bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 662: Evaluation of the anti-cancer effects of the tumor selective vascular disruption agent BNC105 in preclinical renal cancer models
Authors: Lavranos Tina C. , Leske Annabell F. , Beaumont Donna M. , Gasic Jelena , Kremmidiotis Gabriel 
Published: June 2012

Abstract
The disruption of blood vessels that feed tumors represents one of the most promising therapeutic strategies for treating cancer. BNC105 is a tubulin targeting dual acting vascular disruption agent with cytotoxic ability in solid tumors. A prodrug formulation, BNC105P, is under evaluation in phase II clinical trials for malignant mesothelioma and metastatic renal cell carcinoma as a 10min IV infusion. We have conducted a number of preclinical evaluations that provide a strong rationale for combining BNC105P treatment with agents that target mTOR signalling. BNC105 activity operates through the selective disruption of tumor blood vessels. Over 95% of blood flow is disrupted in tumors grown in xenograft animal models using human cancer cell lines representing a number of different cancer types, including breast, lung, colon, brain and mesothelioma. In the renal cancer setting we evaluated the anti-cancer effects of BNC105 in a Caki-1 xenograft model and a syngeneic murine renal cancer orthotopic model. Animals carrying Caki-1 solid tumors were treated with a single dose of BNC105P. Disruption of blood flow within the tumors was observed as early as 3 hr post-treatment. Similarly, blood flow disruption was seen in mice carrying solid tumors orthotopically inoculated in the kidney capsule using the RENCA mouse renal cancer cell line. Interestingly, BNC105P treatment also caused blood flow disruption in lung metastatic lesions seen in a number of the animals orthotopically inoculated with RENCA. The vasculature in non-cancerous portions of the kidney and all normal tissues examined, remained intact. Tumor re-vascularisation following BNC105P treatment was observed 2 days following administration. Immunohistochemical and Western blot analyses in BNC105P treated tumors revealed that a number of proteins involved in the mTOR signalling pathway exhibit expression changes consistent with activation of this pathway possibly a result of BNC105P induced tumor hypoxia. Up-regulation in phosphorylated mTOR, Hif1a and down-regulation of phosphorylated 4EBP1 were observed. The consequences of targeting mTOR in combination with BNC105P are currently under investigation in these preclinical models.
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 662. doi:10.1158/1538-7445.AM2011-662
Abstract 67: High-throughput cellular assays for interrogating epigenetic histone modifications
Authors: Hallis Tina , Bi Kun , Machleidt Thomas , Hermanson Spencer , Wilkinson Jennifer , Wetter Justin 
Published: June 2012

Abstract
Epigenetic histone modifications such as, methylation, acetylation, and phosphorylation play important roles in regulating the structure and functions of histones which in turn regulate essential gene expression. Dysregulation of the enzymes responsible for these modifications has been linked to cancer and many other diseases. In particular, histone deacetylases (HDACs) and histone methyl transferase (HMTs) have been a recent focus for drug discovery. However, detection of these enzymatic activities in an HTS cell-based format has remained challenging, especially since many of these enzymes may require the formation of protein complexes for relevant activity. To help overcome these challenges, we have developed and validated high-throughput compatible LanthaScreen® cellular assays for the analysis of histone methylation, acetylation, and phoshorylation, in cell backgrounds of interest. The acetylation, methylation and phosphorylation of H3 at specific residues can be detected with terbium-labeled antibodies against the specific site and modification. The expression of GFP-H3 substrate allows for detection of antibody binding in cell lysates via TR-FRET between the terbium and GFP. Since the actual modification takes place in the intact cell, native protein complexes that may be important for enzyme function are preserved. Together, these assays enable interrogation of multiple enzymatic activities responsible for epigenetic modifications of challenging histone targets
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 67. doi:10.1158/1538-7445.AM2011-67
Abstract 675: Effects of PBN and OKN007 in rodent glioma models assessed by 1H MR spectroscopy
Authors: He Ting , Doblas Sabrina , Saunders Debra , Casteel Rebba , Floyd Robert A. , Towner Rheal A. 
Published: June 2012

Abstract
Gliomas are the most common and lethal primary brain tumors in the adult, with a median survival time of 12 to 15 months for grade IV gliomas, glioblastoma multiforme. PBN and OKN007 are nitrones which have demonstrated beneficial effects in many aging diseases. In this study, we evaluated the anti-tumor effects of PBN or OKN007 in several rodent glioma models (C6, RG2, and GL261) by assessing metabolite alterations with magnetic resonance spectroscopy (MRS). PBN or OKN007 was administered in drinking water prior to or post tumor formation. MRI and short echo time, single-voxel point-resolved spectroscopy (PRESS) were obtained to assess tumor morphology and metabolites, respectively, following therapy. Major metabolite ratios (Choline, N-acetyl aspartate (NAA), Lipid (methylene), and Lipid (methyl), all compared to Creatine) were assessed. Nitrones induced tumor metabolism changes that resulted in restoring major metabolite ratios close to their normal levels, in the glioma regression phase. Nitrones treatment decreased the Lipid (methylene) to Creatine ratio significantly, which can be a useful marker for evaluation of the efficacy of the treatments, and was found to be related with the reduction of necrosis. OKN007 was more effective than PBN when administered post-tumor formation in the C6 glioma model. OKN007 was able to inhibit angiogenic factors (VEGF, bFGF and HGF) and induce apoptosis (indicated by an increase of the apoptotic marker m30) in C6 gliomas, which might be potential mechanisms that are involved in the anti-glioma effects. In conclusion, OKN007 and PBN are effective in inhibiting the growth of several experimental gliomas and may be considered as potential therapeutics for a clinical trial in human gliomas.
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 675. doi:10.1158/1538-7445.AM2011-675
Abstract 681: PTX-008, a novel galectin-1 targeting agent, improves the effects of cytotoxic drugs in colon cancer cells
Authors: Astorgues-Xerri Lucile , Serova Maria , Riveiro Maria E. , Cvitkovic Esteban , Noel Kay , Raymond Eric , Faivre Sandrine 
Published: June 2012

Abstract
Background: Addition of targeted therapies has been shown to potentiate the activity of cytotoxic drugs. Compounds with innovative mechanism of action such as PTX-008, a novel galectin-1 targeting agent, might represent an interesting candidate for cytotoxic-based combinations. We explored the effect of PTX-008 in combination with several drugs commonly used in cancer chemotherapy such as cisplatin, oxaliplatin, 5-FU, 5’-DFUR, taxotere and gemcitabine in colon cancer cell lines.
Methods: Antiproliferative effects were evaluated in two human colon (Colo205 and HT29) cancer cell lines by MTT assay. Effects of different schedules of exposure of PTX-008-based combinations were determined by median effect plot analysis (Chou & Talalay).
Results: PTX-008 induced significant growth inhibition at concentrations below 10 µM in HT29 and Colo205 cancer cell lines. Combination of PTX-008 with cisplatin and oxaliplatin was additive or synergistic in both Colo205 and HT29 cells for all administration schedules. Combination of PTX-008 with antimetabolites 5-FU and 5’-DFUR was synergistic for sequential administration schedule, especially when PTX-008 was given prior to 5-FU and 5’-DFUR in colon cancer cells. Simultaneous exposure to these drugs induced additive effects. Combination with taxotere was at least additive using all schedules of administration. PTX-008/gemcitabine combination were highly synergistic in Colo205 and HT29 cells for sequential schedules and additive/synergistic for simultaneous administration.
Conclusions: Combination studies showed that PTX-008 displays at least additive, often synergistic effects with a wide range of cytotoxic drugs (including cisplatin, oxaliplatin, 5-FU, gemcitabine and taxotere). Those data provide preliminary evidences that inhibition of galectin-1 using PTX-008 may be an attractive approach for combinations with anticancer drugs in clinical trials.
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 681. doi:10.1158/1538-7445.AM2011-681
Abstract 687: Enhanced expression of multidrug resistance (MDR) protein in malignant pleural mesothelioma (MPM) patients is possibly achieved via Osteoponin, CD44 variants and p-AKT expression
Authors: Bahnassy Abeer A. , Zekri Abdel-Rahman N. , Eid Salem , Abdel-Rahman Abdel-Rahman M. , Mahmoud Moustafa R. , Gaafar Rabab M. 
Published: June 2012

Abstract
Malignant pleural mesothelioma (MPM) is an aggressive disease, which is discovered late. It is resistant to chemotherapy and thus shows a dismal prognosis. Recently, in vitro studies demonstrated that osteoponin (is involved in the development of MPM via induction of multidrug resistance through unidentified mechanism(s).
Tissue and serum samples from 55 Egyptian cases of MPM were assessed for OPN, MDR, p-AKT and CD44 proteins and RNA by ELISA, immunohistochemistry (IHC) and RT-PCR. Normal pleural samples (20) were used as a control. Results were correlated with standard prognostic factors and survival.
In tissues, OPN, CD44, MDR and p-AKT protein overexpression was detected in 39, 26, 37 and 25 cases; respectively whereas RNA expression was reported in 31, 24, 30, 24 cases; respectively. In sera, OPN, CD44, MDR and p-AKT proteins were found in 36, 20, 40, 28 cases; respectively. There was a significant correlation between OPN expression and other markers, at the protein and RNA levels (p&lt;0.05). The concordance between OPN and MDR expression was the highest (98%). Control samples were negative for the studied markers except for 4 cases that showed faint focal expression of p-AKT and CD44 proteins. OS was significantly associated with performance status, increased expression of OPN, MDR and CD44 in univariate and multivariate analysis (p&lt;0.01). A borderline significance was reported between poor response to treatment and increased expression of OPN, CD44, MDR either singly (p=0.063) or combined (p=0.045)
In conclusion, OPN, CD44, and p-AKT could be used as poor prognostic markers in MPM being associated with reduced OS rates and poor response to treatment. This could be achieved via enhanced MDR expression with subsequent resistance to chemotherapy.
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 687. doi:10.1158/1538-7445.AM2011-687
Abstract 698: β-arrestin-1 as nuclear signalling element essential for endothelin A receptor-induced epithelial to mesenchymal transition and chemoresistance
Authors: Rosanò Laura , Cianfrocca Roberta , Castro Valeriana Di , Spinella Francesca , Nicotra Maria Rita , Natali Pier Giorgio , Bagnato Anna 
Published: June 2012

Abstract
The onset of chemoresistance is the major challenge in epithelial ovarian cancer (EOC). Emerging evidence suggests molecular and phenotypic association between chemoresistance and epithelial-mesenchymal transition (EMT) in cancer. We recently demonstrated that β-arrestin-1, scaffold and signaling protein of G-protein-coupled receptors, is recruited to endothelin A receptor (ETAR) to form molecular signaling complexes which concur to activate β-catenin transcriptional activity, EMT and metastasis. Here, by using biochemical and imaging techniques, we provide evidence that in EOC cells, ETAR activation by endothelin-1 (ET-1) induces nuclear translocation of β-arrestin-1 and its association with β-catenin. ChIP assays demonstrated that following this translocation, β-arrestin-1 was selectively enriched at specific promoters of β-catenin target genes, such as ET-1, MMP-2, cyclin D1. Further experiments showed that ET-1 promotes the nuclear association between histone acetyltransferase p300 and β-arrestin and the recruitment of p300 on these promoters, resulting in H3 and H4 histone acetylation and enhanced gene transcription. In chemoresistant EOC cells, ET-1/ETAR axis is overexpressed associated with EMT marker expression. Most importantly, the transcriptional activity of β-catenin was upregulated in chemoresistant EOC cells, associated with enhanced ETAR and β-arrestin-1 expression, providing molecular evidence that the ETAR/β-arrestin-1-mediated EMT signaling in EOC can represent a “salvage pathway” occurring during chemoresistance development. Interestingly, ETAR blockade with zibotentan, a specific ETAR antagonist, or its silencing with siRNA, abrogates both the engagement of β-arrestin-1 in the nucleus and the interplay between ET-1 and the β-catenin in controlling gene transcription. In vivo, zibotentan inhibited tumor growth of sensitive and resistant EOC xenografts, associated with reduction of EMT markers, and sensitized to chemotherapy. Analysis of EOC human tissues revealed that ETAR is overexpressed in resistant tumors and is associated with EMT phenotype. Our data provide the first evidence that blockade of ETAR/β-arrestin-1-driven EMT can overcome chemoresistance and inhibit tumor progression, improving the outcome of EOC patients’ treatment. Supported by AIRC
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 698. doi:10.1158/1538-7445.AM2011-698
Abstract 699: HSP70 specifically binds to 15 bp deletion mutant EGFR and modulates sensitivity to EGFR-TKI
Authors: Kadofuku Tsuyoki , Kanome Tomoko , Ichihashi Yoko , Yamaoka Toshimitsu , Hirose Takashi , Adachi Mitsuru , Saijo Nagahiro , Ohmori Tohru 
Published: June 2012

Abstract
[Purpose] Non small lung cancer (NSCLC) cells that expressed mutant EGFR are more sensitive to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) than that expressed wild type EGFR. Recent clinical trials revealed that more than 70% NSCLC patients that expressed mutant EGFR showed sensitivity to EGFR-TKIs, such as gefitinib and erlotinib. To elucidate the mechanism of this hypersensitivity, we explored the difference of EGFR-binding proteins between wild type EGFR and 15 bp deletion mutant EGFR using respective stable transfectants.
[Methods] Wild type EGFR and a 15 bp deletion mutant EGFR plasmids were transfected into HEK293 cells. The stable transfectant cells were established, and were designated 293_pEGFR and 293_pΔ15, respectively. Cells were incubated in a medium with/without 10 ng/ml of TGFα for 1 h and lysed. Cell lysate was precleared by centrifugation at 15,000 rpm for 15 min. The supernatant was mixed with a polyclonal EGFR antibody for 1 h and EGFR was immunoprecipitated by Protein A-Sepharose. After adequate washing, coprecipitated proteins that bound to EGFR were eluted and separated by 2D-PAGE (Immobiline DryStrip (pH3-10 NL, 7 cm) and 10% SDS-PAGE). Proteins were visualized by silver staining and identified by LC-MS/MS. HSP70 siRNA was transfected into the cells by lipofection method. Sensitivity to gefitinib was measured by MTT assay. EGFR binding affinity to gefitinib was measured using [14C] gefitinib.
[Results and Discussion] We detected several EGFR binding proteins. Among these proteins, one candidate (lesser binding to wild type EGFR than the mutant EGFR) was identified as HSP 70 by LC-MS/MS. The total amount of HSP70 protein was not different between 293_pEGFR and293_pΔ15 cells. A specific binding of this protein to the mutant EGFR was confirmed by Western blotting analysis. This binding was not modulated by EGFR activation. Knockdown of HSP 70 protein by a specific siRNA enhanced gefitinib sensitivity in the mutant EGFR transfectant.
These results suggest that HSP 70 may decrease sensitivity to EGFR-TKIs in the cells that expressed 15 bp deletion mutant EGFR. There is a possibility that HSP70 overexpression might be a newly resistant mechanism to EGFR-TKIs in NSCLC patients that expressed mutant EGFR.
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 699. doi:10.1158/1538-7445.AM2011-699
Abstract 70: A role for the chromatin remodeling protein CHD3 in ovarian cancer therapy response
Authors: Cutter Noelle , Banerjee Nila , Vigliotti Michele , Janevski Angel , Levine Douglas , Dimitrova Nevenka , Lucito Robert 
Published: June 2012

Abstract
Carboplatin and cisplatin are chemotherapeutic agents that are used extensively for treating epithelial ovarian cancer. These drugs can be highly effective, yet tumors are frequently refractory to treatment or become resistant upon tumor relapse. Epigenetic silencing, particularly at promoter regions of genes regulates important cell function and has been associated with all stages of tumor formation and progression and may contribute to therapy response. We analyzed the epigenome of 50 primary ovarian tumors and 12 normal ovarian samples using an array based method previously developed in our lab and associated Affymetrix U133 expression data. We then identified gene candidates that segregate patients based on platinum sensitivity and patient survival. These candidates were then pooled into a genome-wide RNAi-based screen where we validated a gene encoding a chromatin remodeling protein, CHD3, a member of the Mi-2 NuRD complex, and show that it is linked to chemoresistance. CHD3 is silenced through an epigenetic mechanism in both ovarian cancer cell lines and primary ovarian tumors. When ovarian cancer cell lines that are transcriptionally silenced for CHD3 are challenged with carboplatin they display a striking slow growth phenotype as well as increased resistance to the chemotherapy drugs carboplatin and cisplatin. Taken together, we provide the first evidence for a role for CHD3 as an important mediator of chemoresistance in ovarian cancer. Furthermore, CHD3 might represent a response predictor and potential therapeutic target for predicting chemoresistance in this disease.
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 70. doi:10.1158/1538-7445.AM2011-70
Abstract 707: Acquisition of chemoresistance and epithelial to mesenchymal phenotype is linked with activation of the endothelin A receptor pathway in ovarian carcinoma cells
Authors: Cianfrocca Roberta , Rosanò Laura , Castro Valeriana Di , Spinella Francesca , Nicotra Maria Rita , Lucidi Alessandro , Ferrandina Gabriella , Natali Pier Giorgio , Bagnato Anna 
Published: June 2012

Abstract
Understanding the molecular mechanisms underlying chemoresistance is of utmost importance for improving the treatment of epithelial ovarian cancer (EOC). Emerging evidence suggests molecular and phenotypic association between chemoresistance and epithelial-mesenchymal transition (EMT) in cancer cells. Endothelin-1 (ET-1) and the endothelin A receptor (ETAR) axis is implicated in the pathobiology of EOC by driving different tumor-promoting effects, including EMT. By employing two cisplatin- and taxol-resistant ovarian cancer cell lines, we demonstrated that in the resistant EOC cells ET-1 and ETAR are upregulated, at both mRNA and protein level, paralleled by enhanced MAPK and AKT phosphorylation and cell proliferation. To assess whether the chemoresistance in A2780 cells was associated with EMT molecular changes, we examined the expression of epithelial and mesenchymal markers. Enhanced Snail, Slug, Twist, N-cadherin and vimentin mRNA expression was observed in resistant cells, associated with a concomitant decrease in E-cadherin expression and promoter activity. Moreover, ET-1 induced a significant induction of Snail promoter activity in resistant cells, and the E-cadherin promoter sequences were detected bound to Snail in a time-dependent manner, as demonstrated by chromatin immunoprecipitation assays, suggesting that the ET-1-dependent and sustained binding of Snail in the E-cadherin promoter might account for EMT and chemoresistant phenotype of these cells. Moreover, the invasiveness and proteinase activity of chemoresistant cells was greater, compared with sensitive cells. Interestingly, ETAR blockade with the specific ETAR antagonist, zibotentan, or its silencing with siRNA, reverted EMT, restored drug sensitivity to cytotoxic-induced apoptosis, and inhibited the invasive potential of resistant cells. In vivo, zibotentan inhibited tumor growth of sensitive and resistant EOC xenografts, and sensitized to chemotherapy. Finally, analysis of EOC tissues, with different responses to chemotherapy, revealed that ETAR is overexpressed in resistant tumors and is associated with EMT marker expression. All these data indicate that blockade of ETAR-driven EMT can overcome chemoresistance in EOC, improving the outcome of EOC patients’ treatment. Supported by AIRC
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 707. doi:10.1158/1538-7445.AM2011-707