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Ocak S.,Vanderbilt University | Ocak S.,Catholic University of Louvain | Ocak S.,Cliniques Universitaires Mont Godinne | Pedchenko T.V.,Vanderbilt University | And 12 more authors.
European Respiratory Journal | Year: 2012

Polymeric immunoglobulin receptor (pIgR) expression is downregulated in lung cancer, but its implications in lung tumourigenesis remain unknown. We hypothesised that loss of pIgR expression occurs early, and is associated with cell proliferation and poor prognosis. pIgR expression was evaluated by immunohistochemistry in airways of patients with normalmucosa, pre-invasive lesions and invasive lesions, and correlated with clinical outcomes. 16-HBE and A549 cells stably transfected with pIgR were tested for proliferation, apoptosis and cell cycle progression. Immunostaining was strong in normal epithelium, but severely reduced in pre-invasive lesions and most lung cancers. Persistent expression was associated with younger age and adenocarcinoma subtype but not survival. pIgR overexpression significantly reduced A549 and 16-HBE proliferation. Growth inhibition was not due to cell cycle arrest, increased apoptosis or endoplasmic reticulum stress, but we observed altered expression of genes encoding for membrane proteins, including NOTCH3. Interestingly, NOTCH3 expression was inversely correlated with pIgR expression in cell lines and tissues. pIgR expression was lost in most lung cancers and pre-invasive bronchial lesions, suggesting that pIgR downregulation is an early event in lung tumourigenesis. pIgR overexpression in A549 and 16-HBE cells inhibited proliferation. Future investigations are required to determine the mechanisms by which pIgR contributes to cell proliferation. Copyright©ERS 2012.

Ocak S.,Vanderbilt University | Ocak S.,Catholic University of Louvain | Chen H.,Vanderbilt University | Callison C.,Vanderbilt University | And 4 more authors.
Cancer | Year: 2012

Background: The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase linked to tumor growth, invasion, and metastasis. FAK is overexpressed and associated with prognosis in many cancers, but its prognostic value in small-cell lung carcinoma (SCLC) is unknown and was the focus of this study. Methods: Total FAK expression was analyzed via immunohistochemistry in tissue microarrays consisting of formalin-fixed, paraffin-embedded SCLC specimens from 85 patients. FAK staining scores were tested for correlations with pathological characteristics and clinical outcomes. Phospho-paxillin was also tested in 35 of the 85 specimens to evaluate whether FAK expression was associated with downstream signaling. Results: Specific FAK expression was localized to the cytoplasm of 78/85 (92%) SCLCs. FAK expression was scored low in 11 (13%), moderate in 17 (20%), and high in 50 (59%) SCLCs. FAK staining scores treated as continuous variables did not correlate with SCLC disease stage, response to therapy, recurrence/progression-free survival, or overall survival. Moreover, total FAK expression did not correlate with phospho-paxillin Tyr 118 expression. Conclusions: Total FAK is strongly expressed in a majority of SCLC tumors. However, the expression evaluated via immunohistochemistry is not a prognostic factor in patients with SCLC. © 2011 American Cancer Society.

Miyabayashi K.,University of Tokyo | Ijichi H.,University of Tokyo | Mohri D.,University of Tokyo | Tada M.,Chiba University | And 10 more authors.
Cancer Research | Year: 2013

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers worldwide. Although many regimens have been used for PDAC treatment, the combination of the EGF receptor (EGFR) inhibitor erlotinib with gemcitabine has been the only molecular-targeted drug tested so far that has been superior to gemcitabine alone. The mechanism underlying this effective combinational regimen remains unknown. Here, we show that the combination is superior to gemcitabine alone in blocking progression and prolonging survival in a murine model of PDAC (Kras activation with Tgfbr2 knockout). We found that gemcitabine induced mitogen-activated protein kinase signaling, which was dramatically inhibited by erlotinib even in the Kras-activated PDAC cells in the mouse model. Mechanistic investigations suggested that gemcitabine induces EGFR ligand expression and ERBB2 activation by increasing heterodimer formation with EGFR, thereby maintaining high levels of ERBB2 protein in PDAC cells. Overall, our findings suggest a significant role of ERBB in PDAC treatment. © 2012 American Association for Cancer Research.

Ocak S.,Catholic University of Louvain | Friedman D.B.,Vanderbilt University | Chen H.,Vanderbilt University | Ausborn J.A.,Vanderbilt University | And 7 more authors.
Journal of Thoracic Oncology | Year: 2014

INTRODUCTION: Small-cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with no early detection strategy or targeted therapy currently available. We hypothesized that difference gel electrophoresis (DIGE) may identify membrane-associated proteins (MAPs) specific to SCLC, advance our understanding of SCLC biology, and discover new biomarkers of SCLC. METHODS: MAP lysates were prepared from three SCLCs, three non-small-cell lung cancers, and three immortalized normal bronchial epithelial cell lines and coanalyzed by DIGE. Subsequent protein identification was performed by mass spectrometry. Proteins were submitted to Ingenuity Pathway Analysis. Candidate biomarkers were validated by Western blotting (WB) and immunohistochemistry (IHC). RESULTS: Principal component analysis on the global DIGE data set demonstrated that the four replicates derived from each of the nine cell lines clustered closely, as did samples within the same histological group. One hundred thirty-seven proteins were differentially expressed in SCLC compared with non-small-cell lung cancer and immortalized normal bronchial epithelial cells. These proteins were overrepresented in cellular/tissue morphology networks. Dihydropyrimidinase- related protein 2, guanine nucleotide-binding protein alpha-q, laminin receptor 1, pontin, and stathmin 1 were selected as candidate biomarkers among MAPs overexpressed in SCLC. Overexpression of all candidates but RSSA in SCLC was verified by WB and/or IHC on tissue microarrays. These proteins were significantly associated with SCLC histology and survival in univariables analyses. CONCLUSION: DIGE analysis of a membrane-associated subproteome discovered overexpression of dihydropyrimidinase-related protein 2, guanine nucleotide-binding protein alpha-q, RUVB1, and stathmin 1 in SCLC. Results were verified by WB and/or IHC in primary tumors, suggesting that investigating their functional relevance in SCLC progression is warranted. Association with survival requires further validation in larger clinical data sets. Copyright © 2014 by the International Association for the Study of Lung Cancer.

McArthur G.A.,University of Vic | McArthur G.A.,University of Melbourne | Puzanov I.,Vanderbilt Ingram Comprehensive Cancer Center | Amaravadi R.,University of Pennsylvania | And 8 more authors.
Journal of Clinical Oncology | Year: 2012

Purpose: Imaging with [ 18F]fluorodeoxyglucose (FDG) -positron emission tomography (PET) allows early recognition of a response to agents that target key driver mutations in human cancer. We aimed to determine the metabolic response rate to vemurafenib in patients with advanced BRAF-mutant melanoma. Patients and Methods: Baseline and day 15 FDG-PET was evaluated in 31 patients with advanced melanoma treated in a phase I study of dose escalation of vemurafenib (PLX06-02), which included four patients treated at subtherapeutic doses and 24 patients treated at 960 mg twice a day, which is the maximum-tolerated dose of vemurafenib. Results: All 27 patients treated at potentially therapeutic levels had at least a partial metabolic response, and three patients achieved a complete metabolic response. In the 27 patients, there was an 80% ± 3% reduction in the maximum standardized uptake value (SUVmax) of target lesions and an 87% ± 3% decrease in the percentage of injected dose (%ID) in all identified disease sites. There was a positive correlation between %ID in all identified disease and target-lesion SUVmax (r 2 = 0.66; P < .001) that indicated a significant homogeneity of the response between lesions in individual patients. Although no relationship was found between the reduction in target lesion SUVmax and best response according to RECIST (Response Evaluation Criteria in Solid Tumors), there was a trend for patients with greater reductions in uptake of FDG to have longer progression-free survival. Conclusion: FDG-PET is a useful marker of an early biologic response to vemurafenib. Little variability in PET response was found between lesions in individual patients, which suggested minimal intrapatient molecular heterogeneity. FDG-PET is a useful tool for the evaluation of the biologic impact of inhibiting mutant BRAF and may allow for the more effective development of novel agents. © 2012 by American Society of Clinical Oncology.

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