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Grant Details

Grant Number: 5R01CA161608-06 Interpret this number
Primary Investigator: Motsinger-Reif, Alison
Organization: North Carolina State University Raleigh
Project Title: Genetic Etiology of Cancer Drug Response
Fiscal Year: 2018
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Abstract

Abstract: Important progress continues to be made in the treatment of most common cancers, but therapeutic benefit remains difficult to predict and severe or fatal adverse events occur frequently. The Human Genome Project has fueled the notion that genetic information can produce effective and cost-efficient selection of therapies for individual patients, but validated genetic signatures that predict response to most chemotherapy regimens remain to be identified. Numerous genes potentially influence drug response, but current candidate-gene approaches are limited by the requirement of a priori knowledge about the genes involved and the moderate size of most clinical trials often limits the power of in vitro genome wide association studies (GWAS) for cancer pharmacogenomics discovery. In response to these limitations, we have undertaken a thorough, pharmacogenomic assessment of cytotoxic effect of the majority of FDA approved anti-cancer compounds using an ex vivo model system to determine the heritability of drug-induced cell killing to prioritize drugs for pharmacogenomic mapping. These results are an important first step, and while high heritability of a trait does not guarantee successful association mapping results, it represents an important first step and the results will be used to prioritize drugs with high heritabilities for genome-wide association mapping. In the current proposal, GWAS mapping of cytotoxic agents will be performed in a European American population, and then replication GWAS mapping will be performed in an East Asian population. In addition to discovering and validating genetic variants that predict drug response, the wealth of data collected will be used to dissect the underlying etiology of drug response traits, including assessing the relative contribution of genetic, environmental, and interaction components of variation. These results will provide crucial insight to prioritize genetic variants for follow-up in precious clinical population resources, and potentially reveal new insight into the overall etiology of drug responses.

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Publications

Gene set analysis methods: a systematic comparison.
Authors: Mathur R. , Rotroff D. , Ma J. , Shojaie A. , Motsinger-Reif A. .
Source: Biodata Mining, 2018; 11, p. 8.
EPub date: 2018-05-31 00:00:00.0.
PMID: 29881462
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An Introduction to Terminology and Methodology of Chemical Synergy-Perspectives from Across Disciplines.
Authors: Roell K.R. , Reif D.M. , Motsinger-Reif A.A. .
Source: Frontiers In Pharmacology, 2017; 8, p. 158.
EPub date: 2017-04-20 00:00:00.0.
PMID: 28473769
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Discordance Of Somatic Mutations Between Asian And Caucasian Patient Populations With Gastric Cancer
Authors: Jia F. , Teer J.K. , Knepper T.C. , Lee J.K. , Zhou H.H. , He Y.J. , McLeod H.L. .
Source: Molecular Diagnosis & Therapy, 2016-12-30 00:00:00.0; , .
PMID: 28039579
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The Pharmacogenomics Of Drug Resistance To Protein Kinase Inhibitors
Authors: Gillis N.K. , McLeod H.L. .
Source: Drug Resistance Updates : Reviews And Commentaries In Antimicrobial And Anticancer Chemotherapy, 2016 Sep; 28, p. 28-42.
PMID: 27620953
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Pharmgkb Summary: Succinylcholine Pathway, Pharmacokinetics/pharmacodynamics
Authors: Alvarellos M.L. , McDonagh E.M. , Patel S. , McLeod H.L. , Altman R.B. , Klein T.E. .
Source: Pharmacogenetics And Genomics, 2015 Dec; 25(12), p. 622-30.
PMID: 26398623
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Budget Impact Analysis Of Cyp2c19-guided Voriconazole Prophylaxis In Aml
Authors: Mason N.T. , Bell G.C. , Quilitz R.E. , Greene J.N. , McLeod H.L. .
Source: The Journal Of Antimicrobial Chemotherapy, 2015 Nov; 70(11), p. 3124-6.
PMID: 26233624
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Prediction Of Human Population Responses To Toxic Compounds By A Collaborative Competition
Authors: Eduati F. , Mangravite L.M. , Wang T. , Tang H. , Bare J.C. , Huang R. , Norman T. , Kellen M. , Menden M.P. , Yang J. , et al. .
Source: Nature Biotechnology, 2015 Sep; 33(9), p. 933-40.
PMID: 26258538
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Population-based In Vitro Hazard And Concentration-response Assessment Of Chemicals: The 1000 Genomes High-throughput Screening Study
Authors: Abdo N. , Xia M. , Brown C.C. , Kosyk O. , Huang R. , Sakamuru S. , Zhou Y.H. , Jack J.R. , Gallins P. , Xia K. , et al. .
Source: Environmental Health Perspectives, 2015 May; 123(5), p. 458-66.
PMID: 25622337
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Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance).
Authors: Patel J.N. , Jiang C. , Hertz D.L. , Mulkey F.A. , Owzar K. , Halabi S. , Ratain M.J. , Friedman P.N. , Small E.J. , Carducci M.A. , et al. .
Source: Cancer, 2015-04-01 00:00:00.0; 121(7), p. 1025-31.
EPub date: 2015-04-01 00:00:00.0.
PMID: 25417775
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An Investigation Of Gene-gene Interactions In Dose-response Studies With Bayesian Nonparametrics
Authors: Beam A.L. , Motsinger-Reif A.A. , Doyle J. .
Source: Biodata Mining, 2015; 8, p. 6.
PMID: 25691918
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Pharmacogenomic Assessment Of Mexican And Peruvian Populations
Authors: Marsh S. , King C.R. , Van Booven D.J. , Revollo J.Y. , Gilman R.H. , McLeod H.L. .
Source: Pharmacogenomics, 2015; 16(5), p. 441-8.
PMID: 25916516
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Evaluating The Role Of Admixture In Cancer Therapy Via In Vitro Drug Response And Multivariate Genome-wide Associations
Authors: Jack J. , Havener T.M. , McLeod H.L. , Motsinger-Reif A.A. , Foster M. .
Source: Pharmacogenomics, 2015; 16(13), p. 1451-63.
PMID: 26314407
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Beyond Ic50 S: Towards Robust Statistical Methods For In Vitro Association Studies
Authors: Beam A. , Motsinger-Reif A. .
Source: Journal Of Pharmacogenomics & Pharmacoproteomics, 2014-03-01 00:00:00.0; 5(1), p. 1000121.
PMID: 25110614
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Genome-wide Association And Pharmacological Profiling Of 29 Anticancer Agents Using Lymphoblastoid Cell Lines
Authors: Brown C.C. , Havener T.M. , Medina M.W. , Jack J.R. , Krauss R.M. , McLeod H.L. , Motsinger-Reif A.A. .
Source: Pharmacogenomics, 2014 Feb; 15(2), p. 137-46.
PMID: 24444404
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Application Of Next Generation Sequencing To Ceph Cell Lines To Discover Variants Associated With Fda Approved Chemotherapeutics
Authors: Hariani G.D. , Lam E.T. , Lam E.J. , Havener T. , Kwok P.Y. , McLeod H.L. , Wagner M.J. , Motsinger-Reif A.A. .
Source: Bmc Research Notes, 2014; 7, p. 360.
PMID: 24924344
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An Adaptive Permutation Approach For Genome-wide Association Study: Evaluation And Recommendations For Use
Authors: Che R. , Jack J.R. , Motsinger-Reif A.A. , Brown C.C. .
Source: Biodata Mining, 2014; 7, p. 9.
PMID: 24976866
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Lymphoblastoid Cell Lines Models Of Drug Response: Successes And Lessons From This Pharmacogenomic Model
Authors: Jack J. , Rotroff D. , Motsinger-Reif A. .
Source: Current Molecular Medicine, 2014; 14(7), p. 833-40.
PMID: 25109794
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Bayesian Neural Networks For Detecting Epistasis In Genetic Association Studies
Authors: Beam A.L. , Motsinger-Reif A. , Doyle J. .
Source: Bmc Bioinformatics, 2014; 15, p. 368.
PMID: 25413600
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Genome-wide association studies in pharmacogenomics: successes and lessons.
Authors: Motsinger-Reif A.A. , Jorgenson E. , Relling M.V. , Kroetz D.L. , Weinshilboum R. , Cox N.J. , Roden D.M. .
Source: Pharmacogenetics And Genomics, 2013 Aug; 23(8), p. 383-94.
PMID: 20639796
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Cancer Pharmacogenomics: Early Promise, But Concerted Effort Needed
Authors: McLeod H.L. .
Source: Science (new York, N.y.), 2013-03-29 00:00:00.0; 339(6127), p. 1563-6.
PMID: 23539596
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Risk score modeling of multiple gene to gene interactions using aggregated-multifactor dimensionality reduction.
Authors: Dai H. , Charnigo R.J. , Becker M.L. , Leeder J.S. , Motsinger-Reif A.A. .
Source: Biodata Mining, 2013-01-08 00:00:00.0; 6(1), p. 1.
EPub date: 2013-01-08 00:00:00.0.
PMID: 23294634
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Loss Of Power In Two-stage Residual-outcome Regression Analysis In Genetic Association Studies
Authors: Che R. , Motsinger-Reif A.A. , Brown C.C. .
Source: Genetic Epidemiology, 2012 Dec; 36(8), p. 890-4.
PMID: 22941732
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A Genome-wide Association Analysis Of Temozolomide Response Using Lymphoblastoid Cell Lines Shows A Clinically Relevant Association With Mgmt
Authors: Brown C.C. , Havener T.M. , Medina M.W. , Auman J.T. , Mangravite L.M. , Krauss R.M. , McLeod H.L. , Motsinger-Reif A.A. .
Source: Pharmacogenetics And Genomics, 2012 Nov; 22(11), p. 796-802.
PMID: 23047291
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Multivariate Methods And Software For Association Mapping In Dose-response Genome-wide Association Studies
Authors: Brown C.C. , Havener T.M. , Medina M.W. , Krauss R.M. , McLeod H.L. , Motsinger-Reif A.A. .
Source: Biodata Mining, 2012; 5(1), p. 21.
PMID: 23234571
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Genomic Profiling In Ceph Cell Lines Distinguishes Between The Camptothecins And Indenoisoquinolines
Authors: Watson,V.G. , Hardison,N.E. , Harris,T. , Motsinger-Reif,A. , McLeod,H.L. .
Source: Molecular Cancer Therapeutics, 2011 Oct; 10(10), p. 1839-45.
PMID: 21750217
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Pharmacogenomic Characterization Of Us Fda-approved Cytotoxic Drugs
Authors: Peters,E.J. , Motsinger-Reif,A. , Havener,T.M. , Everitt,L. , Hardison,N.E. , Watson,V.G. , Wagner,M. , Richards,K.L. , Province,M.A. , McLeod,H.L. .
Source: Pharmacogenomics, 2011 Oct; 12(10), p. 1407-15.
PMID: 22008047
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Identification And Replication Of Loci Involved In Camptothecin-induced Cytotoxicity Using Ceph Pedigrees
Authors: Watson,V.G. , Motsinger-Reif,A. , Hardison,N.E. , Peters,E.J. , Havener,T.M. , Everitt,L. , Auman,J.T. , Comins,D.L. , McLeod,H.L. .
Source: Plos One, 2011; 6(5), p. e17561.
PMID: 21573211
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Optimization Of Nonlinear Dose- And Concentration-response Models Utilizing Evolutionary Computation
Authors: Beam,A.L. , Motsinger-Reif,A.A. .
Source: Dose-response : A Publication Of International Hormesis Society, 2011; 9(3), p. 387-409.
PMID: 22013401
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A Comparison Of Association Methods For Cytotoxicity Mapping In Pharmacogenomics
Authors: Brown C. , Havener T.M. , Everitt L. , McLeod H. , Motsinger-Reif A.A. .
Source: Frontiers In Genetics, 2011; 2, p. 86.
PMID: 22303380
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