title: Translational validation of personalized treatment strategy based on genetic characteristics of glioblastoma.
abstract: Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patient's surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated.
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea; Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
authors.forename: Young Taek
authors.initials: YT
authors.lastname: Oh
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea; Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea; Samsung Advanced Institute of Technology, Samsung Electronics Co., Ltd., Seoul, Korea.
authors.forename: Jinkuk
authors.initials: J
authors.lastname: Kim
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Kyoohyoung
authors.initials: K
authors.lastname: Rho
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Yun-Jee
authors.initials: YJ
authors.lastname: Seo
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Yeon-Sook
authors.initials: YS
authors.lastname: Choi
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jung
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Hyeon Suk
authors.initials: HS
authors.lastname: Song
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea; Department of Neurosurgery, School of Medicine, Sungkyunkwan University, Seoul, Korea.
authors.forename: Doo-Sik
authors.initials: DS
authors.lastname: Kong
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea; Department of Neurosurgery, School of Medicine, Sungkyunkwan University, Seoul, Korea.
authors.forename: Ho Jun
authors.initials: HJ
authors.lastname: Seol
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea; Department of Neurosurgery, School of Medicine, Sungkyunkwan University, Seoul, Korea.
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Lee
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea; Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
authors.forename: Yeup
authors.initials: Y
authors.lastname: Yoon
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea; Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea; Department of Neurosurgery, School of Medicine, Sungkyunkwan University, Seoul, Korea.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea; Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea; Department of Anatomy and Cell Biology, School of Medicine, Sungkyunkwan University, Seoul, Korea.
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D023281:Genomics; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010597:Pharmacogenetics; D057285:Precision Medicine; D011379:Prognosis; D057170:Translational Research, Biomedical; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents
references.citation: J Neurosci Methods. 2003 May 30;125(1-2):147-57
references.pmid: 12763241
references.citation: Cell Rep. 2013 Jan 31;3(1):260-73
references.pmid: 23333277
references.citation: Glia. 2011 Aug;59(8):1169-80
references.pmid: 21446047
references.citation: N Engl J Med. 2005 Mar 10;352(10):997-1003
references.pmid: 15758010
references.citation: Blood. 2002 Nov 1;100(9):3175-82
references.pmid: 12384415
references.citation: Clin Cancer Res. 2007 Jul 1;13(13):3989-98
references.pmid: 17606733
references.citation: Lab Invest. 2008 Aug;88(8):808-15
references.pmid: 18560366
references.citation: Clin Cancer Res. 2008 Sep 1;14(17):5447-58
references.pmid: 18765536
references.citation: Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5645-9
references.pmid: 1608975
references.citation: Clin Cancer Res. 2006 Aug 1;12(15):4652-61
references.pmid: 16899615
references.citation: Cancer Res. 2006 Apr 1;66(7):3351-4, discussion 3354
references.pmid: 16585151
references.citation: N Engl J Med. 2005 Mar 10;352(10):987-96
references.pmid: 15758009
references.citation: J Natl Cancer Inst. 1993 May 5;85(9):704-10
references.pmid: 8478956
references.citation: Cell Stem Cell. 2011 May 6;8(5):482-5
references.pmid: 21549324
references.citation: PLoS One. 2010 Nov 23;5(11):e15543
references.pmid: 21124904
references.citation: Nat Med. 2011 Oct 23;17(11):1514-20
references.pmid: 22019887
references.citation: Int J Cancer. 2011 Jun 1;128(11):2527-35
references.pmid: 21365651
references.citation: Neuro Oncol. 2005 Apr;7(2):164-76
references.pmid: 15831234
references.citation: BMC Cancer. 2009 Dec 29;9:465
references.pmid: 20040089
references.citation: Cancer Cell. 2010 Jan 19;17(1):98-110
references.pmid: 20129251
references.citation: Expert Opin Investig Drugs. 2009 Aug;18(8):1061-83
references.pmid: 19555299
references.citation: J Neuropathol Exp Neurol. 1981 Sep;40(5):493-511
references.pmid: 7276991
references.citation: Acta Neuropathol. 2007 Aug;114(2):97-109
references.pmid: 17618441
references.citation: J Transl Med. 2008 Dec 03;6:77
references.pmid: 19055779
references.citation: Cancer. 1999 Nov 15;86(10):2117-23
references.pmid: 10570440
references.citation: Int J Radiat Oncol Biol Phys. 1998 Jan 1;40(1):51-5
references.pmid: 9422557
references.citation: BMC Syst Biol. 2012 Jul 02;6:80
references.pmid: 22748168
references.citation: Semin Liver Dis. 2010 Feb;30(1):35-51
references.pmid: 20175032
references.citation: Eur Urol. 2011 Apr;59(4):619-28
references.pmid: 21167632
references.citation: J Clin Oncol. 2002 Mar 1;20(5):1383-8
references.pmid: 11870183
references.citation: Zhongguo Fei Ai Za Zhi. 2010 Jun;13(6):568-74
references.pmid: 20681441
references.citation: Neuro Oncol. 2012 Nov;14 Suppl 5:v1-49
references.pmid: 23095881