bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 695: LA480, a c-Met antibody with neutralization and internalization properties, inhibits HGF-dependent and HGF-independent c-Met pathway activation and tumor growth
Authors: Wortinger Mark A. , Zeng Wei , Yang Wei Jennifer , Peek Victoria , Yan Lei , Lu Jirong , Chow Chi-Kin , Vaillancourt Peter , Davies Julian , Denning Irene , Weir Spring , Wooldridge James , Liu Ling 
Published: February 2011

Abstract
c-Met is a receptor tyrosine kinase that binds hepatocyte growth factor (HGF) and has been implicated in human cancer. Inappropriate activation of c-Met can be induced by ligand-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation, or by ligand-dependent autocrine or paracrine mechanisms. Indeed, amplification of the c-Met gene, with consequent protein overexpression and constitutive kinase activation, has been reported in a number of human cancers, including gastric, esophageal and non-small-cell lung carcinomas. Activating mutations of the c-Met gene have been found in a subset of patients with hereditary and sporadic papillary renal cancer, lung cancer, childhood hepatocellular carcinoma and gastric carcinoma. Another common constitutive c-Met activation in human tumors is increased protein expression as a consequence of transcriptional upregulation, in the absence of gene amplification. c-Met expression level has been correlated with poor prognosis in multiple tumor types. In addition, cMet activation by an elevated level of HGF has also been described in gliobastoma, breast carcinomas, rhabdomyosarcoma and osteosarcoma. We report here that LA480, a humanized monoclonal c-Met antibody, inhibits HGF-dependent and HGF-independent c-Met pathway activation and tumor growth. Our data demonstrate that LA480 blocks binding of HGF to c-Met as shown by ELISA, blocks HGF stimulation of phospho-Met in HCT116 cells, and blocks HGF stimulation of primary human hepatocyte proliferation. Moreover, LA480 internalizes and depletes cell surface c-Met, significantly reduces phospho-c-Met and total c-Met in multiple tumor cell lines, and inhibits proliferation of tumor cell lines that have c-Met gene amplification. In addition, LA480 does not stimulate biological activities that are elicited by HGF. Furthermore, LA480 reduces total c-Met and phospho-Met in xenograft tumors and significantly inhibits tumor growth in both ligand-independent and ligand-dependent mouse xenograft models. These findings suggest that LA480 may be a promising therapy for treatment of cancers driven by ligand-dependent and ligand-independent c-Met activation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 695.
Abstract 702: RON receptor tyrosine kinase: A potential therapeutic target in malignant pleural mesothelioma
Authors: Gray Steven G. , Easty David , Nonaka Daisuke , Soltermann Alex , Murer Bruno , Kennedy M John , O'Donnell Dearbhaile M. , Mutti Lucciano , Pass Harvey I. , O'Byrne Kenneth J. 
Published: February 2011

Abstract
BACKGROUND: Expression of receptor tyrosine kinases (RTK) and their cognate ligands has been described in mesothelioma, leading to the hypothesis that autocrine growth pathways could be therapeutic targets of tyrosine kinase inhibitors (TKIs).
METHODS: Phospho-RTK arrays were used to evaluate phosphorylation of 42 RTKs in 4 mesothelioma cell lines and 11 mesothelioma surgical specimens. Western Blot analysis, IHC, cellular migration and invasion assays were performed.
RESULTS: Tumours contained 14 phospho-RTKs. RON emerged as a frequently identifed kinase which has not been previously reported in mesothelioma. An extended panel of sixteen mesothelioma tumour and five benign pleural tissue samples were characterised by western blot analysis. The presence of RON message was confirmed by RT-PCR with specific primers in mesothelioma cell lines Western blot analysis detected RON in 16 tumours and 4 cell lines but not in the SV-40 transformed normal mesothelial MET-5A cells. Mesothelioma expressed different isoforms of RON compared to benign pleural plaques: both benign pleural plaques and mesotheliomas expressed the shortform of RON (sf-RON), whereas, the larger RON variants, Δ160 and Δ165, were seen in mesothelioma samples.
IHC was subsequently carried out on a large series of FFPE samples (n&gt;400), with clinical followup to determine if RON expression correlates with prognosis or response to therapy. Scratch assays using antibodies directed against RON prevented MPM cell line migration
CONCLUSIONS: Mesothelioma contains multiple activated RTKs including RON. Previously, RON was shown to mediate epithelial mesenchymal transition (EMT). This may be significant given the epithelioid to sarcomatoid spectrum of mesothelioma. Expression of Δ160 and Δ165 was previously reported in gastric and colorectal cancers and may be associated with oncogenesis. RON has been identified as a therapeutic target in pancreatic cancer and this may also apply in mesothelioma. Functional studies on targeting RON in mesothelioma are ongoing.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 702.
Abstract 703: Suppression of neurotensin receptor type 1 expression and function by apigenin in human colorectal cancers involves protein kinase CK2/JNK pathway
Authors: Wang Xiaofu , Gulhati Pat , Rychahou Piotr G. , Silva Scott R. , Evers B. M. 
Published: February 2011

Abstract
Apigenin, a nonmutagenic chemopreventive agent found naturally in fruits and green vegetables, is an inhibitor of protein kinase CK2 (formerly casein kinase II), which is frequently upregulated in human cancers. Neurotensin (NT), a gut peptide, stimulates growth of colorectal cancers (CRCs) through its high affinity receptor (NTR1). In this study, we found that treatment with apigenin suppressed NTR1 expression in CRC cells HCT116, SW480 and SW620. Additionally, treatment with emodin, another natural inhibitor of CK2, and TBB (4,5,6,7-tetrabromo-1H-benzotriazole), a selective chemical inhibitor of CK2, suppressed NTR1 expression in these CRC cells, indicating that CK2 plays a role in NTR1 regulation. Moreover, apigenin significantly decreased phosphorylation of JNK1/2, whereas TBB decreased phosphorylation of JNK1 and emodin decreased phosphorylation of JNK2 in HCT116 cells; all three compounds decreased phosphorylation of JNK1 in SW480 cells. Treatment with the selective JNK1/2 inhibitor, SP600125, suppressed NTR1 expression in all CRC cell lines examined. Furthermore, apigenin significantly inhibited CRC cell proliferation and prevented NT-stimulated expression of IL-8, c-myc and Mcl-1, all which contribute to CRC proliferation or metastasis. We conclude that apigenin suppresses endogenous NTR1 expression and function in multiple CRC cell lines; this effect may involve CK2/JNK signaling. The downregulation of NTR1 in CRCs may represent an important mechanism for the anti-cancer effects of apigenin.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 703.
Abstract 713: Active hedgehog pathway in human primary gastric tumor models
Authors: Yu Shijun , Wu Chao , Song Xiaoming , Chen Taiping , Wery Jean-Pierre , Chen Yiyou 
Published: February 2011

Abstract
The hedgehog (Hh) signaling pathway is known to be essential for multiple aspects of embryonic development, and activation of the Hh pathway leads to the development of several human malignancies such as basal cell carcinoma and medulloblastoma. Recent data have implicated a much broader role of the Hh pathway in other human cancer as well as the maintenance of cancer stem cells. Loss-function mutation of Ptc and gain of gunction mutation of Smo in human malignancies make the components in Hh pathway attractive therapeutic targets. However, this pathway is readily deactivated once human tumor cells are propagated in cell culture, a prerequisite of most preclinical human cancer models. In order to identify useful models for the evaluation of novel therapeutics targeting the Hh pathway, we profiled the expression of Ptc, Smo, Gli in a cohort of twenty established human primary gastric tumor models by TaqMan real-time quantitative PCR reaction and immunohistochemistry (IHC). Seven of the twenty models displayed high expression of either Gli-1 or Gli-2. Eight models were found to have high expression level of Shh. And three models were found to have high level of Ptc. The Gli protein expression level is also examined with IHC. High levels of Gli and Shh in the selected models will be very useful to evaluate anticancer drugs against Hh signaling pathway for their drug activity and pharmacodynamic responses. These models, together with the associated clinical and pathological information, provide a unique platform to evaluate the in vivo activities of pharmaceutical agents targeting the Hh pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 713.
Abstract 734: Development of small molecule inhibitors of the phosphatase Shp2 by fragment screening
Authors: Wu Xin , Scott Latanya , Chen Liwei , Lawrence Harshani R. , Luo Yunting , Sebti Said M. , Wu Jerry , Lawrence Nicholas J. 
Published: February 2011

Abstract
Protein tyrosine phosphorylation, which is controlled by tyrosine kinase (PTK) and tyrosine phosphatase (PTP), regulates numerous cellular processes, including proliferation, survival, differentiation, migration and apoptosis. Accumulating evidence has shown that defective function of PTPs leads to aberrant protein phosphorylation, which is associated with many humane diseases, including cancer. Src homology 2 phosphatase-2 (Shp2) is a cytoplasmic, nonreceptor protein tyrosine phophatase. It is the first proto-oncogene identified in the PTP superfamily. The structure of Shp2 consists of two SH2 (N-SH2 and C-SH2) domains, a single PTP region and a C-terminal hydrophilic tail. In the basal state, Shp2 displays a low catalytic activity due to close interactions between the N-SH2 and PTP domains that keep the phosphatase in an autoinhibited closed conformation. Upon growth factor or cytokine stimulation, the SH2 domains of Shp2 binds to tyrosine phosphorylated docking proteins such as Gab1 and Gab2, which activates Src, Ras, and the Erk1/2 (Erk) mitogen-activated protein (MAP) kinase pathway. Shp2 gain-of-function mutations are found in leukemias and solid tumors and are linked to Noonan syndrome. Although Shp2 is involved in pathogenesis of human cancers, it is not clear how Shp2 mediates tumorigenesis. To aid chemical biology studies and ultimately experimental therapy, we have been actively engaged in the search potent and selective Shp2 inhibitors. We will describe the results of a fragment-based screen as a method for identifying Shp2 inhibitors. The fragment libraries were both purchased and constructed in-house with a bias towards compounds that would potentially function as phosphotyrosine mimics. This has revealed compounds with moderate to low activity (IC50 200-500 µM) that have served as the starting pints for fragment-to-lead development. The emerging structure-activity relationships will be discussed as well as synthesis, modeling and X-ray studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 734.
Abstract 772: Effects of natural products on proliferation of human breast cancer cells induced by estrogen or PhIP, a heterocyclic amine compound derived from cooked meat
Authors: Lee Choong Jae , Lee Mi Nam , Lee Hyun Jae , Lee Su Yel , Seok Jeong Ho , Jordan Mary Ann , Wilson Leslie 
Published: February 2011

Abstract
According to the traditional Asian medicine, herbs containing daidzein, hesperidin, oleanolic acid and bacalein were used as anti-inflammatory and anti-tumor folk medicines. On the basis of this information, in this study, we investigated whether natural products including daidzein, hesperidin, oleanolic acid and bacalein affect proliferation of MCF-7 human breast cancer cells stimulated by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) or estradiol. The results were as follows : (1) Both estradiol and PhIP significantly induced proliferation of MCF-7 cells at the concentrations of 10nM and 100nM, respectively; (2) Oleanolic acid and baicalein inhibited proliferation of PhIP-induced proliferation of MCF-7 cells, dose-dependently; (3) Daidzein and hesperidin also inhibited proliferation of estradiol-induced proliferation of MCF-7 cells, dose-dependently. We suggest that these four natural compounds can be novel drug candidates for preventing breast cancer provoked by dietary estrogenic compounds found in cooked meat such as PhIP. Also, effects of these four natural compounds on MAPK-ERK pathway should be investigated for elucidation of action mechanism through future study.
(Key words: Natural products, MCF-7, PhIP, Estradiol)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 772.
Abstract 777: Rosehip (Rosa canina) extracts prevent Akt-mediated cell proliferation in glioblastoma cells
Authors: McNair Patrice , Goktepe Ipek , Martin Patrick M. 
Published: February 2011

Abstract
Glioblastoma multiforme (GBM) are aggressive malignant tumors that develop in the brain. GBMs demonstrate increased rates of cell proliferation, a lack of apoptosis as well the propensity to migrate to distal sites in the brain. The clinical management of glioblastoma consists of surgical resection followed by radiotherapy and chemotherapy. However, this treatment regimen is not very effective and more effective therapies need to be developed. Activation of several signaling pathways has been associated with the increased proliferative capacity of GBM cells. Activity of the Akt/mTOR pathway is exceptionally high in GBMs and may regulate sensitivity to chemotherapy and radiotherapy. Akt and its downstream effector p70S6 kinase (p70S6K) demonstrate a high amount of activity in GBMs. Inactivation of Akt and p70S6K attenuate GBM cell growth and may inhibit GBM cell proliferation. Therefore, we investigated the antiproliferative capacity of extracts from the Rosehip (Rosa canina) plant. Rosehip extracts have been used as dietary supplements to relieve symptoms associated with diarrhea, gastritis and rheumatoid arthritis. U-1242MG, a human GBM cell line, treated with Rosehip extracts (250 µg/ml) demonstrated a decrease in cell proliferation. The Rosehip extract-mediated decrease in cell proliferation was equal to the decrease of cell proliferation observed when LY294002 (20 µM),a known Akt inhibitor was utilized. Additionally, pretreatment of the U-1242 MG cells with these Rosehip extracts (250 µg/ml) decreased p70S6K phosphorylation, suggesting these extracts prevent GBM cell proliferation by blocking Akt/mTOR signaling mechanisms. Taken together these data suggest that p70S6K positively regulates GBM cell proliferation, and Rosehip extracts may serve as an alternative or supplement to current therapeutic regimens for GBMs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 777.
Abstract 797: Kinase activity profiling of tumor tissues of different origin
Authors: Ruijtenbeek Rob , Houkes Liesbeth , Umar Arzu , Oosterwijk-Wakka Jeannette , de Wijn Rik , Thijssen Victor , Martens John , Dingemans Anne-Marie , Oosterwijk Egbert , Hilhorst Riet 
Published: February 2011

Abstract
Introduction:
Many new anti-cancer drugs target kinase activity. Unfortunately, methods to monitor the drug effects at the enzymatic level in patient derived tumor tissue are lacking. Here, a novel molecular profiling method for application in biomarker discovery is presented. This method is based on measuring kinase activities in tumor tissue extracts, and involves assessment of inhibition by a drug of interest. This ex vivo activity-based approach is enabled by dynamic peptide microarrays. These arrays comprise of peptides, which are known substrates for phosphorylation by protein kinases. Here we investigated the applicability of this approach in the classification of multiple tumors of different origin.
Method:
Patient-derived fresh frozen tissues of different tumor types (24 breast cancer (BC), 14 non-small cell lung cancer (NSCLC), 12 renal cell carcinomas (RCC)) were used for extraction of total protein in lysis buffer. Dependent on the tissue source, 6 slices of 10 µm were sufficient for 20-100 microarray analyses. Equal amounts of total protein were analyzed for kinase activity on dynamic PamChip peptide microarrays. These arrays comprised 144 or 256 different peptides. A PamChip96 plate format was used, enabling 96 microarray incubations per run. Protein amounts ranging from 1 − 5 µg were used per microarray analysis. Tumor extracts were analysed in the presence and absence of kinase inhibitor drugs (RCC: sorafenib and sunitinib, NSCLC: gefitinib).
Results:
We show here that from different tumors kinase activity profiles could be generated reproducibly (10-15% CV for selected peptides). Control experiments showed protein concentration and ATP dependency. In the RCC experiments different phosphorylation profiles were obtained when the non-tumor tissue was compared to tumor tissue derived from the same patient, showing higher kinase activities in the latter. In addition, inhibitor dependent modulation of the peptide phosphorylations was observed (sorafenib vs. sunitinib). Furthermore, differential kinase activity profiles were obtained that could be correlated to different patient subgroups (BC) or clinical data (long vs. short term survivors; NSCLC).
Conclusion:
A novel molecular profiling approach was successfully applied for classification of different tumors. This approach is based on detection of kinase activities as well as inhibition of kinase activity in tumor tissues. Application of this method in the discovery of biomarkers for diagnosis, prognosis or prediction of drug response is foreseen.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 797.
Abstract 838A: Characterization of sphingosine kinase isoenzyme selective inhibitors
Authors: Gao Peng , Zhuang Yan , Smith Charles D. 
Published: February 2011

Abstract
Sphingosine kinases (SphKs) play key roles in cell proliferation, migration and inflammation by catalyzing the formation of sphingosine-1-phosphate (S1P). However, the two isoenzymes, SphK1 and SphK2, play only partially overlapping roles in tumor epithelial cells. Our genetic approach (siRNA) revealed that SphK2 knockdown cells had more effects on decreasing cell proliferation and migration than SphK1 knockdown. A novel non-radioactive HPLC method based on florescence was developed to measure the activities of SphK. It revealed the increased SphK1 activity induced by SphK2 knockdown could not rescue the cells from apoptosis. In order to confirm the results from the genetic approach, we developed pharmacological approaches that used SphK isoenzymes selective inhibitors to dissect the functions of SphK isoenzymes. After the structure optimization of the lead compounds identified by high throughput screening, two compounds were identified as SphK inhibitors: 3-(4-Chlorophenyl)adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide hydrochloride salt - termed ABC294640 and 3-(4-Chlorophenyl)adamantane-1-carboxylic acid [2-(3,4-dihydroxyphenyl)ethyl]amide - termed ABC294735. The inhibition specificities of these compounds were characterized. ABC294640 is a SphK2 selective inhibitor (IC50 60μM), while ABC294735 (IC50SphK1 6μM, IC50SphK2 10μM) and SKI-II (IC50SphK1 2μM, IC50SphK2 1μM) are dual inhibitors in the presence of 10μM sphingosine as substrate. Lineweaver-Burk plots using the data from recombinant SphK1/2 active enzymes and kinase assay kit revealed ABC294640, ABC294735 and SKI-II were SphK competitive inhibitors. A possibly SphK1-selective inhibitor has also been identified by high-throughput screening and is currently being characterized.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 838A.
Abstract 842: The detection of circulating tumor cells is a negative prognostic factor in colorectal cancer
Authors: Srovnal Josef , Vyslouzil Kamil , Jancik Sylwia , Drabek Jiri , Radova Lenka , Duda Miloslav , Skalicky Pavel , Klementa Ivo , Stary Lubomir , Cwiertka Karel , Straznicka Jana , Sramek Vlastimil , Melichar Bohuslav , Hajduch Marian 
Published: February 2011

Abstract
Purpose: We tested the hypothesis that the presence of circulating tumor cells (CTCs) is a negative prognostic factor in patients with stage I-III colorectal cancer (CRC).
Patients and methods: This was a prospective study to test for the presence of CTCs in peripheral blood and bone marrow in 182 colorectal cancer patients at the time of surgery and one month after surgery using real-time RT-PCR for carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20).
Results: Overall, 24 of 147 (16.3%) stage I-III CRC patients developed recurrence/metastasis postoperatively in a mean follow-up period of 22.9 months. There was no correlation between CTCs and conventional clinical pathological features. In total, 51.7% of patients were CTC positive detected in peripheral blood and/or bone marrow at the time of surgery using CEA and/or CK20 and 47% of patients were CTC positive one month after surgery. At surgery, CTC positive patients measured as CEA mRNA copy number in peripheral blood showed significantly poorer disease-free survival (DFS) (p=0.05). One month after surgery, both increased above threshold CEA and/or CK20 mRNA levels in bone marrow and CK20 mRNA level in blood correlated with shorter DFS (p=0.005, resp. p=0.0035). In addition, systemic increase in CEA gene expression, even if the values remained below cut-off threshold also correlated with poorer DFS (p=0.005).
Conclusion: Detection of CTCs at surgery and/or one month after surgery is an independent negative prognostic factor for relapsing-free survival in stage I-III colorectal cancer.
Acknowledgments of research support: This study was supported by grants MSM 151100001, IGA MZCR NR/7804-5 and IGA MZCR NR/9076.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 842.