title: An Integrative Approach to Precision Cancer Medicine Using Patient-Derived Xenografts.
abstract: Cancer is a heterogeneous disease caused by diverse genomic alterations in oncogenes and tumor suppressor genes. Despite recent advances in high-throughput sequencing technologies and development of targeted therapies, novel cancer drug development is limited due to the high attrition rate from clinical studies. Patient-derived xenografts (PDX), which are established by the transfer of patient tumors into immunodeficient mice, serve as a platform for co-clinical trials by enabling the integration of clinical data, genomic profiles, and drug responsiveness data to determine precisely targeted therapies. PDX models retain many of the key characteristics of patients' tumors including histology, genomic signature, cellular heterogeneity, and drug responsiveness. These models can also be applied to the development of biomarkers for drug responsiveness and personalized drug selection. This review summarizes our current knowledge of this field, including methodologic aspects, applications in drug development, challenges and limitations, and utilization for precision cancer medicine.
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Sung-Yup
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Wonyoung
authors.initials: W
authors.lastname: Kang
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Jee Yun
authors.initials: JY
authors.lastname: Han
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Seoyeon
authors.initials: S
authors.lastname: Min
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Jinjoo
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Ahra
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea ; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
authors.forename: Jee Young
authors.initials: JY
authors.lastname: Kwon
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea ; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea ; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
authors.forename: Hansoo
authors.initials: H
authors.lastname: Park
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D006085:Graft Survival; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods*; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D057285:Precision Medicine; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D000077146:Irinotecan; D002166:Camptothecin
keywords: cancer drug development; cancer genomics; patient-derived xenografts; precision medicine
references.citation: Cancer Cell. 2010 Jan 19;17(1):98-110
references.pmid: 20129251
references.citation: Breast Cancer Res. 2013 Jan 22;15(1):201
references.pmid: 23339383
references.citation: Neuro Oncol. 2012 May;14(5):574-83
references.pmid: 22459127
references.citation: Nat Genet. 2013 Oct;45(10):1113-20
references.pmid: 24071849
references.citation: Clin Cancer Res. 2010 Apr 15;16(8):2352-62
references.pmid: 20371695
references.citation: Oncogene. 2016 Jan 21;35(3):290-300
references.pmid: 25893296
references.citation: Nat Med. 2011 Oct 23;17(11):1514-20
references.pmid: 22019887
references.citation: Mol Carcinog. 2012 Sep;51(9):746-53
references.pmid: 22125164
references.citation: Int J Cancer. 2008 Nov 1;123(9):2222-7
references.pmid: 18688847
references.citation: Adv Drug Deliv Rev. 2014 Dec 15;79-80:222-37
references.pmid: 25305336
references.citation: Neoplasia. 2013 Oct;15(10):1138-50
references.pmid: 24204193
references.citation: Mol Oncol. 2013 Aug;7(4):776-90
references.pmid: 23607916
references.citation: Cancer Res. 2013 Aug 1;73(15):4885-97
references.pmid: 23737486
references.citation: Nat Protoc. 2007;2(2):247-50
references.pmid: 17406581
references.citation: Sci Rep. 2015 Mar 30;5:9447
references.pmid: 25819560
references.citation: Front Oncol. 2013 Dec 04;3:295
references.pmid: 24363999
references.citation: Clin Cancer Res. 2012 Oct 1;18(19):5160-2
references.pmid: 22912394
references.citation: J Clin Oncol. 2010 Dec 10;28(35):5219-28
references.pmid: 20975063
references.citation: J Clin Oncol. 2011 Dec 1;29(34):4548-54
references.pmid: 21969517
references.citation: Cancer Discov. 2011 Nov;1(6):508-23
references.pmid: 22586653
references.citation: Nat Biotechnol. 2014 Apr;32(4):364-72
references.pmid: 24633240
references.citation: Adv Cancer Res. 2007;96:191-212
references.pmid: 17161681
references.citation: J Clin Oncol. 2013 May 20;31(15):1803-5
references.pmid: 23589545
references.citation: Cell Rep. 2013 Jan 31;3(1):260-73
references.pmid: 23333277
references.citation: Cancer Res. 2014 Feb 15;74(4):1272-83
references.pmid: 24356420
references.citation: Curr Opin Genet Dev. 2015 Feb;30:42-8
references.pmid: 25796043
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16281-6
references.pmid: 19805294
references.citation: Nature. 2011 Jun 29;474(7353):609-15
references.pmid: 21720365
references.citation: Clin Cancer Res. 2013 Feb 15;19(4):855-64
references.pmid: 23251001
references.citation: Cancer Discov. 2014 Sep;4(9):998-1013
references.pmid: 25185190
references.citation: Nat Rev Cancer. 2015 Aug;15(8):451-2
references.pmid: 26422835
references.citation: Cancer Res. 2015 Sep 1;75(17):3466-78
references.pmid: 26113085
references.citation: Cancer Cell. 2015 Jan 12;27(1):85-96
references.pmid: 25500121
references.citation: Nature. 2012 Oct 4;490(7418):61-70
references.pmid: 23000897
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6456-68
references.pmid: 18927285
references.citation: Nature. 2010 Apr 15;464(7291):999-1005
references.pmid: 20393555
references.citation: Cell Rep. 2013 Sep 26;4(6):1116-30
references.pmid: 24055055
references.citation: Nat Med. 2015 Nov;21(11):1318-25
references.pmid: 26479923
references.citation: J Clin Oncol. 2011 Jan 10;29(2):142-8
references.pmid: 21135282
references.citation: Proc Natl Acad Sci U S A. 2015 Oct 6;112(40):12492-7
references.pmid: 26401016
references.citation: Clin Cancer Res. 2007 Jul 1;13(13):3989-98
references.pmid: 17606733
references.citation: Blood. 2009 Feb 19;113(8):1619-30
references.pmid: 18827185
references.citation: Br J Cancer. 2001 May 18;84(10):1424-31
references.pmid: 11355958
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11
references.pmid: 15329413
references.citation: Science. 2009 Jun 26;324(5935):1670-3
references.pmid: 19556499
references.citation: Clin Cancer Res. 2011 Sep 1;17(17):5793-800
references.pmid: 21742805
references.citation: Am J Pathol. 2015 May;185(5):1297-303
references.pmid: 25770474
references.citation: Nat Rev Cancer. 2015 May;15(5):311-6
references.pmid: 25907221
references.citation: Bioinformatics. 2015 May 15;31(10):1655-62
references.pmid: 25573920
references.citation: Nature. 2008 Jan 17;451(7176):345-9
references.pmid: 18202660
references.citation: Prostate. 2015 May;75(6):585-92
references.pmid: 25585936
references.citation: Clin Pharmacol Ther. 2013 Sep;94(3):329-35
references.pmid: 23739536
references.citation: Nat Rev Clin Oncol. 2012 Apr 17;9(6):338-50
references.pmid: 22508028
references.citation: Cancer Res. 2013 Sep 1;73(17):5315-9
references.pmid: 23733750
references.citation: Nature. 2015 Feb 19;518(7539):422-6
references.pmid: 25470049
references.citation: Neuro Oncol. 2010 Mar;12(3):233-42
references.pmid: 20167811
references.citation: Cancer Res. 1996 Dec 15;56(24):5713-9
references.pmid: 8971180
references.citation: Breast Cancer Res. 2012 Jan 16;14(1):R11
references.pmid: 22247967
references.citation: Breast Cancer Res. 2015 Feb 10;17:17
references.pmid: 25849559
references.citation: PLoS One. 2012;7(6):e39294
references.pmid: 22723990
references.citation: Cancer Res. 2015 Apr 15;75(8):1675-81
references.pmid: 25878147
references.citation: Biochem Pharmacol. 2014 Sep 15;91(2):135-43
references.pmid: 24950467
references.citation: Nature. 2012 Jul 18;487(7407):330-7
references.pmid: 22810696
references.citation: Clin Cancer Res. 2010 Mar 1;16(5):1442-51
references.pmid: 20179238
references.citation: Nature. 2013 Feb 14;494(7436):251-5
references.pmid: 23302800
references.citation: Lancet Oncol. 2011 Oct;12(11):1004-12
references.pmid: 21933749
references.citation: Clin Cancer Res. 2012 Oct 1;18(19):5314-28
references.pmid: 22825584
references.citation: Lab Invest. 2013 Sep;93(9):970-82
references.pmid: 23917877
references.citation: J Thorac Oncol. 2012 Jul;7(7):1101-8
references.pmid: 22617243
references.citation: Nat Med. 2012 Sep;18(9):1332-4
references.pmid: 22961158
references.citation: Cancer Discov. 2011 Jul;1(2):108-16
references.pmid: 22116793
references.citation: Mol Cancer Ther. 2011 Aug;10(8):1311-6
references.pmid: 21673092
references.citation: N Engl J Med. 2011 Oct 6;365(14):1273-83
references.pmid: 21991949
references.citation: N Engl J Med. 2013 Oct 31;369(18):1691-703
references.pmid: 24131140