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Improving gastric cancer preclinical studies using diverse in vitro and in vivo model systems.
Chang, Hae Ryung; Park, Hee Seo; Ahn, Young Zoo; Nam, Seungyoon; Jung, Hae Rim; Park, Sungjin; Lee, Sang Jin; Balch, Curt; Powis, Garth; Ku, Ja-Lok; Kim, Yon Hui.
Afiliação
  • Chang HR; New Experimental Therapeutics Branch, National Cancer Center of Korea, Ilsan, Goyang-si, Gyeonggi-do, Republic of Korea. haeryung.chang@ip-korea.org.
  • Park HS; Cancer Biology Research Laboratory, Institut Pasteur Korea, Bundang, Seongnam-si, Gyeonggi-do, Republic of Korea. haeryung.chang@ip-korea.org.
  • Ahn YZ; Animal Sciences Branch, National Cancer Center of Korea, Ilsan, Goyang-si, Gyeonggi-do, Republic of Korea. heeseo@ncc.re.kr.
  • Nam S; New Experimental Therapeutics Branch, National Cancer Center of Korea, Ilsan, Goyang-si, Gyeonggi-do, Republic of Korea. yzahn@ncc.re.kr.
  • Jung HR; New Experimental Therapeutics Branch, National Cancer Center of Korea, Ilsan, Goyang-si, Gyeonggi-do, Republic of Korea. nams@gachon.ac.kr.
  • Park S; Department of Life Sciences, College of BioNano Technology, Gachon University, Sungnam, South Korea. nams@gachon.ac.kr.
  • Lee SJ; College of Medicine, Gachon University, Incheon, South Korea. nams@gachon.ac.kr.
  • Balch C; New Experimental Therapeutics Branch, National Cancer Center of Korea, Ilsan, Goyang-si, Gyeonggi-do, Republic of Korea. hrjung3@ncc.re.kr.
  • Powis G; New Experimental Therapeutics Branch, National Cancer Center of Korea, Ilsan, Goyang-si, Gyeonggi-do, Republic of Korea. oscar.park@gmail.com.
  • Ku JL; Department of Life Sciences, College of BioNano Technology, Gachon University, Sungnam, South Korea. oscar.park@gmail.com.
  • Kim YH; College of Medicine, Gachon University, Incheon, South Korea. oscar.park@gmail.com.
BMC Cancer ; 16: 200, 2016 Mar 09.
Article em En | MEDLINE | ID: mdl-26955870
ABSTRACT

BACKGROUND:

"Biomarker-driven targeted therapy," the practice of tailoring patients' treatment to the expression/activity levels of disease-specific genes/proteins, remains challenging. For example, while the anti-ERBB2 monoclonal antibody, trastuzumab, was first developed using well-characterized, diverse in vitro breast cancer models (and is now a standard adjuvant therapy for ERBB2-positive breast cancer patients), trastuzumab approval for ERBB2-positive gastric cancer was largely based on preclinical studies of a single cell line, NCI-N87. Ensuing clinical trials revealed only modest patient efficacy, and many ERBB2-positive gastric cancer (GC) patients failed to respond at all (i.e., were inherently recalcitrant), or succumbed to acquired resistance.

METHOD:

To assess mechanisms underlying GC insensitivity to ERBB2 therapies, we established a diverse panel of GC cells, differing in ERBB2 expression levels, for comprehensive in vitro and in vivo characterization. For higher throughput assays of ERBB2 DNA and protein levels, we compared the concordance of various laboratory quantification methods, including those of in vitro and in vivo genetic anomalies (FISH and SISH) and xenograft protein expression (Western blot vs. IHC), of both cell and xenograft (tissue-sectioned) microarrays.

RESULTS:

The biomarker assessment methods strongly agreed, as did correlation between RNA and protein expression. However, although ERBB2 genomic anomalies showed good in vitro vs. in vivo correlation, we observed striking differences in protein expression between cultured cells and mouse xenografts (even within the same GC cell type). Via our unique pathway analysis, we delineated a signaling network, in addition to specific pathways/biological processes, emanating from the ERBB2 signaling cascade, as a potential useful target of clinical treatment. Integrated analysis of public data from gastric tumors revealed frequent (10 - 20 %) amplification of the genes NFKBIE, PTK2, and PIK3CA, each of which resides in an ERBB2-derived subpathway network.

CONCLUSION:

Our comprehensive bioinformatics analyses of highly heterogeneous cancer cells, combined with tumor "omics" profiles, can optimally characterize the expression patterns and activity of specific tumor biomarkers. Subsequent in vitro and in vivo validation, of specific disease biomarkers (using multiple methodologies), can improve prediction of patient stratification according to drug response or nonresponse.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Gástricas Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Gástricas Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article