bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4356: EphB4 as a novel therapeutic target for head-neck SCC.
Authors: Liu Ren , Yen Hai-yun , Masood Rizwan , Sinha Uttam , El-Khoueiry Anthony , Liu Stephen , Gitlitz Barbara , Gill Parkash S. 
Published: August 2014

Abstract
Introduction: Receptor tyrosine kinase EphB4 and its cognate trans-membrane ligand EphrinB2 regulate venous-artery determination and are critically required for fusion of vein and arterial compartments, as well as vessel maturation in development and in pathological angiogenesis. Aberrant induction of EphB4 in certain tumors and pro-tumor cell survival function independent of its role in tumor angiogenesis have been reported. We have studied the expression and function of EphB4 in head neck squamous cell cancer.
Methods: EphB4 expression in 78 freshly frozen head/neck squamous cell carcinoma tumor samples were studied by immunostaining, western blot analysis, gene copy number, and correlated with stage. Head/neck tumor cell lines also were studied for expression and significance of EphB4 expression on survival by knock down studies using EphB4 lentiviral shRNA. Inhibition of EphB4 activation using decoy soluble EphB4 receptor fused in frame at the C-terminus with human albumin (sEphB4-HSA) was evaluated for in vivo studies of human tumor xenografts.
Results: EphB4 was expressed in all human tumor tissues, and the levels correlated directly with stage. High EphB4 also predicted shortened survival. EphB4 protein levels varied in tumor cell lines, and loss of cell viability with EphB4 shRNA knock down was highest in cell lines with highest EphB4 levels (range 25-78%). Tumor xenografts in sEphB4-HSA treated mice were reduced over 80% compared to the control PBS treatment. Tissue analysis revealed reduction in tumor vessel density, reduced recruitment of pericytes, and decreased perfusion of the tumor vessels. sEphB4-HSA treatment also decreased tumor tissue PI3K activity manifested by reduced phosphorylated AKT and S6 level. Tumor cell death by apoptosis was widespread consistent with combined anti-angiogenic activity and direct tumor cell toxicity.
Conclusion: EphB4 receptor tyrosine kinase is highly expressed in head/neck squamous cell cancer. EphB4 provides survival signal to the tumor cells directly. Decoy EphB4 inhibitor sEphB4-HSA is highly potent in in vivo tumor xenograft models. sEphB4-HSA is thus a candidate for investigation in human trials and the clinical trials are underway.
Citation Format: Ren Liu, Hai-yun Yen, Rizwan Masood, Uttam Sinha, Anthony El-Khoueiry, Stephen Liu, Barbara Gitlitz, Parkash S. Gill. EphB4 as a novel therapeutic target for head-neck SCC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4356. doi:10.1158/1538-7445.AM2013-4356
Abstract 4374: Identification of novel, biologically relevant, G-quadruplexes formed within the critical promoter of kRAS as promising molecular targets.
Authors: Hockings Chi-Fan , Greer Kristen M. , Brooks Tracy A. 
Published: August 2014

Abstract
To date, kRAS is one of, if not the, most established oncogenic anomalies identified. It is either upregulated or mutationally activated in a variety of cancers, most notably pancreatic adenocarcinoma, non-small cell lung and colon cancers. Pancreatic cancer carries the highest mortality rate of all cancers, with only a 3-6 month median survival, and a 5-year survival of &lt;5%. Lung and colon cancers harboring a mutant kRAS are associated with a worsened prognosis and shorter disease-free survival, and such mutations are independent factors for poor prognosis. To date no attempts to modulate kRAS activity, localization, or signaling have produced clinically active moieties; there is a desperate need for new, kRAS-focused therapeutics. Various silencing technologies have demonstrated that decreasing kRAS expression is sufficient to produce cancer cell kill, and the presented works describe a novel target to downregulate kRAS expression - secondary structures within the proximal promoter, which contains a unique string of G-rich DNA. Negative superhelicity induced by transcription results in this region opening up to form unique secondary structures called G-quadruplexes (G4s). These G4s most often act as silencer elements, forming globular structures that mask binding sites for transcriptional factors, allowing for specific molecular targeting by small molecule drugs, modulating transcription, and protein expression. The G-rich region of the kRAS promoter is extensive, containing three separate putative G4-forming regions. Initial works described the near G4 as a unique ‘kinked’ structure, as well as described two compounds that stabilize different isoforms of this structure, but do not appear to contribute much to the transcriptional control of kRAS. Further elucidation of promoter activity has highlighted new, and more biologically important, G4s existing more distally from the transcriptional state site. Stabilization of this region in a plasmid system significantly decreases luciferase expression, and the mid-G4-forming region forms several stable, complex, structures. These formations have been examined by EMSA, polymerase stop, and footprinting methods. From these data, the elucidated predominant structures are currently the target of further studies with the ultimate goal of describing a new molecular structure, and its dynamic regulation, for future drug development.
Citation Format: Chi-Fan Hockings, Kristen M. Greer, Tracy A. Brooks. Identification of novel, biologically relevant, G-quadruplexes formed within the critical promoter of kRAS as promising molecular targets. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4374. doi:10.1158/1538-7445.AM2013-4374
Abstract 4382: Genome-Wide Gene Expression analysis and molecular portraits regulated by NASEp, an inhibitor of CREB and CBP interaction, in non-small cell lung cancer.
Authors: Park Sin-Aye , Platt James , Park Hee Sun , Lee Jong Woo , Stern David F. , Herbst Roy S. , Koo Jaseok Peter 
Published: August 2014

Abstract
Cyclic-AMP response element-binding protein (CREB)-cAMP response element (CRE) transcriptional pathway plays a critical role in the growth and survival of non-small cell lung cancer (NSCLC) cells. Recruitment of CREB binding protein (CBP) is essential for the transcriptional activity of CREB. However, there is no specific drug in use blocking CREB-CRE transcriptional pathway which may become a new therapeutic target in anti-cancer strategy. Naphthol AS-E phosphate (NASEp) was identified as an inhibitor of CREB transcriptional activity by binding to the KIX domain of CBP and blocking its access to the KID domain in CREB. Our objective was to identify which genes and molecular pathways could be affected by NASEp that may alter target molecules through the regulation of a subset of CRE-containing genes. The effects of the CREB inhibitor NASEp on A549 lung carcinoma cells were examined on an Affymetrix HuGene 1.0 expression microarray and a list of significantly differentially regulated genes was generated. Gene Set Enrichment Analysis (GSEA) shows down-regulation of multiple cancer-related pathways including proliferation, RAS signaling, drug resistance and metastasis. Most significantly, a strong negative correlation with Rosty Cervical Cancer Proliferation Cluster, shows that NASEp inhibits the same set of genes which are up regulated by the E6 and E7 viral oncogenes. These viral elements are known to interact with CBP, which is the direct target of NASEp. Since CBP is known to be a cofactor to multiple transcription factors, we performed an additional round of GSEA using the motif-based Transcription Factor Targets gene set collection and represented the results using a Cytoscape network diagram to illustrate the multifactorial effects of NASEp. Particularly, we focused that several transcription factors regulating cell cycle-related genes. This study implicates potential combinational blockage of CREB and cell cycle-regulated proteins as a cancer therapy.
Citation Format: Sin-Aye Park, James Platt, Hee Sun Park, Jong Woo Lee, David F. Stern, Roy S. Herbst, Jaseok Peter Koo. Genome-Wide Gene Expression analysis and molecular portraits regulated by NASEp, an inhibitor of CREB and CBP interaction, in non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4382. doi:10.1158/1538-7445.AM2013-4382
Abstract 4383: Transglutaminase-2 mediates the pro-malignant effects of oncostatin-M receptor overexpression in cervical squamous cell carcinoma.
Authors: Caffarel Maria M. , Chattopadhyay Anasuya , Scarpini Cinzia G. , Coleman Nicholas 
Published: August 2014

Abstract
An important feature of cervical squamous carcinogenesis is genomic instability caused by deregulated expression of HPV oncogenes in proliferating epithelial cells. A genomic imbalance that is commonly selected in advanced cervical squamous cell carcinoma (SCC) is copy number gain of chromosome 5p. One gene that is likely to drive selection of this abnormality is the oncostatin-M receptor (OSMR; located at 5p13.1), which is commonly up-regulated in cervical SCC and produces a significantly worse clinical outcome when over-expressed. Cervical SCC cells that over-expressed OSMR showed enhanced responsiveness to the major ligand OSM, which induced multiple pro-malignant effects, including increased cell migration and invasiveness. We now show that transglutaminase-2 (TGM2) is an important mediator of the ligand-dependent phenotypic effects of OSMR over-expression in cervical carcinoma cells. TGM2 expression correlated with disease progression and with OSMR levels in clinical samples of SCC of the cervix and head and neck. TGM2 depletion in cervical SCC cells abrogated the increased migration and invasiveness induced by OSM. TGM2 was shown to interact with integrin-α5β1 and fibronectin in cervical SCC cells, with OSM treatment strengthening the interaction. Importantly, integrin-α5β1 and fibronectin were over-expressed in cervical SCC samples, where levels correlated with those of OSMR. We conclude that an OSMR-TGM2-integrin-α5β1 pathway is of biological significance in cervical SCC and a candidate for therapeutic targeting.
Citation Format: Maria M. Caffarel, Anasuya Chattopadhyay, Cinzia G. Scarpini, Nicholas Coleman. Transglutaminase-2 mediates the pro-malignant effects of oncostatin-M receptor overexpression in cervical squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2013-4383
Abstract 4385: The green tea polyphenol EGCG induces mesenchymal to epithelial transition (MET) and tumor regression in triple negative breast cancer (TNBC) cells and mouse xenograft model: involvement of CCN5.
Authors: Das Amlan , Banerjee Snigdha , De Archana , Haque Inamul , Maity Gargi , McEwen Matt , Banerjee Sushanta K. 
Published: August 2014

Abstract
Background: Epithelial to Mesenchymal transition (EMT) is an important and coordinated series of events associated with tumor metastasis and invasion. Recent studies had shown the importance of CCN5 (also known as WISP-2,Wnt-1-induced signaling protein-2) in the regulation of various carcinomas including the breast cancer. Recent studies had showed that ectopic expression of CCN5 can reverse Epithelial-Mesenchymal transition (EMT) and inhibit cancer metastasis. Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, has been extensively studied as a bioactive dietary component against various types of carcinomas through multiple mechanisms such as anti-oxidation, induction of apoptosis, inhibition of angiogenesis and metastasis. However, the mechanism of action of EGCG in breast carcinoma is uncertain.
Objective: The objective of the present study is to determine whether CCN5 plays any significant role in EGCG-mediated cytotoxicity in triple negative breast cancer cells.
Results: Exposure of triple negative human breast cancer (TNBC) cells, MDA-MB-231 and HCC70 to EGCG resulted in a dose-dependent inhibition of proliferation after 72h and the IC50 was observed around 75μM for MDA-MB-231 cells and 50μM for HCC70 respectively. We found EGCG-treatment effectively induces MET and inhibits the in vitro migration parallel with the induction of CCN5 expression in TNBC cells in a dose-dependent fashion. Furthermore, consistent with in vitro findings, tumor progression was drastically inhibited in EGCG-treated MDA-MB-231-tumor xenograft in nude mouse model.
Conclusion: EGCG imparts its anti-cancer activity in both TNBC cells as well as MB-231-tumor xenografts via induction of CCN5.
Citation Format: Amlan Das, Snigdha Banerjee, Archana De, Inamul Haque, Gargi Maity, Matt McEwen, Sushanta K. Banerjee. The green tea polyphenol EGCG induces mesenchymal to epithelial transition (MET) and tumor regression in triple negative breast cancer (TNBC) cells and mouse xenograft model: involvement of CCN5. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4385. doi:10.1158/1538-7445.AM2013-4385
Abstract 4390: Aurora kinases: potential therapeutic targets in K-Ras-induced lung cancer.
Authors: dos Santos Edmilson O. , Aoki Mateus N. , Bassères Daniela S. 
Published: August 2014

Abstract
K-Ras-induced lung cancer is a very common disease, for which there are currently no effective therapies. Intense efforts are underway to identify K-Ras targets that play a crucial role in oncogenesis. We have previously shown that K-Ras-induced lung tumorigenesis is potentiated by the transcription factor NF-κB; and others have shown that Aurora kinases, not only play a significant role in tumorigenesis, but also can activate NF-κB. Therefore, we hypothesized that Aurora A and/or Aurora B are important K-Ras targets in lung cancer. In order to test this hypothesis, we first determined whether oncogenic K-Ras induces Aurora kinase expression. For that purpose, we used three different cell-based models: (1) an immortalized primary lung epithelial cell line and its isogenic K-Ras-transformed counterpart, (2) H1703 lung cancer cell line engineered to express oncogenic K-Ras inducibly, and (3) K-Ras positive lung cancer cell lines H358 and A549 stably expressing inducible shRNAs targeting K-Ras. In all cases, K-Ras expression positively correlated with Aurora A and Aurora B expression. In order to validate Aurora A an B as therapeutically relevant K-Ras targets in lung cancer, we used genetic and/or pharmacological approaches in the abovementioned cells to inactivate Aurora A or B. Inducible shRNA-mediated knockdown of Aurora A or B, as well as treatment with a dual Aurora A and B inhibitor (AI II), decreased growth, viability and migration of K-Ras positive H358 and A549 cell lines. Interestingly, in our primary isogenic model and in our H1703 K-Ras-inducible cell line, AI II reduced viability and induced apoptosis in an oncogenic K-Ras-dependent manner. This suggests that Aurora kinase inhibition therapy can specifically target K-Ras transformed cells. In conclusion, our results support our hypothesis that Aurora kinases are important K-Ras targets in lung cancer and suggest Aurora kinase inhibition as a novel approach for K-Ras-induced lung cancer therapy.
Citation Format: Edmilson O. dos Santos, Mateus N. Aoki, Daniela S. Bassères. Aurora kinases: potential therapeutic targets in K-Ras-induced lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4390. doi:10.1158/1538-7445.AM2013-4390
Abstract 4408: A functional genomics approach for identification of sirolimus sensitizer genes regulated by HDAC inhibitors.
Authors: Gamache Benjamin J. , Simmons John , Patel Jyoti , Ou Lihui , Michalowski Aleksandra , Sullivan Patrick , Wei Bih-Rong , Simpson R. Mark , Zhang Shuling , Zhang Ke , Kuehl W. Michael , Landgren Ola , Caplen Natasha , Mock Beverly 
Published: August 2014

Abstract
The molecular pathogenesis of many cancer types, including multiple myeloma (MM), involves alterations in the PI3K/Akt/mTOR and cyclin/CDK/CDKI/Rb (Rb) pathways. We have shown the combination of a Class I-specific HDAC inhibitor (entinostat, MS-275) with the mTOR inhibitor sirolimus to be synergistic in a large panel of B cell tumor cell lines including multiple myeloma, mantle cell and Burkitt's lymphoma. While tumor outgrowth occurred in both single agent arms, the combination effectively controlled in vivo tumor growth in long-term preclinical studies. The combination was also highly effective in a tumor-cell specific bioluminescence assay where myeloma cells are co-cultured with bone marrow stromal cells to mimic the protective effects of the tumor microenvironment. We found the combination antagonized the oncogenic activation of the AKT pathway associated with single-agent rapamycin treatment, inhibited the ERK/MAPK pathway, decreased pro-survival signaling, and increased growth inhibitory signals to a much greater extent than either single agent alone. To further understand the molecular mechanisms contributing to the synergy of this combination, a functional genomics approach utilizing high-throughput RNAi screening and gene expression profiling was taken. Several cell cycle-specific kinases were identified that upon inhibition enhance the activity of sirolimus and are significantly down-regulated by entinostat. Thus far, we have confirmed by western blot that PLK1 and AURKB are decreased in a dose-dependent manner by entinostat. Specific inhibition of these targets synergizes with sirolimus. Additionally, we found very low (&lt;EC20) entinostat/sirolimus combination doses to hyper-sensitize tumor cells to a number of cell cycle inhibitors. These findings are further supported by increased cell cycle arrest seen in the combination treatment compared to either drug alone, as well as marked reduction in the cell cycle progression marker phospho-Histone H3. Taken together, our findings indicate the anti-tumor synergy of combined HDAC/mTOR inhibition is the result of multiple cooperative effects.
Citation Format: Benjamin J. Gamache, John Simmons, Jyoti Patel, Lihui Ou, Aleksandra Michalowski, Patrick Sullivan, Bih-Rong Wei, R. Mark Simpson, Shuling Zhang, Ke Zhang, W. Michael Kuehl, Ola Landgren, Natasha Caplen, Beverly Mock. A functional genomics approach for identification of sirolimus sensitizer genes regulated by HDAC inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4408. doi:10.1158/1538-7445.AM2013-4408
Abstract 4414: Differential effects of functionalized and non-functionalized short multi-wall carbon nanotubes on survival and cell signaling in pancreatic cancer cells.
Authors: Zhang Yao , Lai James C.K. , Bhushan Alok ,   Biomedical and Pharmaceutical Sciences Department, College of Pharmacy, Division of Health Sciences.
Published: August 2014

Abstract
Pancreatic cancer is an aggressive type of cancer with poor prognosis and low five-year survival rate. Because chemotherapeutic and radiation treatments are not effective, new treatments for this cancer are needed to improve its prognosis. Carbon nanotubes (CNTs) constitute one novel and important nanomaterial extensively examined for potential biomedical applications (e.g., drug delivery vehicles and diagnostic agents). Modification of CNTs with functional groups improves solubility and may serve as attachment site of other molecules and/or drugs. This study elucidated the cytotoxicity induced by CNTs and the underlying mechanisms. We employed MTT assay to determine survival of PANC1 cells treated with different concentrations of short-multi-wall CNTs (SMWCNTs) or SMWCNTs-COOH for 24, 48, and 72 hrs. Our results suggested that functionalization with carboxyl group to SMWCNTs lowers their cytotoxicity. Therefore we hypothesized that the induced cytotoxicity by both SMWCNTs and SMWCNTs-COOH is a result of either up-regulation of apoptotic pathways or down-regulation of cellular survival/proliferation/differentiation pathways or a combination of both. We carried out western-blot analysis to examine the effects of CNTs on ERK, phospho-ERK, AKT, phospho-AKT signal transduction pathways and on the NF-κB pathway. PANC1 cells were treated with 2, 20, and 200 μg/ml SMWCNTs-COOH or SMWCNTs for 48hrs. The expressions of phospho-ERK were decreased in cells treated with 2 μg/ml SMWCNTs-COOH. However, as the concentration of SMWCNTs-COOH increased from 2 to 200 μg/ml, the phospho-ERK expression was increased: however, the total ERK expression was unaffected. The NF-κB expression in the cells was increased compared to control group as the concentration of SMWCNTs-COOH increased from 2 to 200 μg/ml. Our study demonstrates that both SMWCNTs and SMWCNTs-COOH induced cytotoxicity in pancreatic cancer cells and functionalization with carboxyl group lowered their cytotoxicity. One mechanism underlying their cytotoxicity may be the altered regulation of cellular survival/proliferation pathways such as ERK. Thus, our results may have implications in cytotoxicity of SMWCNTs in pancreatic cells and in designing therapies for pancreatic cancer.
Citation Format: Yao Zhang, James C.K. Lai, Alok Bhushan, Biomedical and Pharmaceutical Sciences Department,College of Pharmacy, Division of Health Sciences. Differential effects of functionalized and non-functionalized short multi-wall carbon nanotubes on survival and cell signaling in pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4414. doi:10.1158/1538-7445.AM2013-4414