p. 891-4.
PMID: 22960662
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Pathway-based pharmacogenomics of gemcitabine pharmacokinetics in patients with solid tumors.
Authors: Mitra AK, Kirstein MN, Khatri A, Skubitz KM, Dudek AZ, Greeno EW, Kratzke RA, Lamba JK
Source: Pharmacogenomics, 2012 Jul;13(9), p. 1009-21.
PMID: 22838949
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Pharmacogenomics of cytarabine in childhood leukemia.
Authors: Lamba JK
Source: Pharmacogenomics, 2011 Dec;12(12), p. 1629-32.
PMID: 22118048
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Genetic variants in cytosolic 5'-nucleotidase II are associated with its expression and cytarabine sensitivity in HapMap cell lines and in patients with acute myeloid leukemia.
Authors: Mitra AK, Crews KR, Pounds S, Cao X, Feldberg T, Ghodke Y, Gandhi V, Plunkett W, Dolan ME, Hartford C, Raimondi S, Campana D, Downing J, Rubnitz JE, Ribeiro RC, Lamba JK
Source: J Pharmacol Exp Ther, 2011 Oct;339(1), p. 9-23.
EPub date: 2011 Jun 28.
PMID: 21712425
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Impact of genetic variation in FKBP5 on clinical response in pediatric acute myeloid leukemia patients: a pilot study.
Authors: Mitra AK, Crews K, Pounds S, Cao X, Downing JR, Raimondi S, Campana D, Ribeiro RC, Rubnitz JE, Lamba JK
Source: Leukemia, 2011 Aug;25(8), p. 1354-6.
EPub date: 2011 Apr 12.
PMID: 21483441
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Identification of predictive markers of cytarabine response in AML by integrative analysis of gene-expression profiles with multiple phenotypes.
Authors: Lamba JK, Crews KR, Pounds SB, Cao X, Gandhi V, Plunkett W, Razzouk BI, Lamba V, Baker SD, Raimondi SC, Campana D, Pui CH, Downing JR, Rubnitz JE, Ribeiro RC
Source: Pharmacogenomics, 2011 Mar;12(3), p. 327-39.
PMID: 21449673
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The emerging role of electronic medical records in pharmacogenomics.
Authors: Wilke RA, Xu H, Denny JC, Roden DM, Krauss RM, McCarty CA, Davis RL, Skaar T, Lamba J, Savova G
Source: Clin Pharmacol Ther, 2011 Mar;89(3), p. 379-86.
EPub date: 2011 Jan 19.
PMID: 21248726
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Genetic factors influencing cytarabine therapy.
Authors: Lamba JK
Source: Pharmacogenomics, 2009 Oct;10(10), p. 1657-74.
PMID: 19842938
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PROMISE: a tool to identify genomic features with a specific biologically interesting pattern of associations with multiple endpoint variables.
Authors: Pounds S, Cheng C, Cao X, Crews KR, Plunkett W, Gandhi V, Rubnitz J, Ribeiro RC, Downing JR, Lamba J
Source: Bioinformatics, 2009 Aug 15;25(16), p. 2013-9.
EPub date: 2009 Jun 15.
PMID: 19528086
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Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity.
Authors: Hartford CM, Duan S, Delaney SM, Mi S, Kistner EO, Lamba JK, Huang RS, Dolan ME
Source: Blood, 2009 Mar 5;113(10), p. 2145-53.
EPub date: 2008 Dec 24.
PMID: 19109566
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Reference alignment of SNP microarray signals for copy number analysis of tumors.
Authors: Pounds S, Cheng C, Mullighan C, Raimondi SC, Shurtleff S, Downing JR
Source: Bioinformatics, 2009 Feb 1;25(3), p. 315-21.
EPub date: 2008 Dec 3.
PMID: 19052058
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