bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C43: The impact of ADAM-9 protease activity on invasiveness of gastric cancer.
Authors: Kim Jeong Min , Rha Sun Young , Yu Eun Jeong , Kim Tae Soo , Shin You Keun , Kim Hyo Song , Chung Hyun Cheol , Roh Jae Kyung , Jeung Hei-Cheul 
Published: June 2012

Abstract
ADAM (A Disintegrin and Metalloproteinase)-9 is a cell-surface membrane glycoprotein, which enables diverse roles in a wide range of cellular process. Over-expression of ADAM-9 has been reported in several cancers but its biological role remained to be clarified in gastric cancer. Herein, we investigated the possible involvement of ADAM-9 related to invasion and metastasis in gastric cancer. We also evaluated its possibility as a therapeutic target for anti-metastasis treatment.
We examined transcription and expression pattern of ADAM-9 in 24 gastric cancer cell lines. ADAM-9 protease activity was measured using fluoregenic ADAM-9 substrate (R&D systems). We conducted trans-well assay coated with matrigel to associate ADAM-9 expression with invasion activity. A specific anti-ADAM-9 monoclonal antibody (RAV-18, Macrogenics, Inc.) was used to evaluate its anti-invasion property. And then, to evaluate the ADAM-9 protease activity in vivo, MKN-28, one of high ADAM-9 cell lines, was subcutaneously inoculated in flank of mice. The IP of mice were injected with or without RAV-18.
The protein expression and protease activity of ADAM-9 was various by each cell line. The protease activities were moderately correlated with the protein expressions (mature form) (R2 = 0.49). ADAM-9 protease activity was decreased dose-dependently on RAV-18 treatment, being remarkable in the cells of high ADAM-9 expression (SNU-638, YCC-1, MKN-74 and MKN-28) compared with low expressing cells (YCC-6, YCC-7 and HS-746T). Baseline level of invasiveness was poorly correlated with ADAM-9 expression, but in high ADAM-9 cells, the administration of RAV-18 significantly suppressed invasiveness, while not in low ADAM-9 cells. Exposure to hypoxia (1% O2, 5% CO2, 37°C) up-regulated protease activity and invasiveness in low ADAM-9 cells, and these were suppressed dose-dependently by the treatment of RAV-18. RAV-18 inhibited ERK phosphorylation in high ADAM-9 cells, which suggests that that ADAM-9-related invasiveness depends on its protease activity and it is, at least partially, via MAPK pathway. In vivo, the tumor volume of mice of RAV-18 treated group (n=7) was smaller than control group (n=7). As in vitro results, EGFR and Erk phosphorylation were reduced in RAV-18 treated group than control group.
This study shows that ADAM-9 is upregulated in gastric cancer, and that ADAM-9 might be a plausible target for therapeutic inhibition of invasion/metastatic process.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C43.
Abstract C6: Composite profiling of angiogenic factors using Bio-Plex Pro™ Human Cancer Biomarker Panel-I.
Authors: Zimmerman Richard B. , Hamilton Tim , Gupta Vinita , Ma Li 
Published: June 2012

Abstract
Angiogenesis is a feature of over 50 different disease states. These include cancer, rheumatoid arthritis, cardiovascular diseases, diabetes and psoriasis. Methods developed to study these diseases are important tool to establish a model for testing potential therapeutics. These methods include both in vivo and in vitro assays. In vivo angiogenesis assays are considered to be the most informative because of the complex nature of vascular responses to test reagents and responses that no in vitro model can achieve. However in vivo assays can be expensive, laborious and require extensive training to perform. In contrast, in vitro assays can be carried out expeditiously, less costly and easier to interpret. Often, these in vitro assays provide maximum benefit when developed as a multivariate index assay where the data of multiple assays function to yield a composite result to interpret experimental studies. Using the Luminex xMAP technology, we have developed a multiplex Bio-Plex Pro™ Human Cancer Biomarker Panel I that employs a magnetic bead-based workflow to measure angiogenesis biomarkers in diverse matrices including serum, plasma, cell culture supernatant and many other sample types. In combination with the Bio-Plex® suspension array and the Bio-Plex Pro™ wash station, the multiplexing feature makes it possible to quantify the level of multiple angiogenesis targets in a single well of a 96-well microplate in just 3 hours, using as little as 12.5 μL of serum or plasma. The panel of 16 markers includes sEGFR, FGF basic, Follistatin, G-CSF, sHER2/neu, HGF, sIL-6Ra, Osteopontin, Leptin, PDGF-BB, PECAM-1, Prolactin, SCF, sTie-2, sVEGFR-1 and sVEGFR-2. These markers were selected because of their direct relevance to the pathogenesis of tumor-associated angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C6.
Abstract C63: Targeting FGFR3 with monoclonal antibody impairs bladder cancer growth in vivo.
Authors: Du Xiangnan , Li Hao , Ingalla Ellen , Ross Sarajane , French Dorothy , Tien Janet , Ashkenazi Avi , Qing Jing 
Published: June 2012

Abstract
Fibroblast growth factor receptor 3 (FGFR3) belongs to a family of receptor tyrosine kinases that control cell proliferation, differentiation, and survival. Mutational activation of FGFR3 has been reported in about 50–60% low grade and 15–20% muscle-invasive bladder cancer. FGFR3 is also overexpressed in about 50% of muscle invasive bladder cancer, suggesting a potential role for this receptor in the early stage of bladder carcinogenesis. However, the expression pattern of FGFR3 and its functional importance in metastatic bladder cancer remain to be determined. Using immunohistochemistry, we have found that FGFR3 is overexpressed in 8/13 cases (about 62%) of lymph-node metastasis of bladder cancer. Extensive in vivo efficacy studies with an FGFR3-specific affinity-matured human monoclonal antibody (designated R3Mab) show that R3Mab as a single agent blocks FGFR3 signaling and suppresses the growth of multiple bladder tumor xenografts in mice. Importantly, R3Mab further enhances the anti-tumor activity of chemotherapeutics including gemcitabine and carboplatin. These results demonstrate that FGFR3 is required for the maintenance of bladder cancer of various stages, and support the clinical development of R3Mab in locally advanced and metastatic bladder cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C63.
Abstract C72: Counteracting autophagy allows to overcome resistance to the mTOR everolimus in mantle cell lymphoma.
Authors: Rosich Laia , Xargay-Torrent Silvia , Lopez-Guerra Monica , Campo Elias , Colomer Dolors , Roue Gael 
Published: June 2012

Abstract
Background: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoid neoplasm genetically characterized by the t(11;14)(q13;q32) leading to the overexpression of cyclin D1, which causes cell cycle deregulation at the G1-S phase transition. As a consequence of its poor response to conventional chemotherapy and relatively short patient survival, new therapeutic strategies are required.
The phosphatidylinositol 3-kinase/Akt/mTOR survival pathway is constitutively activated in MCL, thereby making the mTOR inhibition a very attractive strategy for its treatment. The first clinical studies conducted in relapsed MCL patients have reported a significant, but relative short duration of response to the oral rapamycin derivative everolimus (RAD001). In this context, our aim was to analyze the mechanism of action related to resistance/sentitivity of this drug in MCL cells, and to propose further combination strategies.
Methods: The sensitivity to everolimus was analyzed in MCL primary cultures, MCL cell lines and peripheral blood lymphocytes from healthy donors. Cells were treated for up to 72h with increasing doses of everolimus, followed by cytotoxicity quantification, cell-cycle determination and western blot analysis of the PI3K/Akt/mTOR pathway. Autophagy was studied by LC3I/II expression and Cell-ID™ Green staining of autophagolysosomes by flow cytometry and fluorescence microsopy.
Results: Everolimus exerted heterogeneous antitumoral effect on MCL cells, while sparing normal cells. This effect was associated with G1 cell-cycle arrest and reduced phosphorylation of the mTOR downstream targets, 4E-BP1 and S6. However, Akt re-phosphorylation was observed after 48h of everolimus treatment, suggesting feedbacks loops within the mTOR signaling pathway. Accordingly, everolimus combination studies with the Akt inhibitor VIII, isozyme-selective (Akti-1/2) showed synergistic cytotoxic effect in MCL cells and overcame Akt mechanism of resistance in a sub-set of MCL samples. When compared to these samples, increased levels of autophagic hallmarks such as autophagic vacuoles and LC3 processing were found in everolimus/Akti-1/2 low-responsive cells. In these cells, the combination with the autophagy inhibitor hydroxychloroquine overcame the resistance to mTOR/Akt inhibitors, and efficiently induced apoptosis, thus suggesting a prosurvival role of autophagy.
Conclusions: This study suggests that targeting autophagy as anticancer therapy may represent an attractive sensitizing strategy for everolimus-based therapy in MCL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C72.
Abstract C82: Identification and preclinical characterization of inhibitors of the ubiquitin-activating enzymes UBA1 and UBA6.
Authors: Bence Neil , Fleming Paul , Ciavarri Jeff , Milhollen Michael , Pulukuri Sai , Hyer Marc , Traore Tary , Huck Jessica , Tou Derek , Sappal Darshan , Hoar Kara , Gavin James , Yang Yu , Brownell James , Smith Peter , Dick Lawrence , Veiby Petter , Manfredi Mark , Claiborne Christopher 
Published: June 2012

Abstract
Millennium Pharmaceuticals, Inc. is dedicated to the discovery and development of novel oncology therapeutics in the area of protein homeostasis. Here we report the identification and characterization of compounds that target the ubiquitin activating enzymes, UBA1 and UBA6. These compounds are mechanism based inhibitors that inactivate the ubiquitin E1 enzymes by forming a ubiquitin compound adduct that remains tightly associated with the E1 adenylate binding site. Treatment of cells with these inhibitors results in cellular effects consistent with known Uba1 biology including rapid loss of E2 ubiquitin thioesters, loss of total ubiquitin conjugates, and accumulation of many ubiquitin proteasome system substrates. Following prolonged treatment, cells primarily arrest in the G2 phase of the cell cycle and ultimately undergo apoptosis. Reflecting the extensive cellular roles of ubiquitin, the compounds also impact global protein turnover, ER stress and DNA damage repair. UBA1 inhibition impairs ubiquitination of PCNA and the Fanconia Anemia protein FANCD2 leading to defective repair of UV induced DNA damage. UBA1 inhibition impacts numerous biological pathways relevant to cancer, results in apoptosis in vitro and is capable of inhibiting tumor growth in mouse xenografts in vivo. These data implicate UBA1 as a target for the treatment of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C82.
Abstract C9: Response to cetuximab is associated with EGFR gene amplification in gastric cancinoma patient derived xenograft models.
Authors: Yang Jie , Chen Dawei , Yang Mengmeng , Deng Jiangyun , Song Xiaoming , Cai Jie , Chen Taiping , Li Henry , Chen Yiyou 
Published: June 2012

Abstract
Gastric carcinoma is a common cancer in Asia with high mortality and few effective treatment options, with the exception of Herceptin in erbb2 over-expressing gastric cancer patients. Cetuximab has been approved for CRC and H&N, but not yet for gastric carcinoma. In this study, we set out to explore potential clinical utilities by testing cetuximab in a cohort of gastric cancer patient derived xenograft (PDX) models.
Among the 10 PDX models tested, all with wild type EGFR, 4 models (40%) were sensitive to cetuximab single agent treatment. Detailed gene expression and copy number variation analysis revealed that these 4 models have amplified EGFR gene, and correspondingly high EGFR mRNA expression level. In contrast, none of the 6 resistant models demonstrated EGFR amplification. The strong association suggests that EGFR gene amplification is a major driver for the maintenance of gastric cancer. In summary, by modeling clinical trial, our studies using large panel PDXs has identified a promising predictive biomarker for cetuximab responsiveness in gastric carcinoma patients. Further clinical investigation on patients with EGFR gene amplification is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C9.
Abstract C95: A flexible kinase inhibitor assay platform for active, nonactivated, and impure kinase preparations.
Authors: Lebakken Connie S. , Reichling Laurie , Ellefson Jason , Bi Kun , Riddle Steven M. 
Published: June 2012

Abstract
Kinase activity-based assays are cost-effective and widely used to drive early drug discovery and lead identification, however, they typically require purified, active kinase preparations be produced that are shown to phosphorylate a known substrate. While it is possible to satisfy these requirements for the well-studied kinases, there are many kinases which lack one or more of these requirements, such as CDK8 and STK33, making drug discovery efforts difficult. To solve for these assay development problems, we have developed a TR-FRET-based binding assay platform which allows for characterization of compounds with kinases that are not sufficiently purified or do not demonstrate measurable activity against putative or potential substrates. This assay addresses kinase assay requirements early in the drug discovery process, and should enable more targets to be screened sooner, resulting in compounds being made available for lead optimization faster. The ability to detect and characterize binding of compounds to non-activated kinases is also a benefit to the lead optimization process, as compounds that bind preferentially to kinases in their non-activated state, such as Imatinib, are sometimes preferred due to their selectivity. In this poster, we present solutions for kinases that are difficult to address with activity assays and provide a comparison of compound affinities for active and non-activated forms of a diverse set of kinases to enable faster lead optimization.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C95.
Abstract PR-12: Loss of the retinoblastoma protein alters glucose and glutamine metabolism.
Authors: Clem Brian F. 
Published: June 2012

Abstract
Tumorigenesis requires not only loss of proliferative control, but also a metabolic shift towards increased glucose and glutamine consumption required for increased energy production and to drive the de novo biosynthesis of nucleotides, amino acids, and lipids essential for cell division. These processes are primarily driven through oncogenes or loss of tumor suppressors, which act to circumvent normal regulatory pathways. The retinoblastoma (Rb) protein, the first described tumor suppressor, is extensively involved in cell cycle regulation, and perturbations within the Rb pathway are found in most tumor types. Beyond cell cycle control, Rb has been implicated in multiple additional biochemical pathways known to be involved in tumor progression, such as metastasis and angiogenesis. However, little is known about the role of Rb in regulating the unique changes in metabolism that have been observed in human cancers. Using stable 13C-glucose isotopomer NMR analysis, we found that triple knock-out (TKO) of all three Rb family members in mouse embryonic fibroblasts (MEFs) resulted in increased glucose uptake and flux to lactate, and simultaneously decreased glucose-derived carbon incorporation into Krebs' cycle intermediates relative to wild-type (WT) MEFs. To supplement this loss of glucose carbons for anaplerosis within the Krebs' cycle, we speculated that the Rb TKO MEFs may increase glutamine uptake for both bioenergetic and anabolic precursors. We observed that loss of Rb caused increased 13C-glutamine uptake and flux into glutamate and Krebs' cycle intermediates using isotopomer NMR analyses. Importantly, this shift towards glutamine utilization was essential for the survival of Rb TKO MEFs and not for the WT MEFs. Preliminary studies of the precise downstream metabolic enzymes that may in part mediate these global changes in metabolism then demonstrated that the expression of distinct regulatory metabolic enzymes, including glucose transporters, hexokinase 2, and glutaminase 1, are simultaneously increased in the Rb TKO MEFs compared to WT MEFs. Combined, these studies suggest that inactivation of the Rb protein in human cancers leads to a global metabolic shift towards enhanced glycolysis and glutamine utilization, which in turn is required for neoplastic immortalization and transformation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr PR-12.
Abstract 100: The effect of synergic anti-proliferation of DNA methyltransferase inhibitor binding to anti-cancer drugs in gastric cancer
Authors: Muguruma Kazuya , Yashiro Masakazu , Tanaka Hiroaki , Kimura Kenjirou , Nagahara Hisashi , Amano Ryousuke , Noda Eiji , Kubo Naoshi , Yamada Nobuya , Maeda Kiyoshi , Ohira Masaichi , Ishikawa Tetsurou , Hirakawa Kosei 
Published: June 2012

Abstract
Epigenetic alterations of DNA methylation play an important role in the regulation of gene expression associated with chemosensitivity of gastric carcinomas. With the aim of improving the chemotherapeutic efficacy of gastric carcinoma, the effect of DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, on the chemosensitivity of five anti-cancer drugs was investigated. Human gastric cancer cell lines, OCUM-2M and MKN-74, and five anti-cancer drugs, 5-fluorouracil, paclitaxel, oxaliplatin, irinotecan, and gemcitabine, were used. In both gastric cancer cell lines, a synergistic anti-proliferative effect by a combination of 5-aza-2′-deoxycytidine at 5μ M was found in irinotecan or gemcitabine. 5-Aza-2′-deoxycytidine at 5μM increased apoptosis induced by irinotecan and gemcitabine in both cell lines. 5-Aza-2′-deoxycytidine increases the expression of DAPK-2 and DAPK-3, RASSF1, and THBS1 gene in both OCUM-2M and MKN-74 cells, but not that of hMLH1, p16, MGMT, E-cadherin, and p53 genes. These findings suggest that 5-aza-2′-deoxycytidine is a promising chemotherapeutical agent for gastric carcinomas in combination with anti-cancer drugs of irinotecan and gemcitabine in apoptosis signaling. The up-regulation of DAPK-2 and DAPK-3, RASSF1, and THBS1 genes by 5-aza-2′-deoxycytidine might be associated with the synergistic effect.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 100. doi:10.1158/1538-7445.AM2011-100
Abstract 1004: Hedgehog signaling promotes tumor vascularization, growth and metastasis of breast cancer via upregulation of CYR61
Authors: Harris Lillianne G. , Pannell Lewis K. , Samant Rajeev S. , Shevde Lalita A. 
Published: June 2012

Abstract
Several clinical trials have used chemotherapeutic drugs that specifically target vascular endothelial cell growth factor (VEGF). Although these trials have demonstrated significant improvements in response rates, findings to date have not indicated substantial benefits in terms of survival. This is likely to be due to the ability of tumor cells to utilize several alternative pathways to establish vasculature. Hence, there is an urgent need to define and target other active pathways that contribute to angiogenesis, such that the vascularity of the tumor can be effectively reduced.
Hedgehog (Hh) signaling, which promotes cell growth and vascularization during fetal development, is activated in several cancers and has been implicated to play a role in promoting cancer progression. We have investigated the role of Hh signaling in impacting tumor malignancy by promoting tumor vascularity. We engineered sonic hedgehog (SHH)-deficient, tumorigenic breast cancer lines, MDA-MB-231 and MCF10AT, to ectopically express the Hh activating ligand, SHH such that the pathway is constitutively activated. Upregulation of SHH-mediated signaling results in the acquisition of enhanced malignant behavior in vitro (increased growth, invasion, migration, and anchorage independent growth) and in vivo (increased tumor take rate and rapidly growing tumors). Furthermore, the SHH expressing cells are able to enhance migration, invasion and network formation of endothelial cells in vitro and elicit increased vasculature in tumor xenografts, in vivo. Using mass spectrometry-mediated analysis of the secretome of the breast cancer cells with constitutive Hh signaling, we identified CYR61 (cysteine-rich angiogenic inducer 61) as a potential mediator of the angiogenic effects of breast cancer cells. Further, our studies show that CYR61 plays a critical role in mediating the vasculature-enhancing effects of breast cancer cells. Taken together, our lab has identified a robust contributor of tumor vascularization which may be an effective VEGF-independent anti-vascularization therapeutic target.
We acknowledge grant support from the Department of Defense-Breast Cancer Research Program (07-1-0400).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1004. doi:10.1158/1538-7445.AM2011-1004