bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1671: Fibroblast growth factor receptor 3 enhances progression of hepatocellular carcinoma
Authors: Paur Jakob , Nika Lisa , Maier Christiane , Kostka Julia , Heffeter Petra , Kappel Sonja , Kandioler Daniela , Holzmann Klaus , Marian Brigitte , Berger Walter , Grusch Michael , Grasl-Kraupp Bettina 
Published: August 2015

Abstract
Purpose of the study. To provide mechanistic evidence that fibroblast growth factor receptor 3 (FGFR3) and its two splice variants, FGFR3-IIIb and -IIIc, impact considerably on the malignant phenotype of hepatocellular carcinoma (HCC).
Experimental procedures. The occurrence of FGFR3 and its two isoforms was analyzed in human HCC samples by qRT-PCR and immunostaining. In hepatoma/hepatocarcinoma cell lines FGFR3-isoforms were overexpressed by lentiviral constructs or were down-modulated by siRNA or an adenoviral kinase-dead FGFR3 (kdFGFR3) construct. Cell lines were tested for anchorage-independent growth, proliferation at low-densities and their cell-cycle distribution, as well as their ability to form tumors after subcutaneous injection into the flanks of SCID-mice.
Results. Upregulated FGFR3 was found in almost 50% of HCC patients, which was often due to the enhanced expression of FGFR3-IIIb. Furthermore, patients with FGFR3-IIIb overexpression showed early tumor recurrence indicating that this isoform may be a major player in tumor progression. In hepatoma/hepatocarcinoma cells, upregulated FGFR3-IIIb or FGFR3-IIIc conferred an enhanced capability for proliferation and tumor growth. Both isoforms enhanced downstream signaling and increased the cells’ ability to grow at low densities. The tumorigenicity of cells in SCID-mice was augmented more by variant IIIb than by IIIc. This stronger impact of FGFR-IIIb on cell proliferation could also be seen in analysis of the cell cycle distribution, which was shifted to the S-phase. Conversely, siFGFR3 and kdFGFR3 affected both receptor-variants and strongly reduced clonogenic growth at low density and anchorage-independent growth. Furthermore, kdFGFR3 arrested the cells in G2/M and strongly attenuated tumor formation in vivo.
Conclusions: Upregulated FGFR3 is associated with development and progression of hepatocellular carcinoma. Accordingly, blockade of FGFR3-mediated signaling may be a promising therapeutic approach to antagonize growth and malignant behavior of HCC cells.
Citation Format: Jakob Paur, Lisa Nika, Christiane Maier, Julia Kostka, Petra Heffeter, Sonja Kappel, Daniela Kandioler, Klaus Holzmann, Brigitte Marian, Walter Berger, Michael Grusch, Bettina Grasl-Kraupp. Fibroblast growth factor receptor 3 enhances progression of hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1671. doi:10.1158/1538-7445.AM2015-1671
Abstract 1675: MEF2 plays a significant role in the tumor inhibitory effects of agarose encapsulated RENCA cells through the EGF receptor
Authors: Martis Prithy C. , Laramore Melissa A. , Dudley Atira , Smith Barry H. , Gazda Lawrence S. 
Published: August 2015

Abstract
Identification of the molecular targets involved in the tumor growth inhibition induced by agarose encapsulated mouse renal adenocarcinoma (RENCA) cells will aid in an understanding of the mechanism of action and may allow for the discovery of key targets for therapeutic intervention. The epidermal growth factor receptor (EGFR/ERBB1/HER1) and related family members have been shown to transduce extracellular signals through the mitogen-activated protein kinase (MAPK) pathway to regulate post-translational regulation of myocyte enhancer factor 2 (MEF2) proteins. We have previously reported that suppression of MEF2 isoforms in target tumor cells reduced the growth inhibitory effect of RENCA macrobeads. In this study, we evaluated signaling through EGFR in response to RENCA macrobead conditioned media and examined post-translational activation of MEF2D, using the human prostate cancer, DU145 and the human breast adenocarcinoma, MCF7 cell lines. DU145 and MCF7 cells exposed to naïve or conditioned media were evaluated using In-Cell Western™ analysis for the expression of phospho-EGFR Y1068 in parallel with total EGFR. Phospho-MEF2D and total MEF2D were assessed in nuclear extracts using western blotting. In the DU145 cells, exposure to RENCA macrobead conditioned media activates EGFR as evidenced by phosphorylation of the receptor at tyrosine 1068 in parallel with the increasing age and inhibitory capacity of macrobeads. Further, the growth inhibition of DU145 cells exposed to RENCA macrobead conditioned media is accompanied by dephosphorylation of MEF2D at Serine 444 supporting a role for increased MEF2D transcriptional activity in the inhibitory effect. MCF7 cells are less sensitive to RENCA macrobead-induced growth inhibition, EGFR is not phosphorylated by 2 hours following exposure to macrobead conditioned media and MEF2D remains phosphorylated at Serine 444. These findings support the hypothesis that RENCA macrobeads signal, at least in part, through the EGF receptor to differentially regulate MEF2D, which is significant for macrobead-induced tumor growth inhibition.
Citation Format: Prithy C. Martis, Melissa A. Laramore, Atira Dudley, Barry H. Smith, Lawrence S. Gazda. MEF2 plays a significant role in the tumor inhibitory effects of agarose encapsulated RENCA cells through the EGF receptor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1675. doi:10.1158/1538-7445.AM2015-1675
Abstract 1678: Bioavailability and anti-tumor activity of capsaicin in human small cell lung cancer
Authors: Hurley John D. , Rollyson William D. , Stover Cody A. , Brown Kathleen C. , Perry Haley E. , Stevenson Cathryn D. , Crabtree Clayton M. , Dom Aaron M. , Lau Jamie K. , Witte Theodore R. , Hardman W E. , Dasgupta Piyali 
Published: August 2015

Abstract
The nutritional compound capsaicin has been shown to display anti-neoplastic activity in breast, prostate and colon tumors xenografted in nude mice. Based on these data from other research laboratories, we wanted to determine the bioavailability of capsaicin in nude mice in vivo. We found that capsaicin was rapidly metabolized primarily in the liver. The bioavailability of intact capsaicin was highest in the lung. Therefore, we hypothesized that capsaicin should suppress the growth of lung tumors. We found that capsaicin induced robust apoptosis in human SCLC cell lines. Capsaicin decreased the growth rates of human SCLC tumors in two in vivo models, namely the CAM model and the nude mouse model. HPLC studies showed intact capsaicin in the tumors excised from nude mice. The heat-sensation activity of capsaicin is mediated by the transient receptor potential vanilloid (TRPV) family of proteins. Capsaicin functions as an agonist of the TRPV1 receptor. The apoptotic activity of capsaicin was found to be mediated by TRPV6 and not TRPV1. Preliminary data shows that capsaicin increases the expression of the TRPV6 receptor, causing apoptosis in human SCLCs.
Citation Format: John D. Hurley, William D. Rollyson, Cody A. Stover, Kathleen C. Brown, Haley E. Perry, Cathryn D. Stevenson, Clayton M. Crabtree, Aaron M. Dom, Jamie K. Lau, Theodore R. Witte, W E. Hardman, Piyali Dasgupta. Bioavailability and anti-tumor activity of capsaicin in human small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1678. doi:10.1158/1538-7445.AM2015-1678
Abstract 1682: Development and activity of a novel antibody-drug conjugate for the treatment of P-cadherin expressing cancers
Authors: Menezes Daniel , Abrams Tinya J. , Karim Christopher , Tang Yan , Ying Chi , Miller Kathy , Fanton Christie , Ghoddusi Majid , Wang Zhen , Patawaran Montesa , Pryer Nancy , Lees Emma , Damiano Jason 
Published: August 2015

Abstract
The cell surface glycoprotein P-cadherin is an attractive target for an antibody-drug conjugate (ADC) therapy as it is known to be highly expressed in a number of malignancies, including those arising in the epithelium of the breast, lung, bladder, esophagus, stomach, endometrium and colon, among others. In breast cancer, P-cadherin is frequently overexpressed in high grade invasive tumors and is a reliable marker of the basal-like breast cancer molecular subtype, a disease with no effective therapeutic treatment options. Based on the expression profile of P-cadherin in human cancer, a highly selective and potent ADC was developed to target cancer types overexpressing this glycoprotein. This ADC consists of a fully human anti-P-cadherin-specific antibody conjugated to the potent maytansine-derived microtubule-disruptor, DM1, via an SMCC non-cleavable thioether linkage (technology licensed from ImmunoGen, Inc.). In vitro, the ADC was demonstrated to selectively bind P-cadherin expressing cell lines, to rapidly internalize and traffic to lysosomes, and to release a sufficient amount of activated payload to potently induce a cytotoxic response in cell viability assays. Profiling of activity in a cell line panel indicated that this ADC can effectively target and kill P-cadherin-positive cancer cells representing breast, head and neck, and bladder carcinomas. In vivo, the ADC was highly efficacious in numerous relevant xenograft models of P-cadherin expressing cancers, including breast, head and neck, bladder and lung. From this promising cellular and in vivo activity, this ADC may be an effective treatment for patients with P-cadherin positive cancers of high unmet medical need.
Citation Format: Daniel Menezes, Tinya J. Abrams, Christopher Karim, Yan Tang, Chi Ying, Kathy Miller, Christie Fanton, Majid Ghoddusi, Zhen Wang, Montesa Patawaran, Nancy Pryer, Emma Lees, Jason Damiano. Development and activity of a novel antibody-drug conjugate for the treatment of P-cadherin expressing cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1682. doi:10.1158/1538-7445.AM2015-1682
Abstract 1683: Pharmacokinetic/pharmacodynamic (PK/PD) and toxicokinetic/toxicodynamic (TK/TD) modeling of preclinical data of FGFR2-ADC (BAY 1187982) to guide dosing in phase 1
Authors: Wittemer-Rump Sabine , Sommer Anette , Kopitz Charlotte , Huynh Hung , Schatz Christoph , Zierz Ruprecht , Braun Manuela , Meyer Kirstin , Laurent Dirk , Lippert Jörg , Prins Klaas 
Published: August 2015

Abstract
BAY 1187982 is an antibody drug conjugate (ADC) directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed in several cancer indications, such as gastric, breast, and ovarian cancer. Anti-tumor efficacy of BAY 1187982 has been demonstrated in several FGFR2-positive cancer cell line as well as patient-derived xenograft models. Toxicology findings from repeated dose preclinical safety studies in monkeys indicated effects related to the liver, kidney, heart and coagulation system. To predict the therapeutic index of BAY 1187982 in humans and to support the design of the first-in-human (FIH) study with respect to selection of dose and regimen, preclinical efficacy and toxicity findings were quantified. All available preclinical PK, TK, tumor response and toxicity data from mouse models and monkey studies were used to create a model framework to describe the PK, TK, PK/PD and TK/TD relationship as functions of BAY 1187982 dose, regimen and time. Human PK parameters based on scaling from monkey were used to predict PK profiles in humans for a range of doses and schedules. These sets of predicted exposure models were combined with the PK/PD as well as the TK/TD model to assess the expected efficacy (according to RECIST criteria) and toxicity range in humans, respectively. The dosing schedule leading to the largest therapeutic index and the dose escalation schema for the FIH study were determined. The FIH study is currently under preparation.
Citation Format: Sabine Wittemer-Rump, Anette Sommer, Charlotte Kopitz, Hung Huynh, Christoph Schatz, Ruprecht Zierz, Manuela Braun, Kirstin Meyer, Dirk Laurent, Jörg Lippert, Klaas Prins. Pharmacokinetic/pharmacodynamic (PK/PD) and toxicokinetic/toxicodynamic (TK/TD) modeling of preclinical data of FGFR2-ADC (BAY 1187982) to guide dosing in phase 1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1683. doi:10.1158/1538-7445.AM2015-1683
Abstract 1696: Blocking activity of a novel anti-MET humanized monoclonal antibody, KTN0216, is enhanced by IgG2 isotype in HGF-dependent and Met-amplified tumors
Authors: Mandiyan Sreekala , Robinson Brett S. , Kimmel Lida , McMahon Gerald , Hadari Yaron , Yang Yan 
Published: August 2015

Abstract
Aberrant activation of MET kinase can be mediated by ligand-dependent mechanisms through paracrine or autocrine stimulation by its ligand, HGF, or by ligand-independent mechanisms through gene amplification, over-expression or mutation. Both mechanisms of activating MET have been associated with promoting tumor growth and progression. The discovery of antagonistic MET antibodies has been challenging as many anti-MET antibodies promote kinase activation that leads to cell proliferation and migration. We have systematically screened MET antibodies using cell based functional assays and identified a number of antibodies that potently block MET-dependent cell proliferation, cell scattering as well as tumor growth in vivo. One such antibody, KTN-MET-IgG1, binds to the Sema/PSI domain and prevents HGF-MET interaction; additionally it induces receptor ubiqutination and degradation. To evaluate if the IgG isotype influences activity on MET activation and tumor growth we grafted the binding domains of this antibody onto 2 other IgG backbones: KTN-MET-IgG2 and KTN-MET-IgG4. Surprisingly, grafting the antibody variable regions onto the IgG2 framework dramatically enhanced the anti-MET activity in vitro and in vivo. Comparing to KTN-MET-IgG1 and KTN-MET-IgG4 antibodies with KTN-MET-IgG2 antibody, it demonstrated significantly better inhibition of receptor phosphorylation and cell proliferation in MET amplified tumor cell lines (EBC1, SNU5) and comparable activity in HGF-dependent tumor cell lines (A549, U87MG). KTN-MET-IgG2 treatment of tumor bearing mice achieved potent and prolonged suppression of tumor growth using the U87MG glioblastoma xenograft model and tumor growth regression with tumors remaining below detection for over 90 days post last dosing using the SNU5 gastric cancer xenograft model. In summary, we have found a novel IgG2 anti-MET antibody that inhibits tumor growth driven by HGF-dependent MET activation and MET amplification. A model to help explain the contribution of IgG2 isotype to enhanced blocking activity will be presented. The humanized version of KTN-MET-IgG2, KTN0216, is currently in preclinical development to evaluate tumor types best suited for KTN0216 treatment.
Citation Format: Sreekala Mandiyan, Brett S. Robinson, Lida Kimmel, Gerald McMahon, Yaron Hadari, Yan Yang. Blocking activity of a novel anti-MET humanized monoclonal antibody, KTN0216, is enhanced by IgG2 isotype in HGF-dependent and Met-amplified tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1696. doi:10.1158/1538-7445.AM2015-1696
Abstract 170: Survival prediction model with long non-coding RNA profile in lung adenocarcinoma cancer
Authors: Wang Wei-An , Lai Liang-Chuan , Tsai Mong-Hsun , Liu Tzu-Pin , Chuang Eric Y. 
Published: August 2015

Abstract
Long non-coding RNAs (LncRNA) are over 200 nucleotides bases non-protein-transcript RNA. Recently, there is a rapid growing literature about LncRNA. LncRNAs are considered as regulator of mRNA, structure components and precursor to small RNAs. However, the mechanism of LncRNA in tumor progression is still not clear yet. Previous studies has validated several LncRNA are associated with prostate cancer and breast cancer (e.g. MATAT-1, PCA3). Here, we investigate the LncRNA expression profile in lung adenocarcinoma cancer and predict patient survival with cox regression model.
We download the dataset GSE30219 on Gene Expression Omnibus, microarray data on Affymetrix U133-plus2 platform. With the LncRNA probes selection pipeline on U133-plus2 investigated by Du et al., total 2,427 probes are associated with LncRNA, and every LncRNA is targeted by at least four probes. It is believed that LncRNAs are subtype specific due to previous studies, so we first defined the differential expression LncRNA probes between Adenocarcinoma and Squamous cancer with student t-test, and selected the top 50 p-value probes. Next, with the profile of these 50 probes and the clinical data, we focus on survival analysis of Adenocarcinoma and cox regression was used to identify the survival related probes in the 50 probes, P-value &lt; 0.05. Finally, the expression profiles of survival related probes were trained with cox regression again to build up a prediction model.
With score given by the prediction model, samples are divided into two groups: high-risk and low-risk when score higher than 0 or score under 0, respectively. The Kaplan-Meier curve was used to illustrate the relationship between two groups. By using GSE30219 as training model set, GSE30219 was used as internal-validation and GSE8894 was used as external validation. The result of internal-validation shows significantly different. The difference of two groups on external- validation shows, although not greatly as internal- validation, there is still exists a slightly differences.
To sum up, LncRNA profiles in Lung Adenocarcinoma might play a role in survival rate. However, further improvement of prediction model is needed since the risk ratio of each sample should be reported, not only the cox scores. Also the Adenocarcinoma specific LncRNA probes should be investigated to enhance the confidence of prediction model.
Citation Format: Wei-An Wang, Liang-Chuan Lai, Mong-Hsun Tsai, Tzu-Pin Liu, Eric Y. Chuang. Survival prediction model with long non-coding RNA profile in lung adenocarcinoma cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 170. doi:10.1158/1538-7445.AM2015-170
Abstract 1703: A 3D tissue culture-based utra-high content screening platform that uses phenotypic profiling of cancer tissues to identify selective inhibitors of receptor tyrosine kinases
Authors: Price Leo S. , Booij Tijmen , Klop Maarten 
Published: August 2015

Abstract
3D tissue cultures provide a more physiologically relevant context for the screening of compounds, compared to 2D cell cultures. Cells cultured in 3D hydrogels also show complex phenotypes, increasing the scope for phenotypic profiling.
Here we describe a high-content screening platform that uses human micro-tissues cultured in 3D in standard 384 well assay plates to study the activity of biologically active molecules. Image analysis tools were developed to process 3D image data to measure 854 phenotype-derived parameters. Multiparametric analysis was used to evaluate the effect of compounds on tissue morphology.
We applied this screening platform to measure the activity and selectivity of inhibitors of the c-Met and EGF receptor (EGFR) tyrosine kinases in 3D cultured prostate carcinoma cells. c-Met and EGFR activity was quantified based on the invasive phenotypic profiles induced by their respective ligands, HGF and EGF, which were added in parallel assays. c-Met and EGFR inhibitors generally showed the expected inhibitory profile equivalent to that obtained in the absence of cognate ligand. However, one phase-III c-Met inhibitor, displayed an unexpected phenotypic profile characterised by potent inhibition of tumour cell invasion and off-target effects consistent with a previously reported polypharmacology of this compound. The screening method was applied to a novel collection of 70 bi-specific compounds designed to target both c-Met and EGFR. Compounds were identified that induced phenotypic profiles indicative of selective inhibition of either c-Met, EGFR or both targets.
In conclusion, this poster describes a fully scalable high-content screening platform that uses phenotypic profiling to evaluate receptor tyrosine kinase inhibitor selectivity and activity in a physiologically relevant setting.
Citation Format: Leo S. Price, Tijmen Booij, Maarten Klop. A 3D tissue culture-based utra-high content screening platform that uses phenotypic profiling of cancer tissues to identify selective inhibitors of receptor tyrosine kinases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1703. doi:10.1158/1538-7445.AM2015-1703