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• W2182065306 abstract "As new target-directed anticancer agents emerge, preclinical efficacy studies need to integrate target-driven model systems. This approach to drug development requires rapid and reliable characterization of the new targets in established tumor models, such as xenografts and cell lines. Here, we have applied tissue microarray technology to patient- derived, re-growable human tumor xenografts. We have profiled the expression of five proteins involved in cell migration and/or angiogenesis: vascular endothelial growth factor (VEGF), matrix metalloproteinase 1 (MMP1), protease activated receptor (PAR1), cathepsin B, and β1 integrin in a panel of over 150 tumors and compared their expression levels to available patient outcome data. For each protein, several target overexpressing xenografts were identified. They represent a subset of tumor models prone to respond to specific inhibitors and are available for future preclinical efficacy trials. In a proof o f concept experiment, we have employed tissue microarrays to select in vivo models for therapy and for the analysis of molecular changes occurring after treatment with the anti-VEGF antibody HuMV833 and gemcitabine. Whereas the less angiogenic pancreatic cancer PAXF736 model proved to be resistant, the highly vascularized PAXF546 xenograft responded to therapy. Parallel analysis of arrayed biopsies from the different treatment groups revealed a down-regulation of Ki-67 and VEGF, an altered tissue morphology, and a decreased vessel density. Our results demonstrate the multiple advantages of xenograft tissue microarrays for preclinical drug development. Recent advances in molecular medicine have deepened our understanding of the pathological basis of oncogenesis. This development has had far reaching consequences for drug development in oncology. Whilst traditional procedures for evaluation of drug efficacy are based on empirical screens measuring cytotoxicity, more recent algorithms emphasize additional aspects of malignancy such as angiogenesis, metastasis or signal transduction (1, 2). Nevertheless, the characterization of new target proteins and their validation for the clinic remains a labor intensive and time-consuming exercise. In order to ease this bottleneck, further research is urgently needed into the development of suitable high throughput methods. Since their introduction in the late nineties, tissue microarrays have become a well established method for the parallel evaluation of gene and protein expression in hundreds of tissue biopsies (3). Fluorescent in situ hybridization (FISH) and immunohistochemistry allow a classification of tissues according to gene expression, protein levels and histology. Moreover, the relationship between gene expression, pathological variables and clinical outcome data can be studied, which permits the assessment of the target's relevance for therapy, diagnosis and prognosis of cancer. Thus, tissue microarrays have proven to be a valuable tool for the study of the human oncoproteome (3-4). We have applied tissue microarray technology to our collection of human tumor xenografts. Over the past 20 years, our institute has established over 400 tumor models" @default.
• W2182065306 created "2016-06-24" @default.
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• W2182065306 date "2008-09-01" @default.
• W2182065306 modified "2023-10-14" @default.
• W2182065306 title "Tissue Microarrays of Human Tumor Xenografts: Characterization of Proteins Involved in Migration and Angiogenesis for Applications in the Development of Targeted Anticancer Agents" @default.
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