bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2308: MUC1 modulation of E-cadherin through miR-200c and ZEB1
Authors: Mohr Ashley M. , Lewallen Michelle E. , Radhakrishnan Prakash , Liu Xiang , Bailey Jennifer M. , Hollingsworth Michael A. 
Published: August 2012

Abstract
MUC1, a cell-surface glycoprotein implicated in tumorigenesis and metastasis, has a cytoplasmic tail (MUC1.CT) that is phosphorylated by different receptor tyrosine kinases and conducts these signals by binding and altering the function or stability of transcription factors, thereby influencing gene transcription. MicroRNAs (miRNAs), short RNAs (19-22 nucleotides), regulate gene expression at the transcriptional level and are differentially regulated in cancer and metastasis. We discovered that MUC1.CT influences expression of miRNAs that contribute to metastasis, including miR-200c. MiR-200c is a known regulator of epithelial-to-mesenchymal transition (EMT) through regulation of ZEB1, a transcriptional repressor of E-cadherin. In addition, ZEB1 is a repressor of miR-200c in a feedback loop. Overexpression of MUC1 results in a dramatic decrease in miR-200c levels, resulting in increased levels of ZEB1. Chromatin immunoprecipitation (ChIP) was used to demonstrate that MUC1.CT occupies the ZEB1 binding motif upstream of the miR-200c start site. In addition, we found that ZEB1 occupancy of the miR-200c promoter region was enhanced 3.5-fold in MUC1 overexpressing cells, indicating that MUC1.CT may influence the expression and stability of ZEB1 at the miR-200c promoter. Co-immunoprecipitation experiments determined that MUC1.CT directly interacts with ZEB1. We evaluated levels of proteins affected by the miR-200c pathway in MUC1 overexpressing cells and observed an increase in ZEB1 levels and a decrease in E-cadherin levels, consistent with induction of EMT. We also confirmed an increase of ZEB1 occupancy at the E-cadherin promoter in MUC1 overexpressing cells, further confirming our hypothesis. In addition, MUC1.CT is differentially phosphorylated by several receptor tyrosine kinases. Antibodies against different phospho-isoforms were used with ChIP to investigate the signaling cascades that influence localization of the MUC1.CT to the miR-200c promoter. The phospho-YEKV form of MUC1.CT, which is representative of signaling through epidermal growth factor/receptor (EGF/EGFR), was the only phospho-MUC1.CT detected at the ZEB1 binding motif of the miR-200c promoter. EGF signaling is linked to a loss of E-cadherin, and our work is the first to link EGF signaling through the MUC1.CT as a direct regulator of miR-200c expression. These data portray a novel pathway of EMT modulation. EGF signaling via MUC1 regulates levels of miR-200c, altering regulation E-cadherin. Grant support was provided by grants from the NCI (Training Grant CA09476, R01CA57362, U01 CA111294) and student assistantships from UNMC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2308. doi:1538-7445.AM2012-2308
Abstract 2314: Dovitinib demonstrates antitumor and anti-metastatic activities in xenograft models of hepatocellular carcinoma
Authors: Hung Huynh T. , Choo Su Pin , Soo Khee Chee , Ong Richard , Linnartz Ronald , Shi Michael Ming 
Published: August 2012

Abstract
Background and aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death. Although sorafenib has been shown to improve survival of patients with advanced HCC, this improvement is modest and patients eventually have refractory disease. This study aims to investigate the antitumor, antiangiogenesis and antimetastatic activities of dovitinib in preclinical models of HCC. Methods: 21-0208 and SK-HEP1 cells as well as patient-derived HCC models were employed to study of the antitumor effect of dovitinib. Changes of biomarkers relevant to FGFR/VEGFR/PDGFR pathways were determined by Western blotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry. Results: Treatment of SK-HEP1 cells with dovitinib resulted in G2/M cell cycle arrest, inhibition of colony formation in soft agar and blockade of bFGF-induced cell migration. Dovitinib inhibited basal expression and FGF-induced phosphorylation of FGFR-1, FRS2-α and ERK1/2. In vivo, dovitinib potently inhibited tumor growth of six HCC lines. Inhibition of angiogenesis correlated with inactivation of FGFR/PDGFR-α/VEGFR-2 signaling pathways. Dovitinib also caused dephosphorylation of retinoblastoma, upregulation of p-histone H2A-X and p27, and downregulation of p-cdk-2 and cyclin B1, which resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. In an orthotopic model, dovitinib potently inhibited primary tumor growth and lung metastasis and significantly prolonged mouse survival. Conclusion: Dovitinib demonstrated significant antitumor and antimetastatic activities in HCC xenograft models. This study provides a compelling rationale for clinical investigation in patients with advanced HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2314. doi:1538-7445.AM2012-2314
Abstract 2315: Pharmacodynamic and antitumor activity of fragment-derived inhibitors of MetAP2 in tumor xenografts
Authors: Smyth Tomoko , Curry Jayne , Wilsher Nicola , Johnson Chris , Berdini Valerio , Richardson Caroline , Massey Frances , McMenamin Rachel , Griffiths-Jones Charlotte , Thompson Neil , Wallis Nicola G. 
Published: August 2012

Abstract
Background: Methionine aminopeptidase (MetAP) 2 is one of the two eukaryotic enzymes responsible for cleaving the N-terminal methionine from newly synthesized polypeptides to allow further post-translational modifications such as myristoylation to take place. The enzyme is the target of the anti-angiogenic natural product, fumagillin and so is believed to play a role in angiogenesis. Fumagillin analogues have shown activity in several disease models including oncology, inflammation and obesity indicating MetAP2 is a promising target in a number of indications. The semi-synthetic fumagillin analogue, TNP470, has shown activity in a Phase I/II cancer trial, suggesting that MetAP2 is a good oncology target. Here we describe the discovery, optimization and anti-tumor activity of fragment-derived MetAP2 inhibitors. Results: We identified fragment hits to MetAP2 using our fragment-based screening approach, Pyramid™. These were optimized by structure-based drug design to novel, potent lead compounds with sub-100 nM potency against the isolated MetAP2 enzyme. The two most advanced compounds inhibited proliferation of HUVECs with potencies of 130 nM and 300 nM. Levels of the MetAP2 substrate, Met-14-3-3, were shown to increase on treatment of HUVECs with these compounds indicating that Met-14-3-3 was not being processed and hence MetAP2 was being inhibited. The compounds also inhibited HUVEC tubule formation demonstrating their anti-angiogenic properties. The two lead compounds were further tested in vivo. Both compounds were well tolerated at doses up to 200 mg/kg bid. Levels of Met-14-3-3 were seen to increase in the thymus and spleen (where high expression of MetAP2 has been reported) of mice treated with the compounds, indicating again that MetAP2 was being inhibited in these tissues. Compound 1 was tested in a mouse HCT116 xenograft model. Mice were subcutaneously inoculated with HCT116 cells and oral dosing at 200 mg/kg bid started one day later. Tumor growth was inhibited in treated mice compared with control and growth inhibition was greater in Compound 1 treated mice (T/C 46%) compared with mice treated with 30 mg/kg TNP470 subcutaneously q2d (T/C 61%). Conclusions: The compounds described here are novel small-molecule inhibitors of MetAP2. Their promising tumor growth inhibitory properties merit their testing in further tumor models and potentially other indications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2315. doi:1538-7445.AM2012-2315
Abstract 2320: A multi-domain fusion molecule inhibits tumor growth affecting in-vivo angiogenesis
Authors: Boosani Chandra Shekhar , Gunda Venugopal , Verma Rajkumar , Yakkanti Sudhakar Akul 
Published: August 2012

Abstract
Growth of solid tumors beyond their benign size largely depends on the availability of oxygen and food supply which is accomplished through induced tumor angiogenesis. Inhibition of such de novo angiogenesis should aid in arresting the growth of solid tumors. Besides availability of several monoclonal antibodies and synthetic inhibitors for target molecules that induce tumor angiogenesis, endogenous antiangiogenic molecules are effective candidates with no drug resistance. Several endogenous angioinhibitors have been identified and were proven to inhibit tumor angiogenesis both in-vitro and in-vivo. However, many of them exhibited varied effects in inhibiting tumor growth with multiple mechanism(s) of action. Thus in our present study we developed a fusion antiangiogenic molecule “Combostatin” using the functional domains from two of the known antiangiogenic molecules reported by us. Here we show that Combostatin is an effective inhibitor of angiogenesis and inhibits tumor growth in-vitro and in-vivo. We also show that Combostatin affects several of the antiangiogenic pathways such as endothelial cell proliferation, migration and tube formation which are mediated by its binding to several integrin receptors on the endothelial cell surface. Our studies conclude that Combostatin is a more potent inhibitor of tumor angiogenesis than its parent molecules generated form type IV and Type XVIII collagen.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2320. doi:1538-7445.AM2012-2320
Abstract 2324: LHT-7 as multi-targeting and anti-angiogenic agent to growth factor receptors
Authors: Bae Sang Mun , Park Rang-Woon , Jung Yoonjae , Yoo-Jin Yang , Chi Lianhua , Byun Youngro 
Published: August 2012

Abstract
Angiogenesis is a highly regulated process that is critical for tumor growth and metastasis. Angiogenesis depends on the balance between different molecules released by the host and tumor cells such as vascular endothelial growth factor (VEGF), fibroblast growth factor basic (bFGF), platelet-derived endothelial cell growth factor (PDGF), insulin-like growth factors (IGF-1 and IGF-2) and scatter factor, which are potential targets for development of angiogenesis inhibitor and depend on heparin sulfate for their biological functions. Heparan sulfate is located in cell surface and in the extracellular matrix and plays crucial regulatory roles in some growth factors. For this reason, heparin has been highlighted as a therapeutic agent as well as anticoagulant. In a previous study, we reported new angiogenesis inhibitor, low molecular weight heparin derivative (heparin-taurocholic acid conjugate; LHT-7) and it showed delay of in vivo tumor growth in MDA-MB231 human breast cancer and inhibited phosphorylation of VEGFR2 through the interaction with VEGF in human umbilical vein endothelial cells (HUVECs). In present study, we revealed LHT-7 as multi-targeting agent to several growth factors and on their actions. LHT7 inhibited phosphorylation of VEGFR2 and binding of LHT7 was increased in VEGFR2 over-expressing HEK293 by FACS analysis. In HUVECs, binding of LHT-7 was shown in a dose-dependent manner by FACS analysis and co-localized with VEGFR2 by immunofluorescence. LHT-7 also inhibited vessel formation enhanced by PDGF-bb in matrigel plug assay and phosphorylation of PDGFR-ß in human vascular smooth muscle cell (HuVSMC). Binding of LHT-7 was increased in a dose-dependent manner by FACS analysis and decreased in PDGFR-ß-siRNA HuVSMC by immunofluorescence. Finally, LHT-7 inhibited phosphorylation of FGFR-1 in HUVECs and binding of LHT-7 was decreased in FGFR-1-siRNA MDA-MB-361. Overall, LHT-7 has inhibitory effect on phosphorylation of growth factors and binding of LHT-7 was increased in a dose-dependent manner but decreased in a growth factor down-regulated cell. Therefore we suggest that LHT7 would target to VEGFR2, PDGFR- ß and FGFR-1 and inhibit their angiogenic roles.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2324. doi:1538-7445.AM2012-2324
Abstract 2327: Anti-angiogenic activity of a CovX bi-functional antibody conjugate targeting both activin-receptor like kinase type 1 (ALK-1) and vascular endothelial growth factor (VEGF)
Authors: Lee Alice , Stock Joseph , Do Janet , Matin Marla , Rosario Joselyn Del , feng Lijin , Yamamoto Sachiko , Souratha Jennifer , Tchistiakov Lioudmila , Gallo Michael , Gao Yijie , Pirie-Shepherd Steven , Bissonnette Reid , Lappe Rodney , Woodnutt Gary , Blot Vincent 
Published: August 2012

Abstract
Angiogenesis is essential for tumor growth and metastasis, and controlling tumor-associated angiogenesis is a proven therapeutic intervention to limit tumor progression. Several pathways have been involved in tumor-associated angiogenesis and the predominant target of current interventions is the vascular endothelial growth factor (VEGF) pathway. Recently, Activin-receptor like kinase type 1 (ALK-1) has been proven to be a novel and potent target of tumor angiogenesis. Our results indicate that inhibiting VEGF and ALK1 have different effects on tumor vasculature, suggesting that targeting both pathways could have a more potent effect than targeting either pathway alone. We have created a bi-functional antibody conjugate targeting both ALK-1 and VEGF by conjugating VEGF-trap peptides to an anti-ALK1 monoclonal antibody. We demonstrate that our bi-functional molecule binds both ALK-1 and VEGF with high affinity in vitro, blocks both ALK-1 and VEGF pathways in HUVEC primary human endothelial cells and has good pharmacokinetics properties in mice. Finally, in a MDA-MB-231 xenograft model in SCID mice, the ALK-1/VEGF bi-functional antibody conjugate slowed tumor growth and prolonged survival with greater efficacy than anti-VEGF therapy alone.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2327. doi:1538-7445.AM2012-2327
Abstract 2331: Select epidithiodiketopiperazine (ETP) compounds disrupt the HIF-1α/p300 interaction and HIF-mediated transcription
Authors: Richardson Emily D. , Reece Kelie M. , Campbell Tessa J. , Pressler Heather , Pisle Stephen T. , Figg William D. 
Published: August 2012

Abstract
As solid tumors grow, regions in the tumor become hypoxic because of increased metabolism, heterogeneous and abnormal vasculature delivering oxygen within the tumor, and greater size. In order for the tumor to continue to grow, it depends on survival mechanisms to overcome this hypoxic state, including up-regulation in glycolysis, invasion and metastasis, and angiogenesis, or the growth of new blood vessels. The hypoxia-inducible factor (HIF) transcription factor complex is a major mediator of the cell's response to a hypoxic state and a tumor's survival mechanism under hypoxia. The complex is composed of the hypoxia-dependent HIF-1α subunit and a constitutively expressed HIF-1α subunit, and it requires the co-activator protein p300 to function. In the presence of oxygen, HIF-1α is rapidly degraded. Under hypoxia, HIF-1α forms a complex with HIF-1α and p300 in the nucleus to up-regulate transcription of pro-survival and angiogenic genes. Targeting this transcription factor complex in tumors could circumvent the tumor's hypoxia survival mechanism and lead to growth arrest and cell death. The compounds chetomin, chaetocin, and gliotoxin, members of the epidithiodiketopiperazine (ETP) family of fungal metabolites, have been shown to disrupt the HIF-1α/p300 interaction in an over-expression system. In the following experiments, we sought to validate the disruption of the HIF-1α /p300 transcription factor complex in cells, and to determine the associated downstream cellular effects. By co-immunoprecipitation of the complex from prostate cancer cells, we were able to show that treatment with those select ETPs under hypoxic conditions disrupted the HIF-1α/p300 complex. We performed an enzyme-linked immunosorbent assay (ELISA) to determine the effect of ETPs on levels of secreted vascular endothelial growth factor (VEGF), a major target of HIF transcription. We observed a decrease in VEGF concentration that correlated with ETP treatment under hypoxia. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to examine the transcription levels of other HIF target genes to validate that disruption of the HIF-1α/p300 complex by select ETP treatments indeed affects HIF-mediated transcription. In order to determine the antiangiogenic effects of these agents in vivo, ongoing animal studies in our lab are testing the efficacy of these ETPs in reducing tumor growth and determining feasibility of pre-clinical development. Targeting the HIF complex could circumvent a tumor's survival mechanism under hypoxia, and would be a new treatment strategy in solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2331. doi:1538-7445.AM2012-2331
Abstract 2336: M402, a heparan sulfate mimetic, inhibits tumor revascularization and invasiveness after high-dose taxane treatment in a mouse breast cancer model
Authors: Schultes Birgit C. , Chu Chia L. , Long Alison , D'Alessandro Josephine , Honan Christopher M. , Kishimoto Takashi K. , Venkataraman Ganesh 
Published: August 2012

Abstract
Treatment with certain anti-cancer agents, particularly taxanes and sunitinib, can lead to mobilization of pro-angiogenic factors and an acute mobilization of endothelial progenitor cells (EPCs) and other stromal cells, which migrate to the viable tumor rim where they can enhance tumor vascularization, invasion and metastasis. This phenomenon has been linked to rapid tumor regrowth following chemotherapy or treatment with specific angiogenesis inhibitors and may thus diminish the long-term efficacy of the treatment. Stromal cells like EPCs are mobilized in response to circulating growth factors and chemokines (VEGFR, FGF, G-CSF, IL-6, SDF1α, etc.) that are induced by the drug or the progressing tumor. Many of these factors contain heparin binding domains for their anchorage to proteoglycans on cell surfaces or the extracellular matrix. We tested a novel heparan sulfate mimetic, M402, for its ability to inhibit EPC mobilization as well as tumor vascularization and invasion. Mice bearing orthotopic 4T1 breast carcinoma and treated with a single high dose of docetaxel (40 mg/kg) showed highly vascularized tumor rims by histology and Microfil perfusion followed by microCT (vessel volume of 5.8 ± 4.6 mm3 vs. 0.6 ± 0.3 mm3; vessel surface area of 153.9 ± 65.5 mm2 vs. 21.1 ± 6.7 mm2, respectively) as compared to the saline control group. The tumors also showed a higher rate of invasion through the peritoneal wall as compared to vehicle treated mice (5 of 16 mice vs. 2 of 16 mice, respectively). The effect correlated with mobilization of EPCs and other bone marrow derived stromal cells. Treatment with M402 did not show such a response but rather inhibited the effects of docetaxel when dosed concomitantly for 3-5 days, starting with the docetaxel administration. Analysis of the blood, tumor and bone marrow indicated that M402 prevented the mobilization of progenitor cells from the bone marrow and their recruitment into the tumor microenvironment, likely through disruption of the SDF-1α/CXCR4 axis. Furthermore, we observed synergistic anti-tumor and anti-metastatic activity of M402 with docetaxel in this 4T1 model. In conclusion, the experiments provide a rationale for the clinical investigation of M402 in combination with docetaxel or other agents that induce similar effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2336. doi:1538-7445.AM2012-2336
Abstract 2341: Curcumin targets a stem-like subpopulation of Lewis lung carcinoma cells
Authors: Jamasbi Roudabeh J. , Yan Dejun , Geusz Michael E. 
Published: August 2012

Abstract
Curcumin, an active component of the spice turmeric, can exert cytotoxic effects on cancer cells without harming normal tissues. The objectives of this investigation were to a) determine the effects of different doses and durations of curcumin exposure on Lewis lung carcinoma (LLC) cells; b) characterize any curcumin-resistant LLC subpopulation, which may include cancer stem cells (CSCs); and c) demonstrate whether curcumin's cytotoxic effects are enhanced by visible light. Cultured LLC cells were exposed to 10-60 μM curcumin for 2, 4, 8, 16 and 30 hrs at 37°C. After incubation, the cell density was measured by the absorbance of crystal violet staining. The results confirmed that curcumin eliminates LLC cells in a dose and time-dependent manner. We then chose 60 μM curcumin, which caused the highest cell loss (&gt;99%), to select for a curcumin-surviving subpopulation. A cell line established from the survivors was found to have slower growth rate, expressed lower levels of NFκB and aldehyde dehydrogenase (two CSC markers). Tumors developed when syngeneic mice were injected with either LLC cells or the surviving line, although tumor growth appeared slower for the surviving line. The results indicate that curcumin exerts damaging effects not only on cancer cells but also on CSCs. The efficacy of curcumin is hampered outside the digestive tract because of its low bioavailability. To test enhancement of curcumin effects by light, we exposed LLC cells to curcumin and visible light simultaneously. This combination caused greater damage to LLC cells than curcumin or light alone. Our results support a role for curcumin as an anti-cancer agent, especially when combined with visible light or other radiation sources.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2341. doi:1538-7445.AM2012-2341