bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2611: Function blocking ERBB3 antibody inhibits adaptive response to RAF inhibitor
Authors: Kugel Curtis Harrison , Hartsough Edward J. , Davies Michael A. , Aplin Andrew E. 
Published: May 2015

Abstract
ERBB3/HER3 is a member of the EGFR family of receptor tyrosine kinase. Our lab recently showed that treating melanoma cells with the FDAapproved small molecule BRAF inhibitor vemurafenib leads to an increase in ERBB3 signaling when grown in the presence of its ligand neuregulin (NRG1). Here, we show that targeting ERBB3 with a monoclonal antibody inhibits its activation and downstream signaling in the presence of vemurafenib and NRG1. This inhibition of ERBB3 led to a decrease in proliferation and increase in apoptosis in vitro as measured by EdU and AnnexinV/PI staining. Targeting ERBB3 in combination with mutant BRAF in vivo resulted in a delay of tumor re-growth in immune deficient mice compared to targeting mutant BRAF alone. Taken together, these results indicate that targeting ERBB3 in combination with mutant BRAF in melanoma may help enhance the initial effects of vemurafenib in the clinic.
Citation Format: Curtis Harrison Kugel, Edward J. Hartsough, Michael A. Davies, Andrew E. Aplin. Function blocking ERBB3 antibody inhibits adaptive response to RAF inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2611. doi:10.1158/1538-7445.AM2014-2611
Abstract 2627: Use of xenografts for preclinical drug testing
Authors: Lange Mark J. De , Némati Fariba , Versluis Mieke , Jager Martine J. , Luyten Gre P.M. , Decaudin Didier , Velden Pieter A. van der 
Published: May 2015

Abstract
Purpose: Uveal melanoma (UM) originates from melanocytes just like cutaneous melanoma (CM) and similar to CM, the MAPK pathway is involved in the development of UM. However, in vitro we showed an inverse correlation between MAPK and c-Met activation with increasing metastatic potential of UM. In this study, we aimed to target both Src and c-Met with respectively Dasatinib and Crizotinib in an experimental xenograft model.
Methods: We used tissue derived from four different human primary tumors which were subcutaneously transplanted in mice. We used the c-Met inhibitor Crizotinib to inhibit c-Met function and Dasatinib to inhibit MAPK via Src. We monitored pharmacodynamics and analysed treatment efficacy with kinase assays.
Results: Growth inhibition was seen after treatment with Dasatinib in all four tumors whereas Crizotinib effects remained limited. Dasatinib inhibited kinase activity in the xenografts and pre-treatment kinase activity of the xenograft turned out to be predictive for treatment efficacy.
Conclusion: Activated Src and c-Met are in vitro susceptible to Dasatinib and Crizotinib, respectively. In vivo Dasatinib showed an effect on both tumor growth and MAPK activity while Crizotinib effects remained limited to c-Met inhibition. Combined, these results support our in vitro pathway analysis and warrant for clinical trials with Dasatinib in UM and further in vivo analysis with Crizotinib.
Citation Format: Mark J. De Lange, Fariba Némati, Mieke Versluis, Martine J. Jager, Gre P.M. Luyten, Didier Decaudin, Pieter A. van der Velden. Use of xenografts for preclinical drug testing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2627. doi:10.1158/1538-7445.AM2014-2627
Abstract 2629: Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity
Authors: Tai Wei-Tien , Shiau Chung-Wai , Li Yong-Shi , Chang Chun-Wei , Huang Jui-Wen , Hsueh Ting-Ting , Chen Kuen-Feng 
Published: May 2015

Abstract
Background & Aims: Nintedanib, a triple angiokinase inhibitor, is currently being evaluated against advanced HCC in phase I/II clinical trials. Here, we report the underlying molecular mechanism by which nintedanib (BIBF-1120) induces an anti-HCC effect.
Methods: HCC cell lines were treated with nintedanib or its derivative (ΔN) and apoptosis, signal transduction, and phosphatase activity were analyzed. Purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants were used to investigate the potential effect of nintedanib on SHP-1. In vivo efficacy was determined in nude mice with HCC subcutaneous xenografts (n ≥ 8 mice).
Results: Nintedanib induced anti-proliferation in HCC cell lines by targeting STAT3. Ectopic STAT3 abolished nintedanib-mediated apoptosis in HCC cells. Nintedanib further activated SHP-1 in purified SHP-1 proteins suggesting that nintedanib directly affects SHP-1 for STAT3 inhibition. HCC cells or recombinant SHP-1 proteins expressing deletion of N-SH2 domain or D61A mutants restored the activity of nintedanib suggesting that the auto-inhibition structure of SHP-1 was relieved by nintedanib. To further elucidate whether the effect of nintedanib on SHP-1 is dependent on its angiokinase inhibition activity, we developed a novel kinase-independent derivative of nintedanib, ΔN. Although ΔN only retained the backbone of nintedanib without kinase activity, ΔN still induced substantial anti-HCC activity in vitro and in vivo by targeting STAT3.
Conclusions: Nintedanib induced significant anti-HCC activity independent of angiokinase inhibition activity in a preclinical HCC model by relieving autoinhibition of SHP-1. Our findings provide new mechanistic insight into the inhibition of HCC growth by nintedanib.
Citation Format: Wei-Tien Tai, Chung-Wai Shiau, Yong-Shi Li, Chun-Wei Chang, Jui-Wen Huang, Ting-Ting Hsueh, Kuen-Feng Chen. Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2629. doi:10.1158/1538-7445.AM2014-2629
Abstract 2636: Connexin 43 suppresses tumor angiogenesis by downregulation of vascular endothelial growth factor
Authors: Chen Man-Chin , Lee Che-Hsin 
Published: May 2015

Abstract
Gap junction intercellular communication (GJIC), which is performed by connexins, is crucial in the regulation of cellular functions. Connexin 43 (Cx43) is a general isoform expressed in most epithelial tissues especially in astrocytes. There were some studies indicated that Cx43 played a tumor suppressor which has been found in human tumors compared with adjacent normal tissues. Otherwise, there were some evidences showed that Cx43 overexpression affected metastasis. However, Cx43 plays a controversial role in tumor progression. Hypoxia, a hallmark of many solid tumors, is associated with angiogenesis and tumor progression. It activates a signal cascade that culminates in the stabilization of hypoxia-inducible factor 1 (HIF-1) transcription factor and activation of genes that possess hypoxia response elements (HRE). Herein, the loss of Cx43 was shown to stabilize HIF-1α, which is overexpressed in a majority of cancers and its overexpression correlates with poor prognosis and treatment failure. Meanwhile, we examined HIF-1α expression and activities in cancer cells with various Cx43 statuses. Loss of Cx43 expression in cancer cells resulted in increased HIF-1-dependent transcriptional activity and protein expression. In this study, we also found that Cx43 down-regulated VEGF and inhibited endothelial cell proliferation. Further work is warranted to understand the molecular mechanism leading to Cx43 effects by antiangiogenic signal pathway.
Citation Format: Man-Chin Chen, Che-Hsin Lee. Connexin 43 suppresses tumor angiogenesis by downregulation of vascular endothelial growth factor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2636. doi:10.1158/1538-7445.AM2014-2636
Abstract 2667: RG7287, a novel humanized anti-CDCP1 antibody with superior preclinical in vivo efficacy in combination with Paclitaxel
Authors: Kollmorgen Gwendlyn , Lifke Alexander , Nopora Adam , Bauss Frieder , Niederfellner Gerhard , Bossenmaier Birgit 
Published: May 2015

Abstract
CUB domain-containing protein 1 (CDCP1) is a transmembrane glycoprotein and a substrate of Src family kinase (SFK). It has been shown to be upregulated and significantly contributing to a number of different cancers, including colon, lung, breast, kidney, and pancreas cancer. High expression of CDCP1 has been shown to correlate with poor prognosis. CDCP1 is involved in the regulation of anoikis resistance, cell migration and invasion. We have recently described RG7287, a humanized glycoengineered therapeutic anti-CDCP1 antibody with a dual mode of action. (1) downregulation of the receptor from the cell surface, and (2) engaging immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC). Upon ligation of RG7287 to CDCP1 an initial phosphorylation of CDCP1 occurs, this transient activation results in the down-regulation of CDCP1. RG7287 prohibits the transformation potential of CDCP1 and Src in focus formation assays. In vivo, RG7287 increased the survival time of mice bearing tumors of MCF7 cells stably expressing CDCP1 compared to untreated CDCP1 overexpressing MCF7 tumors. Treatment of three different xenograft models with RG7287 inhibited tumor growth.
In this study we looked at the possibility of eradicating the tumors by combining RG7287 with paclitaxel. Combining the cytostatic with RG7287 increases tumor growth inhibition compared to RG7287 alone in one xenograft model. In another model the combination of RG7287 with paclitaxel leads to tumor stasis. These results indicate a potential combination therapy for RG7287. We also tested whether RG7287 inhibits metastasis in vivo. Using a metastasis model we could show convincing inhibition of metastasis.
Citation Format: Gwendlyn Kollmorgen, Alexander Lifke, Adam Nopora, Frieder Bauss, Gerhard Niederfellner, Birgit Bossenmaier. RG7287, a novel humanized anti-CDCP1 antibody with superior preclinical in vivo efficacy in combination with Paclitaxel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2667. doi:10.1158/1538-7445.AM2014-2667
Abstract 2677: Lysyl Oxidase a therapeutic target in pancreatic cancer
Authors: Saturno Grazia , Lopes Filipa , Viros Amaya , Morton Jennifer , Sansom Owen , Springer Caroline , Marais Richard 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a 5-year survival rate of only 6%. Despite advances in conventional therapies and targeted therapies, survival has not improved in the past three decades. We found that high expression of LOX (Lysyl Oxidase) is a poor prognostic marker in PDAC, suggesting a role in this disease. LOX is an amine oxidase that catalyzes the cross-linking of collagens and elastin in the extracellular matrix (ECM) thus regulating extracellular stiffness and contributing to desmoplasia (abundant fibrotic stroma). LOX inhibition has been associated with decreased phosphorylation of SRC (Proto-oncogene tyrosine-protein kinase Src) and FAK (Focal Adhesion Kinase) as a result of decreased interaction of integrins with the ECM. To further investigate the role of LOX in pancreatic cancer, we obtained PDAC cells derived from a transgenic mouse model that faithfully recapitulates the human disease. We found that LOX was upregulated in tumor cells from Pdx1-Cre KrasG12D/+ Trp53R172H/+ (KPC) mice compared to Pdx1-Cre KrasG12D/+ (KC) mice. Using a genetic approach we developed LOX-relevant models by silencing LOX in KPC cells via shRNA and overexpressing LOX in KC cells. We characterized these cells for their invasion ability and growth in a 3D environment. We then confirmed these in vitro results in allograft models in mice. Collectively, our results validate LOX as a therapeutic target in PDAC and suggest that its inhibition represents a new therapeutic strategy for PDAC patients.
Citation Format: Grazia Saturno, Filipa Lopes, Amaya Viros, Jennifer Morton, Owen Sansom, Caroline Springer, Richard Marais. Lysyl Oxidase a therapeutic target in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2677. doi:10.1158/1538-7445.AM2014-2677
Abstract 2683: Inhibition of BCAT1 suppresses the expression of pro-metastatic proteins and reduces cancer metastasis
Authors: Papathanassiu Adonia E. , Vu Hong A. 
Published: May 2015

Abstract
Recent evidence suggests that the cytosolic presence of branched chain amino acid aminotransferase (BCAT1) in adult tissues is associated with diverse pathological conditions including cancer and inflammatory diseases such as rheumatoid arthritis; in these diseases, BCAT1 appears to modulate the expression of many key proteins and to be a new druggable target. In cancer, BCAT1 physically associates with CD147 and regulates the levels and the cellular localization of the protein in a number of different cell lines in vitro and in vivo. Silencing of Bcat1 gene downregulates the total expression of CD147 in MDA-MB-435 cells, while inhibition of BCAT1 by sodium 4-methyl-5-oxo-hexanoate (ERG240) leads to suppression of the extracellular CD147 in the same cells. In turn, suppression of extracellular CD147 results in downregulation of CD147-associated proteins such as MCT4, matrix metalloproteinases (MMPs), cyclophilin A, and GAPDH. Furthermore, inhibition of BCAT1 is associated with prevention of cancer cell migration and reduction in secretion of metabolic by-products such as lactate. Surprisingly, treatment of MDA-MB-231 tumor-bearing animals with 2-deoxyglucose (2DG), a well-known inhibitor of glycolysis, leads to a decrease in the levels of c-MYC and BCAT1, an increase in the total expression of CD147, and the increased shedding of the extracellular CD147 into the circulation. This observation suggests that BCAT1-driven regulation of CD147 in cancer cells involves a complex mechanism. Inhibition of tumoral BCAT1 is expected to adversely affect the metastatic potential of various tumors not only through a reduction in cell motility but also through alterations in the tumor microenvironment, driven by inhibition of extracellular CD147.
Citation Format: Adonia E. Papathanassiu, Hong A. Vu. Inhibition of BCAT1 suppresses the expression of pro-metastatic proteins and reduces cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2683. doi:10.1158/1538-7445.AM2014-2683
Abstract 2690: Sorafenib/regorafenib and phosphatidyl inositol 3 kinase/thymoma viral proto-oncogene inhibition interact to kill tumor cells
Authors: Booth Larry A. , Cruickshanks Nichola A. , Sajithlal G B. , Hamed Hossein A. , Tavallai Seyedmehrad , Syed J , Grant Steven , Poklepovic Andrew , Dent Paul 
Published: May 2015

Abstract
The present study aimed to determine whether the multikinase inhibitors, sorafenib/regorafenib, worked in conjunction with PI3K/AKT inhibitors to enhance tumor cell death. It has been noted that combination of sorafenib/regorafenib with a PI3K inhibitor acetic acid (PX-866) resulted in tumor cell death, in a greater than additive fashion, in liver, colorectal, lung, breast, kidney and brain cancer cells. Similar data was obtained using AKT inhibitors perifosine and MK2206. Furthermore, even cells lacking PTEN remained as sensitive to this combinational approach as cells expressing PTEN. PX-866 treatment abolished AKT/GSK3 phosphorylation, with tumor cell death correlating with reduced activity of AKT and mTOR. Expression of activated AKT and to a lesser extent activated mTOR reduced drug combination lethality. Expression of B-cell lymphoma-extra large or dominant negative caspase 9, but not cellular FLICE-inhibitory protein short, protected cells from the drug combination. Treatment of cells with PX-866 increased protein levels of p62, LAMP2 and LC3/LC3II which correlated with the resulting increase in LC3-GFP vesicle numbers. Exposure of PX-866 treated cells to sorafenib reduced p62 and LAMP2 levels, decreased the ratio of LC3 to LC3II and reduced LC3-GFP vesicle levels. Knockdown of Beclin1 or ATG5 suppressed drug toxicity by ∼40%. In vivo, combination of either sorafenib and PX-866 or regorafenib and MK2206 cooperated to suppress the growth of established HuH7 and HCT116 tumors, respectively. Collectively our data demonstrates that the combination of sorafenib family kinase inhibitors with inhibitors of the PI3K/AKT pathway kills tumor cells in vitro and in vivo.
Citation Format: Larry A. Booth, Nichola A. Cruickshanks, G B. Sajithlal, Hossein A. Hamed, Seyedmehrad Tavallai, J Syed, Steven Grant, Andrew Poklepovic, Paul Dent. Sorafenib/regorafenib and phosphatidyl inositol 3 kinase/thymoma viral proto-oncogene inhibition interact to kill tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2690. doi:10.1158/1538-7445.AM2014-2690
Abstract 270: The association between medical history and breast cancer risk: A nationwide population-based case-control study using claim data
Authors: Chuang Shu-Chun , Wu Guo-Jie , Lu Yen-Shen , Lin Ching-Hung , Hsiung Chao Agnes 
Published: May 2015

Abstract
Introduction: It is suggested that chronic disease may be associated with increased cancer risk due to common risk factors, treatments to the prior conditions, or other unknown mechanisms. We evaluated the associations between prior medical conditions and subsequent breast cancer risk using the claim data from the Taiwan National Health Insurance (NHI) program.
Material and Method: A matched case-control study was conducted using the NHI 1,000,000 random sample dataset. A list of medical conditions based on literature review was retrieved for each case and control. The odds ratios (OR) and 95% confidence intervals (CI) of the association between medical conditions and breast cancer risk were estimated using conditional logistic regression and adjusted for occupation and number of breast cancer screening. The associations were estimated for younger (&lt;50 years old) and older subjects, separately.
Results: Prior breast diseases, hypertensive diseases, and endometriosis were associated with increased breast cancer risk in both age groups. Thyroid diseases were associated with breast cancer in the younger (OR=1.32, 95% CI=1.04-1.66) but not in the older group (OR=1.02, 95% CI=0.82-1.27). On the other hand, metabolic syndrome, particularly the disorders involved lipid metabolism, was associated with breast cancer only in the older group (OR=1.24, 95% CI=1.04-1.49).
Conclusion: Our analyses support results from previous studies that prior breast diseases and endometriosis were associated with subsequent breast cancer at all ages, thyroid diseases were associated with premenopausal, and metabolic syndrome were associated with postmenopausal breast cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Shu-Chun Chuang, Guo-Jie Wu, Yen-Shen Lu, Ching-Hung Lin, Chao Agnes Hsiung. The association between medical history and breast cancer risk: A nationwide population-based case-control study using claim data. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 270. doi:10.1158/1538-7445.AM2014-270
Abstract 2708: Development of allosteric regulators of the dimerization domains of the plasminogen-related growth factor family for the treatment of pancreatic cancer
Authors: Church Kevin J. , Kawas Leen , Harding Joseph , Lang Malte , McMicheal Michelle 
Published: May 2015

Abstract
The plasminogen-related family of growth factors includes the hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), both of which normally mediate a variety of cellular behaviors including proliferation, survival, and migration. A major contributor to the formation and persistence of various cancers is the dysregulation of these growth factor systems. Overexpression of the HGF receptor, c-Met, is common in many cancers including pancreatic cancer, and is associated with poor prognosis. Dysregulation of this system often leads to tumorigenesis and induction of various malignant phenotypes including increased proliferation, survival, migration, and invasion. In order to activate c-Met, HGF must first undergo an activation step in which it forms an HGF homodimer. Small molecule antagonists with homology to a putative “hinge” region within the HGF sequence have been developed that bind to HGF and allosterically block dimerization, therefore inhibiting c-Met signaling. Norleual [Nle-Tyr-Ile-ψ-(CH2-NH2)3-4-His-Pro-Phe] has previously been shown to inhibit HGF dimerization and HGF-dependent c-Met activation. We have assessed the ability of Norleual to block HGF dimerization and activation of c-Met within pancreatic cancer cells. Similar to the HGF/c-Met system, over-activation of the closely related MSP/Ron (MSP receptor) growth factor system has been identified as a critical contributor to pancreatic cancer progression. Due to overall high sequence homology between HGF and MSP, including the putative “hinge” region, we have hypothesized that MSP must also dimerize in order to efficiently activate the Ron receptor, and that this activation step can be targeted by “hinge” region homologs. Our results indicate that MSP naturally forms dimers and incubation with Norleual and similar “hinge” region antagonists inhibits dimerization. Further, we have demonstrated that MSP dimerization may be biologically significant and inhibition of dimerization suppresses MSP-dependent cell signaling and cell behaviors. The ultimate goal of this work is to develop a dual inhibitor capable of suppressing both the HGF and MSP growth factor systems, and further assess the therapeutic potential of these inhibitors for treatment of pancreatic cancer.
Citation Format: Kevin J. Church, Leen Kawas, Joseph Harding, Malte Lang, Michelle McMicheal. Development of allosteric regulators of the dimerization domains of the plasminogen-related growth factor family for the treatment of pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2708. doi:10.1158/1538-7445.AM2014-2708