Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment.
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.
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ABSTRACT: To assess diagnostic value of Carbohydrate Antigen 19-9 (CA 19-9), combined CA 19-9 and K-ras mutation in plasma DNA in diagnosing patients with pancreatic carcinoma. MEDLINE, EMBASE, the Cochrane Library, Sinomed, CNKI and other databases, from established to November, 2013, were searched for initial studies. All the studies published in English or Chinese relating to the diagnostic value of CA 19-9 and K-ras gene mutation for patients with pancreatic cancer were collected. Methodological quality was assessed. The statistic software called "Meta-disc" (version 1.4) was used for data analysis. 10 studies were included in this meta-analysis. The pooled sensitivity estimate for CA 19-9 (78%) was significantly higher than K-ras mutation (65%). While, for the specificity estimate, K-ras mutation (93%) was significantly higher than CA 19-9 (77%). The pooled DOR estimate for K-ras mutation (21.82) was significantly higher than CA 19-9 (18.36). SROC curves for K-ras mutation showed better diagnostic accuracy than CA 19-9. For CA 19-9 measurement, its diagnostic value decreased in differentiating pancreatic cancer for patients with pancreatitis, especially chronic process. CA 19-9 was a high sensitive and K-ras was a high specific method in diagnosing patients with pancreatic cancer. These two modalities probably act different roles during different conditions in diagnosing pancreatic carcinoma.International Journal of Clinical and Experimental Medicine 01/2014; 7(10):3225-3234. · 1.42 Impact Factor
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ABSTRACT: Purpose: Expression of CBL, an ubiquitin ligase, is decreased in 60% of human pancreatic ductal adenocarcinomas (PDACs) and is associated with shorter overall survival. We sought to determine how low CBL directly contributes to clinically more aggressive PDAC. Experimental Design: Human PDACs were stained for CBL, pEGFR, and EGFR. CBL-low was modeled in PDAC cells (Panc-1, L3.6pl, AsPC-1) via transient transfection (siRNA) or stable knockdown (shRNA). Cell viability and apoptosis were measured by MTT assays and FACS. Immunoblot and a phospho-receptor tyrosine kinase (pRTK) array were used to probe signal transduction. NOD-scid-IL2Rγ(null) mice were subcutaneously implanted with PDAC or PDAC(CBL-low) cells on opposite flanks and treated with gemcitabine ± erlotinib for ≥4 weeks. Results: There was an inverse correlation between CBL and pEGFR protein expression in 12 of 15 tumors. CBL knockdown increased PDAC resistance to gemcitabine and 5-FU by upregulating pEGFR (Y1068), pERK, and pAKT. A pRTK array of PDAC(CBL-low) cells revealed additional activated tyrosine kinases but all to a much lower magnitude than EGFR. Increased chemoresistance from low CBL was abrogated by the EGFR inhibitor erlotinib both in vitro and in vivo. Erlotinib + gemcitabine treated PDAC(CBL-low) cells exhibited greater apoptosis by cleaved PARP, Caspase 3 and Annexin V/PI. Conclusions: Low CBL causes chemoresistance in PDAC via stress-induced EGFR activation that can be effectively abrogated by EGFR inhibition. These results suggest that dysregulation of ubiquitination is a key mechanism of EGFR hyperactivation in PDAC and that low CBL may define PDAC tumors likely to respond to erlotinib treatment.Journal of Surgical Research 10/2014; · 2.12 Impact Factor
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ABSTRACT: Many commercially available cell lines have been in culture for ages, acquiring phenotypes that differ from the original cancers from which these cell lines were derived. Therefore, research on new cell lines could improve the success rates of translational research in cancer. We have developed methods for the isolation and culture of human pancreatic ductal adenocarcinoma (PDAC) cells from murine xenografts of human PDAC. We hypothesize that phenotypes of PDAC cells are modified by in vitro culture conditions over time and by in vivo implantation. Patient-derived xenografts were created in immunodeficient mice using surgically resected tumor specimens. These murine xenografts were then used to establish human PDAC cell lines in culture. Earlier (<5) passage and later (>20) passage cell lines were evaluated separately regarding proliferation, cell cycle, genetic mutations, invasiveness, chemosensitivity, tumorigenesis, epithelial-mesenchymal transition (EMT) status, and proteomics. Later passage cells accelerated their doubling time and colony formation, and were more concentrated in the G0/G1 phase and less in the G2/M checkpoint phase. Later passage cells were more sensitive to gemcitabine and 5-fluorouracil than earlier passage cells, but all four new cell lines were more chemo-resistant compared with commercial ATCC cell lines. EMT induction was observed when establishing and passaging cell lines in vitro and furthermore by growing them as subcutaneous tumors in vivo. This study demonstrates a novel approach to the establishment of PDAC cell lines and observes a process by which newly established cell lines undergo phenotypic changes during in vitro culture and in vivo tumorigenesis. This may help explain differences of treatment effects often observed between experiments conducted in vitro, in vivo, and in human clinical trials.Laboratory Investigation advance online publication, 8 December 2014; doi:10.1038/labinvest.2014.143.Laboratory Investigation 12/2014; · 3.83 Impact Factor