bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B78: Warfarin blocks Gas6-mediated Axl activation required for pancreatic tumor plasticity and metastasis
Authors: Kirane Amanda , Ludwig Kathleen W. , Haaland Gry , Sandal Tone , Ranaweera Renata , Toombs Jason E. , Sullivan Laura A. , Wang Miao , Sorrelle Noah , Dineen Sean P. , Dellinger Michael T. , Lorens James B. , Brekken Rolf A. 
Published: October 2015

Abstract
Warfarin, a vitamin K antagonist anti-coagulant in clinical use for over 50 years, is reported to exert anti-cancer effects. We hypothesized that the molecular mechanism underlying the observed anti-tumor effects of warfarin is unrelated to generalized anti-coagulation, but rather due to inhibition of the Axl receptor tyrosine kinase. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here we document that inhibiting Gas6-mediated Axl activation with low dose warfarin blocks pancreatic cancer progression and spread. Warfarin and other Axl-targeting agents inhibit tumor progression and block spontaneous metastasis in multiple murine models of pancreatic cancer. Warfarin inhibited Axl-dependent tumor cell migration, invasiveness and proliferation while increasing apoptosis and sensitivity to chemotherapy. We demonstrate that Axl signaling is necessary for pancreatic tumor cell epithelial plasticity which is potently reversed by warfarin or selective Axl inhibition in vitro and in vivo. We anticipate Axl is a critical driver of pancreatic cancer progression and its inhibition with low dose warfarin or Axl-selective targeting agents may significantly improve outcome in patients.
Citation Format: Amanda Kirane, Kathleen W. Ludwig, Gry Haaland, Tone Sandal, Renata Ranaweera, Jason E. Toombs, Laura A. Sullivan, Miao Wang, Noah Sorrelle, Sean P. Dineen, Michael T. Dellinger, James B. Lorens, Rolf A. Brekken. Warfarin blocks Gas6-mediated Axl activation required for pancreatic tumor plasticity and metastasis. [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 B78.
Abstract B83: Cannabinoids as an adjuvant therapy for pancreatic cancer
Authors: Hospodor Andy D. 
Published: October 2015

Abstract
In over 20 states, cancer patients have access to cannabinoids (aka medical marijuana) to treat symptoms of chemotherapy, such as nausea and lack of appetite. However, new evidence, both scientific and empirical, suggests that higher doses of cannabinoids may be an effective adjuvant alongside traditional chemotherapy agents, such as Gemcitibine. While daily dosages of 10 to 40mg are commonly used to control nausea, pancreatic cancer cells are known to over express the endo-cannabinoid receptor CB1 one hundred fold, requiring much higher dosages. Cannabinoids target different receptors than traditional chemotherapy agents with low combinatorial toxicity, and as such present a class of new treatments. In an n=1 study of a patient with stage IV pancreatic adeno-carcinoma, we augmented the standard Gemcitibine chemotherapy with balanced initial doses of 50mg THC and 50mg CBD that increased over a four week period to achieve a 12.5 mg/kg total cannabinoid dosage. Curiously, after ten days the patient stopped presenting signs of cannabinoid use, such as red eyes, slurred speech and clumsiness. However, the patient’s CA-19-9 marker increased from 8,800 ul/L at diagnosis to 25,500. Over the next four weeks, dosage of CBD was held constant and THC was increased to 1050mg daily for a combined dosage of 20mg/kg. At week 6, the CA-19-9 marker began decreasing and cannabinoid dosage was leveled off, although a higher dosage was planned for weeks 8-12. At week 15, CA-19-9 markers dropped to pre-diagnosis levels and a CAT scanned revealed shrinkage of the tumor. Rate of decrease in CA-19-9 exceeded previously published rates for patients with positive outcomes from Gemcitibine alone. Although many pancreatic cancer patients have access to cannabinoids, issues such as potency, purity and bio-availablity will impact future adjuvant cannabinoid therapies. We have addressed these issues with existing technology in the hopes of supporting large scale trials that will examine the efficacy of Gemcitibine + cannabinoid adjuvants in the treatment of pancreatic cancer.
Citation Format: Andy D. Hospodor. Cannabinoids as an adjuvant therapy 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 B83.
Abstract B87: Cell lines generated from PDAC transgenic mice reveal integrin αvβ6 modifies the invasive phenotype of pancreatic cancer
Authors: Reader Claire S. , Vallath Sabari , Morton Jennifer , Steele Colin , Kocher Hemant M. , Keyse Stephen M. , Sansom Owen , Marshall John F. 
Published: October 2015

Abstract
Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the UK. Five-year survival rates are less than 3% and haven’t improved over the last 40 years. Thus novel approaches are required urgently. We have found that high expression of the integrin β6 subunit gene (ITGB6) correlates with a significant reduction (Hazard Ratio 1.74; Logrank p=6x10-4) in overall survival from PDAC. Thus we have begun to examine the biological functions mediated by αvβ6 in a transgenic model of PDAC.
A panel of cell lines were generated from PDAC tumors of a novel transgenic mouse and characterized for markers of tissue identity, integrin expression and ability to invade using 3D-organotypic assays. Cell populations appeared to contain both epithelial (E-cadherin positive) and mesenchymal (vimentin positive) characteristics, highlighting their polyclonality. In addition, two cell populations, KVC1 and KPCD3, expressed low levels of αvβ6 and were studied further. KVC1 and KPCD3 cells were labeled with 10D5 (anti-αvβ6) and sorted by FACS to obtain high-αvβ6 expressing monoclonal cell lines. The resulting cell lines after four rounds of sorting (S4) demonstrated mean MFI values of approximately 4.5-fold (KVC1 vs. KVC1 S4 A+) and approximately 3-fold (KPCD3 vs. KPCD3 S4 E+) higher than their parental counterparts. To compare the invasion profile of the parental populations and S4 monoclonal cell lines, cells were placed in 3D organotypic assays with mouse embryonic fibroblasts (MEFs) for 14 days before gels were fixed and processed to paraffin. H&E stained sections revealed that parental populations KVC1 and KPCD3 formed invasive, single-cell walled ductal structures that had penetrated into the matrigel-collagen mix, but only in the presence of MEFs. In contrast, αvβ6-positive S4 populations, KVC1 S4 A+ and KPCD3 S4 E+, also demonstrated strong invasion but the invasive ductal phenotype was lost, the cells invading as small cohesive groups and individual cells. These data suggest that the pattern of PDAC tumour invasion may be modulated by expression of the integrin αvβ6. Current studies explore the mechanisms by which these phenotypic changes are generated.
Citation Format: Claire S. Reader, Sabari Vallath, Jennifer Morton, Colin Steele, Hemant M. Kocher, Stephen M. Keyse, Owen Sansom, John F. Marshall. Cell lines generated from PDAC transgenic mice reveal integrin αvβ6 modifies the invasive phenotype of 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 B87.
Abstract B89: Polyisoprenylated cysteinyl amide inhibitors of PMPMEase inhibit pancreatic cancer cell viability and migration: Implications for pancreatic cancer therapy
Authors: Nkembo Augustine T. , aguilar Byron J. , Duverna Randolph , Amissah Felix , Lamango Nazarius S. 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly neoplasms due to lack of effective targeted therapies. This vacuum stems from the fact that over 90% of pancreatic cancer cases harbor the K-Ras mutation which has been very challenging to drug. The numerous efforts to drug oncogenic Ras have involved inhibiting the post-translational modifications that are essential to its proliferative activity. These drug discovery efforts have largely ignored a critical step in the metabolism of Ras and related proteins involving polyisoprenylated methylated protein methyl esterase (PMPMEase).
The objectives of these studies were to test the hypothesis that PMPMEase hyperactivity promotes pancreatic cancer progression. The potential for polyisoprenylated cysteinyl amide inhibitors (PCAIs) of PMPMEase as potential anticancer agents was evaluated against PDAC cell lines MIAPaCa-2 with K-Ras mutation and BxPC-3 with wild type K-Ras for their effects on cell viability, migration, and cytoskeletal organization.
The PCAIs inhibited the viability of MIAPaCa-2 and BxPC-3 cells with 48 h EC50 values as low as 1.9 and 3.2 µM, respectively. Erlotinib and Salirasib (FTS) were ineffective at concentrations in excess of 20 µM. The PCAIs also inhibited MIAPaCa-2 cell migration by up to 50% at 0.5 µM and disrupted F-actin organization at 5 µM. Further investigations showed that at the EC50 concentrations the PCAIs caused the pancreatic cancer cells to die by apoptosis. The cell cycle analysis for MIAPaCa-2 cells showed that the PCAIs block the cells growth at G0/G1 phase.
The results showed that the PCAIs are over 10-fold more effective than Salirasib and Erlotinib against PDAC cell viability. Furthermore, their effects against cell migration and actin filament organization suggest their potential for treating tumor growth and metastasis in not only PDAC but other cancers with oncogenic Ras.
Citation Format: Augustine T. Nkembo, Byron J. aguilar, Randolph Duverna, Felix Amissah, Nazarius S. Lamango. Polyisoprenylated cysteinyl amide inhibitors of PMPMEase inhibit pancreatic cancer cell viability and migration: Implications for pancreatic cancer therapy. [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 B89.
Abstract B90: Hapten enhanced personalized chemoimmunotherapy by ultra-minimum incision personalized intratumoral chemoimmuno-therapy: UMIPIC-therapy in advanced pancreatic cancer
Authors: Yu Baofa , Gao Feng , Han Wei , Ma Zhenlu 
Published: October 2015

Abstract
Backgound: To evaluate the clinical effectiveness of hapten enhanced chemoimmunotherapy in the treatment of advanced pancreatic cancer by ultra-minimum incision personalized intratumoral chemoimmuno-Therapy (UMIPIC-Therapy) and to further analyze its role as an immune adjuvant.
Method: Patients with late stage pancreatic cancer (92 cases) were treated with UMIPIC-Therapy or just intratumoral Chemotherapy (ITCT) , UMIPIC-Therapy is a proprietary therapeutic regimen which is composed of three components (i.e. an oxidant, a cytotoxic drug and a hapten) that is utilized in chemotherapeutic modulation. The patients (at end of study, 47 patients with complete response analysis data and 45 patients with complete survival data were in the randomly divided two groups: Control group of ITCT alone with an oxidant and a cytotoxic drug without hapten and the experimental group receiving UMIPIC-Therapy with an oxidant, a cytotoxic drug plus hapten.
Result: In the ITCT (control) and UMIPIC (experimental) groups, the clinical response rates were 92.86% and 82.88% respectively; the median survival time and 6-month survival rate were 4.98 months vs 6.45 months and 45% vs 64%, respectively. While all of above mentioned showed no statistical difference (P&gt;0.05), 1-year survival rate of the ITCT group was 5% while those of the ITCIT group was 28% and statistically significant (P&lt;0.05).
Conclusion: The hapten enhanced immunotherapy by ultra-minimum incision personalized intratuoral chemoimmuno-therapy (UMIPIC-Therapy) is shown to be effective in the pancreatic cancer. Our data suggests that the hapten plays an important role in prolonging the patient survival time is could be very valuable in future clinic applications.
Citation Format: Baofa Yu, Feng Gao, Wei Han, Zhenlu Ma. Hapten enhanced personalized chemoimmunotherapy by ultra-minimum incision personalized intratumoral chemoimmuno-therapy: UMIPIC-therapy in advanced 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 B90.
Abstract IA20: Harnessing the immune reaction associated with pancreas carcinoma for therapy
Authors: Beatty Gregory L. 
Published: October 2015

Abstract
Macrophages are a prominent feature of many solid malignancies. However, their presence within tumors most often portends a poor prognosis due to their ability to promote tumor growth, invasion and metastasis. In pancreatic ductal adenocarcinoma (PDAC), macrophages are observed at disease conception and are present throughout all stages of tumor development including metastasis. Strategies to target macrophages in cancer have focused on approaches to 1) deplete macrophages or their precursors, 2) block myeloid cell recruitment to tumor tissues, and 3) inhibit tumor-promoting functions directed by macrophages. However, macrophage biology is largely dependent on cues received from the surrounding microenvironment such that macrophages can be polarized with either tumor promoting or tumor suppressing properties. In this regard, we have previously demonstrated that macrophages can be redirected in vivo with anti-tumor properties leading to depletion of tumor-associated fibrosis and major tumor regressions in both mice and humans. Macrophages responding to systemic activation of the CD40 pathway using an agonist CD40 monoclonal antibody were required for tumor regressions observed in a spontaneous model of murine PDAC. However, not all murine PDAC lesions responded to CD40 therapy. Similarly, treatment response heterogeneity detected on 18FDG-PET/CT was observed in patients with newly diagnosed chemotherapy-naive PDAC who were treated with a fully human CD40 agonist. These findings demonstrate that macrophages associated with PDAC can be harnessed for therapy but also emphasize the importance of tumor intrinsic properties in regulating the efficacy of macrophage immunotherapy in PDAC. Current studies will be presented that investigate 1) the mechanism of action by which macrophages facilitate stromal depletion and 2) potential mechanisms of resistance to macrophage immunotherapy in PDAC.
Citation Format: Gregory L. Beatty. Harnessing the immune reaction associated with pancreas carcinoma for therapy. [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 IA20.
Abstract IA21: The basis of immune suppression in murine pancreatic ductal adenocarcinoma
Authors: Fearon Douglas T. 
Published: October 2015

Abstract
Immune therapy of human pancreatic ductal adenocarcinoma (PDAC) with the T cell checkpoint antagonists, anti-CTLA-4 and anti-PD-L1, has been unsuccessful. To determine the reason for this, we studied the KPC mouse model of autochthonous PDAC in which cancer cells express KrasG12D and p53R172H, and have lost the wild type p53 allele (LOH). These tumors resemble human PDAC in not responding to treatment with anti-CTLA-4 or anti-PD-L1. PDAC-bearing mice have CD8+ T cells specific for antigen(s) expressed by cancer cells. Thus, the ineffectiveness of T cell checkpoint antagonist immune therapy is not explained by the absence of an anti-tumor immune response, and immune suppression in the tumor microenvironment must occur mainly by another means. We have shown that this immune suppressive process depends on the stromal cell known as the “cancer-associated fibroblast” (CAF) that is identified by the membrane protein marker, “fibroblast activation protein” (FAP). Conditionally depleting the FAP+ CAF (Kraman M, et al., Science 2010) leads to T cell-mediated slowing of PDAC growth, and co-treatment with anti-PD-L1 enhances this effect (Feig C, et al. PNAS 2013). Three observations directed attention to the chemokine, CXCL12, as the mediator of immune suppression: the FAP+ CAF is the source of CXCL12 mRNA in PDACs; CXCL12 protein selectively “coats” the cancer cells; and T cells are excluded from the CXCL12-coated cancer cell-containing regions of the tumor. We treated PDAC-bearing mice for 24 hr with AMD3100/Plerixafor, a small molecule antagonist of the CXCL12 receptor, CXCR4, alone or together with anti-PD-L1. Tumors from AMD3100-treated mice exhibit frequent T cells within cancer cell-containing regions, and tumors from dual treated mice have even more T cells. Importantly, whereas tumor volume doubles in control mice in 6 days, AMD3100 alone arrests tumor growth, and AMD3100 + anti-PD-L1 treatment decreases tumor volume by 15%. Both therapies eliminate almost all cancer cells, leaving a residual mass containing only PanIN, inflammatory cells, and desmoplastic matrix. These findings may be relevant not only to human PDAC, but also to colorectal and ovarian carcinoma, all of which also contain FAP+ CAFs and CXCL12-coated cancer cells, demonstrate exclusion of T cells from the vicinity of cancer cells, and are resistant to therapy with anti-PD-1/anti-PD-L1.
Citation Format: Douglas T. Fearon. The basis of immune suppression in murine 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 IA21.
Abstract PR07: Transcriptome meta-analysis identifies new 5-gene classifier for early detection of pancreatic cancer
Authors: Bhasin Manoj , Bucur Octavian , Ndebele Ken , Plati Jessica , Bullock Andrea , Gu Xuesong , Castan Eduardo , Najarian Robert , Yeh Jen Jen , Der Channing , Haines Jon Cody , Ruping Karl , Miksad Rebecca , Khosravi-Far Roya , Libermann Towia Aron 
Published: October 2015

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a truly devastating disease, primarily due to late diagnosis when curative resection is no longer possible and the lack of accurate early detection biomarkers. Therefore, increasing PDAC survival depends heavily on improving the accuracy and effectiveness of early PDAC detection.
Methods:Key PDAC biomarkers were identified through an optimized meta-analysis strategy of raw data in 4 PDAC transcriptome datasets (training sets). Application of identical normalization and statistical testing procedures for each dataset generated a list of differentially expressed genes by empirical Bayes moderated t-statistic. The top ranking PDAC-specific genes from this list that were consistently differentially expressed in these training sets were used for developing a classifier for PDAC. The biomarker panel with the highest sensitivity and specificity in the training sets was validated for diagnostic performance in nine independent validation datasets. A subset of genes in the panel were evaluated by immunohistochemistry (IHC) in human PDAC tissue sections. Cell based assays assessed the effect of two genes on PDAC migration and invasion.
Results and Conclusions: A 5-gene classifier panel was identified that disntinguished between PDAC and normal pancreas with high sensitivity, specificity and accuracy in the four training sets. Validation of this 5-gene predictor in 9 independent test sets confirmed the diagnostic accuracy to not only discriminate accurately between PDAC and healthy controls, but also between pancreatitis and PDAC. IHC analysis of two of the proteins encoded by the panel confirmed enhanced expression in PDAC cells. Cell-based experiments demonstrated that both proteins enhance migration and invasion of PDAC cells as well as soft agar growth, suggesting a causal link to PDAC development and progression. The immediate clinical utility upon further prospective validation of this PDAC biomarker panel will be accurate PDAC diagnosis in patients with pancreatic abnormalities on imaging, risk stratification and evaluation of the risk of malignancy in pancreatic cysts.
This abstract is also presented as Poster B26.
Citation Format: Manoj Bhasin, Octavian Bucur, Ken Ndebele, Jessica Plati, Andrea Bullock, Xuesong Gu, Eduardo Castan, Robert Najarian, Jen Jen Yeh, Channing Der, Jon Cody Haines, Karl Ruping, Rebecca Miksad, Roya Khosravi-Far, Towia Aron Libermann. Transcriptome meta-analysis identifies new 5-gene classifier for early detection of 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 PR07.
Abstract PR08: Pulling out all the stops: Exploiting macropinocytosis inhibition for the treatment of pancreatic cancer
Authors: Commisso Cosimo , Ramirez Craig , Soydaner-Azeloglu Rengin , Bajor David L. , Vonderheide Robert H. , Bar-Sagi Dafna 
Published: October 2015

Abstract
Oncogenic Ras stimulates macropinocytosis, an endocytic mechanism of fluid-phase uptake that produces large intracellular vesicles known as macropinosomes. Recently, we have linked the macropinocytic uptake of extracellular albumin and its subsequent degradation to amino acid supply and proliferation in Ras-transformed cells. The ability of albumin to serve as a nutrient source in oncogenic Ras-expressing cells is blocked by inhibiting its internalization via treatment with 5-(N-Ethyl-N-isopropyl) amiloride (EIPA). We determined that EIPA treatment diminished the growth of pancreatic tumor xenografts and that this effect was selective for tumors with a high macropinocytic index. Currently, we are exploring the feasibility of employing macropinocytosis inhibition as an anticancer therapeutic modality utilizing an autochthonous mouse model of pancreatic cancer. In these autochthonous tumors, macropinocytosis is a prominent feature of pancreatic cells found in mid- to late-stage PanIN lesions, as well as in fibroblasts and immune cells residing within the tumor stroma. We have found that EIPA treatment results in a rapid and robust reduction in proliferative capacity both in tumor cells and the surrounding stromal cells. Intriguingly, our preliminary data indicates that EIPA treatment reduces the number of activated fibroblasts associated with PanIN lesions, decreases collagen deposition and results in an increase in blood vessel diameter. Studies have demonstrated that targeting components of the extracellular matrix within the tumor stroma can cause expansion of the vasculature, which can be harnessed to improve drug delivery and permeability to the tumor. Altogether, our findings suggest that macropinocytosis inhibition could be exploited not only to target the tumor cells, but also to target the tumor stroma and enhance the delivery of chemotherapeutics.
This abstract is also presented as Poster B37.
Citation Format: Cosimo Commisso, Craig Ramirez, Rengin Soydaner-Azeloglu, David L. Bajor, Robert H. Vonderheide, Dafna Bar-Sagi. Pulling out all the stops: Exploiting macropinocytosis inhibition for the treatment of 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 PR08.