Improving gastric cancer preclinical studies using diverse in vitro and in vivo model systems

Autor: Curt Balch, Sang-Jin Lee, Young Zoo Ahn, Hee Seo Park, Sungjin Park, Hae Ryung Chang, Ja-Lok Ku, Hae Rim Jung, Seungyoon Nam, Garth Powis, Yon Hui Kim
Jazyk: angličtina
Předmět:
0301 basic medicine
Oncology
Gastric cancer cell lines
Cancer Research
Receptor
ErbB-2
medicine.medical_treatment
Drug Evaluation
Preclinical
Targeted therapy
Mice
0302 clinical medicine
Trastuzumab
Medicine
Gene Regulatory Networks
Molecular Targeted Therapy
skin and connective tissue diseases
Cell microarray
Gene Expression Regulation
Neoplastic
030220 oncology & carcinogenesis
Biomarker
ERBB2 expression
Gastric cancer cell es
Targeted therapies
Tumor heterogeneity
Xenograftmicroarray
Female
DNA microarray
Signal Transduction
Research Article
medicine.drug
medicine.medical_specialty
Xenograft microarray
Antineoplastic Agents
03 medical and health sciences
Breast cancer
Stomach Neoplasms
In vivo
Cell Line
Tumor
Internal medicine
Genetics
Animals
Humans
Neoplasm Staging
business.industry
Gene Expression Profiling
Gene Amplification
Cancer
medicine.disease
Xenograft Model Antitumor Assays
Gene expression profiling
Disease Models
Animal
030104 developmental biology
Cancer cell
business
Biomarkers
Zdroj: BMC Cancer
BMC CANCER(16)
ISSN: 1471-2407
DOI: 10.1186/s12885-016-2232-2
Popis: 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. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2232-2) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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