These abnormal secretions are related to CFTR defects, in a direct or indirect manner

These abnormal secretions are related to CFTR defects, in a direct or indirect manner

rhaps, the most important feature of preclinical tumor again emphasizing the importance 12826236 of studying genetically diverse human tumors and pointing to the influence of differential gene expression on the tumor cell-microenvironment interactions. Gene Expression Gene expression profiling was performed for xenografted tumors, established cell lines, and normal human pancreatic specimens. Unsupervised clustering is shown as a dendrogram in Validation of a Pancreatic Cancer Xenograft Model models is the faithful maintenance of gene expression signatures between the original patient tumor and subsequent mouse xenografts. Affymetrix based gene expression profiling revealed a high degree of conservation of gene expression with correlation coefficients of 93% to 99% when individual patient tumors were compared to F1 tumors and subsequent tumors passaged through multiple generations. However, one limitation of our approach is the lack of comparison of the tumors to a larger dataset containing unmatched patient tumors and mouse xenografts. Despite this limitation, to our knowledge, this is the first preclinical pancreatic cancer model to display such highly conserved gene expression. The diversity of oncogenic drivers of tumor progression is one of the greatest strengths of the xenograft model and one of the key limitations of engineered cancer models. Patient derived xenografts exhibit multiple, well studied genetic mutations common to human PDACs — KRAS, P53, and SMAD4. The mouse xenografts demonstrated activation of multiple RTKs, notably EGFR and Her2, which are relevant targets in human PDAC. The conserved patterns of RTK activation for individual tumors provide an opportunity to assess different therapeutic strategies, choosing relevant targets and customizing therapy based on the unique features of a particular tumor and identifying biomarkers of response to therapy. Because metastatic lesions provide the greatest therapeutic challenge and impact on survival, an ideal tumor model should recapitulate human metastatic patterns. While subcutaneous injection and spontaneous tumor models are limited or variable in this regard, we observed that mice bearing pancreatic xenografts frequently develop liver, diaphragmatic, and peritoneal metastases, with local retroperitoneal invasion. This xenograft model allows the comprehensive investigation of genetic and molecular pathways that drive metastatic disease as well as directly test new therapeutic strategies targeting metastasis. The impact of the tumor microenvironment cannot be overemphasized, as it influences drug delivery, is an important source of tumor growth factors and contributes to tumor survival in 10757780 the face of therapeutic treatments. The cytokine array data demonstrating production of numerous stromal-interacting cytokines suggests that the xenografts are interacting with and being altered by components of the tumor microenvironment. Investigating tumors within a relevant microenvironment provides study of cancer cell-stromal interactions, and uncovers potential therapeutic targets within the microenvironment. For example, Olive et al. demonstrated that targeting the PDAC microenvironment improves drug delivery and survival. We recently reported that inhibition of RAS pathway Rutin signaling with trametinib, an inhibitor of MEK1/2, blocked pancreatic cancer cell proliferation in a variety of cell lines tested. We also noted that the combined inhibition of EGFR/HER2 with the EGFR/HER2 inhibitor l

Proton-pump inhibitor

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