bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A86: PTEN-Long and gemcitabine combination treatment as a therapeutic for pancreatic cancer
Authors: Ahmed Roshan Ara , Hopkins Benjamin , Palermo Carmine , Sastra Steve A. , Rapp Zachary , Parsons Ramon , Olive Kenneth P. 
Published: October 2015

Abstract
This abstract is also being presented as a short talk in Session 8: Clinical Science Trials. A full abstract is printed in the Proffered Abstracts section (PR14) of the Conference Proceedings.
Citation Format: Roshan Ara Ahmed, Benjamin Hopkins, Carmine Palermo, Steve A. Sastra, Zachary Rapp, Ramon Parsons, Kenneth P. Olive. PTEN-Long and gemcitabine combination treatment as a therapeutic for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A86.
Abstract B08: The role of periostin in pancreatic carcinogenesis and metastatic spread
Authors: Hausmann Simone , Regel Ivonne , Federlein Anna , Mazur Pawel K. , Steiger Katja , Michalski Christoph W. , Erkan Mert , Kleeff Jörg 
Published: October 2015

Abstract
Background: Excessive desmoplasia is a typical feature of pancreatic ductal adenocarcinoma (PDAC) and is highly associated with an aggressive tumor phenotype. The main cell population contributing to the stromal response consists of pancreatic stellate cells (PSCs). Periostin, an extracellular matrix protein (ECM), produced by activated PSCs has been shown to have anti-apoptotic and growth-stimulatory effects on pancreatic tumor cells as well as the ability to create a metastatic niche in the secondary target organ. The main signaling route by which periostin mediates its effects is the integrin signaling pathway. Through binding to different integrin subunits the focal adhesion kinase (FAK) gets phosphorylated and downstream signaling pathways such as RAS/ERK/MEK become additionally activated.
Aim: Analyzing the function of periostin in early pancreatic carcinogenesis as well as metastatic spread.
Methods: A conditional tumor mouse model, expressing oncogenic KrasG12D under the control of a pancreas specific Ptf1a promoter was crossbred with Postn global knockout mice (p48Cre/+;LSL-KrasG12D/+;Postn-/-) and early tumor development was analyzed at two, three and six months of age. In a second approach, a tumor-promoting inflammatory stromal reaction was induced by cerulein injections in p48Cre/+;LSL-KrasG12D/+ mice whereby one group of mice was additionally treated with a daily dose (30mg/kg) of FAK inhibitor. All mice were sacrificed after 7 days and HE staining was performed. Thirdly, to study metastasis formation, murine pancreatic tumor cells were injected into the tail vein of wild type, Postn+/- and Postn-/- mice. After 6 weeks target organs were collected for subsequent analyses.
Results: In the early phases, p48Cre/+;LSL-KrasG12D/+;Postn-/- mice displayed less PanIN lesions, fewer atypical ductal structures and reduced proliferating cells. The inhibition of FAK-signaling blocked pancreatic tumorigenesis and absence of periostin abrogated metastatic spread.
Conclusion: Periostin produced by the pancreatic stellate cell is necessary both for early carcinogenesis and metastatic spread. The effects of periostin can be antagonized by blocking its downstream pathway using FAK inhibitors.
Citation Format: Simone Hausmann, Ivonne Regel, Anna Federlein, Pawel K. Mazur, Katja Steiger, Christoph W. Michalski, Mert Erkan, Jörg Kleeff. The role of periostin in pancreatic carcinogenesis and metastatic spread. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B08.
Abstract B09: Targeting macrophages to degrade fibrosis in pancreatic ductal adenocarcinoma
Authors: Long Kristen B. , Luque Santiago L. , Beatty Gregory L. 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDA) is commonly resistant to chemotherapy due to extensive stromal fibrosis and poor vascularity which combine to inhibit chemotherapy diffusion into tumor tissue. Strategies that target tumor-associated fibrosis have shown promise in preclinical and early clinical trials. We have previously shown that treatment with an agonist CD40 monoclonal antibody (mAb) can induce macrophages to facilitate degradation of tumor-associated fibrosis in PDA, resulting in tumor regressions. Here, we investigated the mechanism by which macrophages facilitate stromal degradation using the KrasG12D; Trp53R172H; Pdx-1 Cre (KPC) genetically engineered mouse model of PDA. By immunofluorescence imaging, we first characterized the extracellular matrix that surrounds PDA tumors in the KPC model. We found high levels of fibronectin, hyaluronic acid and type I collagen present within the surrounding PDA stroma. Treatment with a CD40 mAb resulted in macrophage dependent degradation of both fibronectin and type I collagen, but had no effect on hyaluronic acid. To examine the ability of macrophages to degrade type I collagen, we developed an in vitro colorimetric collagen degradation assay. We found that neither CD40 activation nor classical activation with IFN-γ and LPS were sufficient to induce macrophages to degrade type I collagen. In contrast, classical activation of macrophages in the presence of tumor cells led to &gt;50% collagen degradation in vitro. This effect was correlated with the ability of classically activated macrophages to eliminate tumor cells. Our findings suggest that macrophages acquire the capacity to degrade tumor-associated stromal fibrosis only after activation and successful elimination of tumor cells. This finding has important implications for the design of novel strategies that exploit the anti-fibrotic potential of macrophages for potentially improving drug delivery in PDA.
Citation Format: Kristen B. Long, Santiago L. Luque, Gregory L. Beatty. Targeting macrophages to degrade fibrosis in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B09.
Abstract B11: Understanding how the Hedgehog pathway mediates stromal desmoplasia in Pancreatic Ductal Adencarcinoma
Authors: Thomas Dafydd H. , Lee Albert K. , Sastra Stephen A. , Palermo Carmine F. , Rabadan Raul , Kenneth P Olive 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers partly due to its profound primary chemoresistance. Previous work from this laboratory found that the prominent desmoplastic stroma observed in PDA is a significant factor in the tumor chemoresistance. We reported that, in established tumors, inhibition of the Hedgehog (Hh) pathway in tumor fibroblasts caused a loss of tumor stroma including α-smooth muscle actin positive (α-SMA) cells. This resulted in an increase in drug delivery to the tumor and subsequent reduction in tumor volume, leading to prolonged survival in a clinically relevant mouse model of PDA. However, the mechanisms by which Hh signaling contributes to the desmoplastic stroma in PDA remain unknown.
In this study we have attempted to identify the target genes of the Hh pathway in the stroma of pancreatic tumors. Using a novel tumor biopsy procedure coupled with RNA-SEQ analysis we have identified genes acutely sensitive to Hh pathway inhibition in the KPC mouse model of PDA. Following 2 days of post biopsy treatment with the Smoothened inhibitor IPI926 the Hh pathway genes Gli1 and Ptch2 were significantly down-regulated. In addition, the Hh target gene, wnt inhibitory factor 1 (Wif1) and other novel genes which may be promoting stromal desmoplasia were significantly down-regulated due to Hh pathway inhibition.
In addition to studying the target genes of the Hh-pathway in the stroma we have utilized a Gli1-GFP reporter mouse to study the Hh target cells in the stroma. Previous work has suggested that Hh target cells in pancreatic tumors are myofibroblasts and thus α-SMA positive. However, we observed that while some Gli1 positive stromal cells are α-SMA positive a significant proportion are α-SMA negative. In addition, costaining KPC-Gli1-GFP tumors for other stromal markers, including Fibroblast specific protein-1 (FSP-1), Glial Fibrillic Acidic Protein (GFAP), zinc finger E-box binding homeobox 1 (Zeb1) and Neuron-Glial Antigen 2 (NG-2) reveals subsets of Hh target cells in the tumor stroma. These data suggest a complex mechanism of Hh-regulated development of the desmoplastic stroma.
To date the mechanisms of Hh-mediated stromal desmoplasia remain refractory. Taken together, these studies attempt to uncover the Hh target genes and cell types in the stroma of pancreatic tumors and provide an explanation for Hh-mediated stromal desmoplasia in PDA.
Citation Format: Dafydd H. Thomas, Albert K. Lee, Stephen A. Sastra, Carmine F. Palermo, Raul Rabadan, P Olive Kenneth. Understanding how the Hedgehog pathway mediates stromal desmoplasia in Pancreatic Ductal Adencarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B11.
Abstract B112: Transcriptome analysis in pancreatic cancer reveals a tumor suppressor function for HNF1A
Authors: Hoskins Jason W. , Flandez Marta , Jia Jinping , Parikh Hemang , Collins Irene , Emmanuel Mickey , Ibrahim Abdisamad , Xiao Wenming , Powell John , Malats Nuria , Petersen Gloria M. , Real Fransisco X. , Amundadottir Laufey T. 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC), as with all cancer, is driven by dysregulation of genetic programs due to accumulation of somatic mutations, epigenetic modifications and changes in the micro-environment. Holistic views of perturbations in gene expression networks could illuminate key regulators and pathways for this highly lethal cancer. Toward this end, we performed massively-parallel mRNA-sequencing in normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples as well as pancreatic cancer cell lines (n = 9), and determined differential gene expression (DE) patterns. Sub-network enrichment analyses of all expressed genes based on magnitude of DE identified HNF1A as the regulator of the most significantly and consistently dysregulated expression sub-network in our pancreatic tumor samples (median P = 7.56 x 10-7, median rank = 1, range = 1-25). To explore the effect of HNF1A expression in pancreatic tumor-derived cells we generated stable HNF1A-inducible clones in two pancreatic cancer cell lines. Induction of HNF1A overexpression caused severe growth inhibition (5.3-fold, P = 4.5x10-5 for MIA PaCa-2 clones; 7.2-fold, P = 2.2x10-5 for PANC-1 clones), and G0/G1 cell cycle arrest. This was accompanied by down-regulation of 49 out of 84 assayed cell cycle genes, while only 1 displayed increased expression. These data, combined with HNF1A’s direct regulation of pancreatic development and homeostasis genes (i.e. PDX1, PTF1A and NR5A2), suggest it may be an important tumor suppressor in pancreatic cells.
Citation Format: Jason W. Hoskins, Marta Flandez, Jinping Jia, Hemang Parikh, Irene Collins, Mickey Emmanuel, Abdisamad Ibrahim, Wenming Xiao, John Powell, Nuria Malats, Gloria M. Petersen, Fransisco X. Real, Laufey T. Amundadottir. Transcriptome analysis in pancreatic cancer reveals a tumor suppressor function for HNF1A. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B112.
Abstract B114: c-Rel is a critical mediator of NF-κB dependent TRAIL resistance of pancreatic cancer cells
Authors: Geismann Claudia , Grohmann Frauke , Häsler Robert , Rosenstiel Philip , Schneider Günter , Zeissig Sebastian , Schreiber Stefan , Schäfer Heiner , Arlt Alexander 
Published: October 2015

Abstract
NF-κB has been shown to be critical for resistance of pancreatic ductal adenocarcinoma (PDAC) against chemotherapeutic drug and death receptor induced apoptosis, but little is known about the role of the c-Rel subunit.
In the present study, by analysis of genome-wide patterns of c-Rel dependent gene expression we were able to establish c-Rel as a critical regulator of TRAIL induced apoptosis in PDAC. Transfection with siRNA against c-Rel sensitized the TRAIL resistant PDAC cells and EMSA revealed that c-Rel is part of the TRAIL inducible NF-κB complex. Array analysis identified NFATc2 as a critical downstream target of c-Rel in PDAC. In line, siRNA targeting c-Rel strongly reduced TRAIL induced NFATc2 activity and siRNA targeting NFATc2 sensitized PDAC cells against TRAIL induced apoptosis. Finally, TRAIL induced expression of COX-2 was diminished through siRNA targeting c-Rel or NFATc2 and pharmacological inhibition of COX-2 with celecoxib enhanced TRAIL apoptosis.
In conclusion, we were able to delineate a novel c-Rel, NFATc2 and COX-2 dependent anti-apoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies.
Citation Format: Claudia Geismann, Frauke Grohmann, Robert Häsler, Philip Rosenstiel, Günter Schneider, Sebastian Zeissig, Stefan Schreiber, Heiner Schäfer, Alexander Arlt. c-Rel is a critical mediator of NF-κB dependent TRAIL resistance of pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B114.
Abstract B116: Modeling of early to invasive stages of pancreatic cancer progression with an iPSC-like line from human pancreatic ductal adenocarcinoma
Authors: Kim Jungsun , Zaret Kenneth S. 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of any human malignancy. When human PDAC cells are injected into immunodeficient animals, they create tumors of the late stage from which they were derived. We hypothesized that if human PDAC cells were converted to pluripotency and then allowed to differentiate back into pancreatic tissue, they might undergo early stages of cancer. Although most induced pluripotent stem cell (iPSC) lines that we generated from PDAC were not of the expected cancer genotype, one PDAC iPS-like line, 10–22 cells, conferred the highly disrupted cancer genome of the starting tumor epithelial population. When 10-22 iPS-like cells are injected into immunodeficient mice, they generate pancreatic intraepithelial neoplasia (PanIN) precursors that progress to the invasive stage PDAC. Using this unique system, we established serum-free cultures of human PanIN lesions from immunodeficient mice injected with 10-22 cells and analyzed the proteome of secreted and released proteins. The live human PanIN explants secrete or release proteins from many genes that are known to be expressed in human pancreatic cancer progression and that predicted an HNF4a network achieved in intermediate-stage lesions from new clinical samples. Recent studies show that the PanIN cells progress to metastases at longer time. The 10-22 cell line is being engineered with near-infrared fluorescent protein under the control of the ductal K19 promoter so that populations can be retrieved by FACS for transcriptome analysis as well as tumor progression and regression in response to drugs can be monitored in vivo. We are now assessing the secreted or released proteins from early lesions grown in mice as diagnostic markers for human PDAC prognosis. Thus, rare events allow iPSC technology to provide a live human cell model of early pancreatic cancer and insights into disease progression.
Citation Format: Jungsun Kim, Kenneth S. Zaret. Modeling of early to invasive stages of pancreatic cancer progression with an iPSC-like line from human pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B116.
Abstract B119: Triptolide abrogates expression of the Met and epidermal growth factor receptors in pancreatic cancer
Authors: Sangwan Veena , Jensen Kelsey M. , Dudeja Vikas , Chugh Rohit , Banerjee Sulagna , Vickers Selwyn M. , Park Morag , Saluja Ashok K. 
Published: October 2015

Abstract
Background: Minnelide, a pro-drug of the Chinese herb triptolide, is currently in Phase I clinical trials against pancreatic cancer. Preclinical studies with Minnelide have demonstrated its efficacy in preventing tumor formation and causing tumor regression in multiple animal models of pancreatic cancer. However, its mechanism of action remains unclear. Pancreatic cancer cells overexpress several receptor tyrosine kinases including the Met and EGF receptors which drive proliferation, migration and invasion of these cells. Here, using human pancreatic cancer cells as well as the KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) animal model, we show the ability of triptolide, or its water soluble pro-drug, Minnelide, to down-regulate the Met and EGF receptors, both in vitro and in vivo.
Methods:Pancreatic cancer cells were treated with triptolide for varying times (0-24h) and receptor levels evaluated using western blotting or confocal microscopy. The KPC mouse model recapitulates human disease progression and is therefore the most relevant model for chemotherapeutic drug testing. KPC animals, which spontaneously form pancreatic tumors, were treated with Minnelide for one week and tumors harvested. mRNA expression was analyzed using real time PCR and protein expression assessed by immunohistochemistry.
Results: Treatment with triptolide causes an increase in tyrosine phosphorylation at earlier time points (0.5 - 6h), accompanied by an increase in levels of the Met and EGF receptor tyrosine kinases. However, longer treatments (12-24h) resulted in marked decrease in levels of both Met and EGF receptors. Further investigation using tumors from KPC animals treated with Minnelide show a decrease in gene expression of both the Met and EGF receptors compared with tumors from saline injected animals. Furthermore, immunohistochemical analysis of formalin fixed paraffin embedded sections from these tumors show a decrease in levels of the Met receptor.
Conclusion: Treatment of cells or KPC pancreatic tumor bearing animals with triptolide or Minnelide leads to decreased expression of the Met and EGF receptor tyrosine kinases. These results lend further insight into the mechanism of action of Minnelide, a pro-drug currently in clinical trials against pancreatic cancer.
Citation Format: Veena Sangwan, Kelsey M. Jensen, Vikas Dudeja, Rohit Chugh, Sulagna Banerjee, Selwyn M. Vickers, Morag Park, Ashok K. Saluja. Triptolide abrogates expression of the Met and epidermal growth factor receptors in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B119.
Abstract B12: Circulating stroma-related molecules as potential biomarkers for pancreatic ductal adenocarcinoma
Authors: Belotti Dorina , Resovi Andrea , Taraboletti Giulia , Lawlor Rita T. , Scarpa Aldo , Giavazzi Raffaella 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Early diagnostic serological markers capable of detecting the disease in its asymptomatic early stage can change the fate of PDAC patients. PDAC is characterized by a relevant stroma formation. This study investigates the potential value of circulating stroma-related molecules as PDAC biomarkers.
To select candidate stroma-associated biomarkers for pancreatic cancer, a review of literature regarding proteomic analysis of PDAC was performed. Eight proteomic studies of differentially expressed sera proteins in PDAC patients and in genetically engineered mice (GEM) developing cancer in the pancreas were analyzed and 176 proteins were identified as potential PDAC biomarkers. Of these, 61 were selected as potentially interesting based on: a) presence in at least 2 independent analysis and/or b) relation to tumor/stroma interaction by Gene Ontology. These included extracellular matrix proteins and proteolytic fragments, matrix-degrading enzymes and their inhibitors, growth factors and adhesion molecules. Among them, 37 proteins could be explored by ELISA (BioRad Bio-plex System) in plasma of 25 early stage PDAC patients and 16 control subjects. Fourteen molecules were significantly modulated, with ten molecules up-regulated and four down-regulated.
This preliminary screening identified 14 potential plasma biomarkers. Specificity and sensitivity of these selected biomarkers are being validated on a larger number of PDAC patients and appropriate controls, including pancreatitis patients and on PDAC mouse models. A combination of some of these molecules might provide a useful tool for early PDAC diagnosis.
Supported by AIRC grant n. 2172
Citation Format: Dorina Belotti, Andrea Resovi, Giulia Taraboletti, Rita T. Lawlor, Aldo Scarpa, Raffaella Giavazzi. Circulating stroma-related molecules as potential biomarkers for pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B12.