bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 416: New technology to detect DNA methylation in plasma sample from lung cancer patients
Authors: Shinjo Keiko , Kondo Eisaku , Kondo Yutaka 
Published: May 2015

Abstract
Epigenetic alterations have emerged as a common hallmark of many types of human cancers including lung cancers. Therefore, detection of aberrant DNA methylation from blood samples may be a promising diagnostic tool for cancers. We have been developing a highly sensitive plasma-based approach to detect aberrant DNA methylation in lung cancer patients. First, we identified seven markers from genome-wide methylation analysis, which can diagnose lung cancer in tissue samples with high accuracy (sensitivity, 91%; specificity, 100%). Next, we evaluated DNA methylation status in tissue samples and corresponding plasma samples in each patient using pyrosequencing analysis and qMSP. However, DNA methylation status between tissue and plasma samples were not concordant by both methods (pyrosequencing, 0/19 cases; qMSP, 3/9 cases). Given the concentration of DNA in plasma originated from cancerous tissue might theoretically be very low, we need to use more sensitive and accurate methods. We used digital PCR and next generation sequencer to analyze the methylation status of plasma DNA. These methods are both highly sensitive. Now we invent a new technology using specific probes, which can recognize sequence information including methylated cytosine even in one DNA molecule. This new technology might be applicable as a practical tool for lung cancer diagnosis.
Citation Format: Keiko Shinjo, Eisaku Kondo, Yutaka Kondo. New technology to detect DNA methylation in plasma sample from lung cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 416. doi:10.1158/1538-7445.AM2014-416
Abstract 4164: The druggable proteome: Identifying novel target families for cancer
Authors: Razaz Parisa , Workman Paul , Al-Lazikani Bissan 
Published: May 2015

Abstract
Cancer drug attrition rates in the clinic continue to be unacceptably high (1). As most failures are due to lack of observed efficacy, greater focus is being placed on target validation (1), which in turn is driving drug discovery efforts towards safer targets and pathways. Meanwhile, large scale ‘omic efforts are showing us that there are hundreds of potential cancer drivers outside of the key targets known to the cancer field. Furthermore, cancer drugs can function through the exploitation of non-oncogenes (2). To mirror the systematic, large-scale and objective identification of potential cancer drivers, we have applied a large-scale, objective, systematic and multifaceted chemogenomic approach. This combines biological, chemical, pharmacological and 3D structural data (3,4) to prioritize druggable proteins and protein families, identifying novel untapped families with potential for cancer drug discovery. We have carried out computational druggability assessment of the human proteome (∼35’854 RefSeqs) using ligand-, structure-, network-, precedence- and feature-based druggability analysis methods. This has identified over 20 families that are likely to be druggable and, as can be gleaned from the literature, have had little or no chemical exploration efforts. We combine this with bioinformatics analysis of multiomic data from 18 different cancer types, with a focus on GI cancers of unmet medical need, in order to rank the families based on potential evidence of deregulation in these cancers. Here we present the results of this analysis, along with preliminary RNAi knockdown results of some of the families. Application of these objective methodologies allows identification of previously untapped druggable families for cancers, in addition to establishment and application of a computational pipeline for druggability assessment.
1. Arrowsmith, J. & Miller, P. Trial Watch: Phase II and Phase III attrition rates 2011-2012. Nat Rev Drug Discov 12, 569 (2013).
2. Workman, P. & Al-Lazikani, B. Drugging cancer genomes. Nat Rev Drug Discov 12, 889-890 (2013).
3. Patel, M. N., Halling-Brown, M. D., Tym, J. E., Workman, P. & Al-Lazikani, B. Objective assessment of cancer genes for drug discovery. Nat Rev Drug Discov 12, 35-50 (2013).
4. canSAR.icr.ac.uk at &lt;https://cansar.icr.ac.uk&gt;
Citation Format: Parisa Razaz, Paul Workman, Bissan Al-Lazikani. The druggable proteome: Identifying novel target families for cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4164. doi:10.1158/1538-7445.AM2014-4164
Abstract 4168: Dissect the clinical utility of TCGA genomic data across tumor types
Authors: Liang Han ,   TCGA Pan-Cancer Clinical/Predictor Group
Published: May 2015

Abstract
A central question for the cancer research community is how to use genomic and proteomic data to guide cancer care. We investigated two potential clinical applications of The Cancer Genome Atlas (TCGA) data: predicting patient prognosis and identifying clinically actionable alterations. For four TCGA cohorts, we systematically evaluated the power of molecular data with or without clinical variables in predicting patient survival; and to facilitate further community efforts, we established an open-access model evaluation platform. We demonstrate that incorporating molecular data with clinical variables can improve predictive power. Interestingly, one model derived from ovarian cancer can predict outcomes in kidney cancer, suggesting the potential utility of cross-tumor analysis. Across 12 cancer types, we identified 10,281 somatic alterations in clinically relevant genes in 2,928 out of 3,277 patients (89.4%), revealing recurrent and potentially targetable alterations not revealed in single-tumor datasets. Our study represents the first systematic and comprehensive analysis evaluating the prognostic power of different types of molecular data across multiple cancer types. In addition, the clinically actionable alterations we identified may inform novel clinical trial design and treatment choice.
Citation Format: Han Liang, TCGA Pan-Cancer Clinical/Predictor Group. Dissect the clinical utility of TCGA genomic data across tumor types. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4168. doi:10.1158/1538-7445.AM2014-4168
Abstract 4196: An RNA aptamer-based approach for human glioma treatment
Authors: Camorani Simona , Esposito Carla L. , Catuogno Silvia , Amero Paola , Rienzo Anna , Vita Gennaro D. , Condorelli Gerolama , Franciscis Vittorio de , Cerchia Laura 
Published: May 2015

Abstract
Gliomas are the most common primary central nervous system tumors with a dismal prognosis. Despite recent advances in surgery, radiotherapy, and chemotherapy, current treatment regimens have a modest survival benefit.
Due to a combination of its complex phenotype and organ-specific clinical manifestations, efforts to refine glioma treatment with targeted therapies have largely been frustrated. Hence, finding specific ligands capable of detecting and measuring the altered pattern of gene expression and to discriminate between different tumor phenotypes, is a strategic and plausible objective for the diagnosis and therapy of glioma. To date, antibody-based approaches have been developed for in vivo applications but, in most cases, they show toxicity in vivo and do not reach adequate sensitivity. Thanks to their unique characteristics (low size, good affinity for the target, no immunogenicity, chemical structures that can be easily modified to improve their in vivo applications), single-stranded nucleic acid ligand molecules, named aptamers, represent a valid alternative to antibodies for in vivo targeted recognition as therapeutics or delivery agents for nanoparticles, small interfering RNAs, chemotherapeutic cargos and molecular imaging probes.
By applying cell-SELEX on cancer cells we have generated and characterized different nuclease resistant 2′fluoro-pyrimidines RNA aptamers as high affinity ligands and inhibitors of human receptor tyrosine kinases (RTKs) with a crucial role in glioma, including EGFR, EGFRVIII, EphB3, Axl and PDGFRβ. All the aptamers are able to efficiently and specifically inhibit tumor growth in cell based assays and in animal models of human glioma. Further, some of these aptamers strongly cooperates in inducing inhibition of tumor growth thus providing the basis for further development of antitumor combination therapies.
Citation Format: Simona Camorani, Carla L. Esposito, Silvia Catuogno, Paola Amero, Anna Rienzo, Gennaro De Vita, Gerolama Condorelli, Vittorio de Franciscis, Laura Cerchia. An RNA aptamer-based approach for human glioma treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4196. doi:10.1158/1538-7445.AM2014-4196
Abstract 4200: Interaction between mPGES-1 and iNOS promotes human melanoma progression
Authors: Kim Sun-Hee , Hashimoto Yuuri , Ekmekcioglu Suhendan , Grimm Elizabeth A. 
Published: May 2015

Abstract
Melanoma cells in vivo are well known to express varying inflammatory features, which is not limited by somatic mutational subclass. Among the most prevalent of inflammatory markers are iNOS (inducible Nitric Oxide Synthase) generated NO production and COX-2/PGE2, and for which their active pathways have been shown to enhance carcinogenesis and tumor progression, stimulate angiogenesis, support tumor growth, and promote metastasis. COX-2 inhibitors are well studied agents that inhibit tumor growth and prevent tumor development including melanoma, but the focus of research has shifted to develop inhibitors for enzymes, which are downstream of COX-2, especially microsomal PGE2 synthase-1 (mPGES-1), due to the cardiovascular risk associated with the initial COX-2 inhibitory drugs. Here, we demonstrate crosstalk between iNOS/NO and mPGES-1/PGE2 signaling pathways and suggest that mPGES-1 is a novel potential therapeutic target in human melanoma employing a spectrum of well-defined human cell lines, as well as human tissues. Our melanoma stage III survival Tissue MicroArray analysis shows that the expression of mPGES-1 is elevated in 65% of human stage III melanomas and intense expression of mPGES-1 is significantly associated with the short-term survival of patients. More interestingly, about 90 % of patient samples which express mPGES-1 were also positive for iNOS. In addition, treatment of human melanoma cells with NO donors or constitutively-driven expression of iNOS resulted in increased PGE2 production, which was suppressed by mPGES-1 inhibition, indicating that the pathway is active and targetable. Moreover, iNOS was found to interact directly with mPGES-1, and iNOS or NO donors enhance mPGES-1 activity in melanoma cells and in vitro, suggesting that iNOS-mediated NO promotes PGE2 production through mPGES-1 activation. mPGES-1 inhibition by its shRNA or specific inhibitors suppressed human melanoma cell viability and migration. Collectively, these findings suggest that the interaction between iNOS and mPGES-1 is associated with human melanoma progression and could be considered as a novel target for translational application in melanoma growth regulation.
Citation Format: Sun-Hee Kim, Yuuri Hashimoto, Suhendan Ekmekcioglu, Elizabeth A. Grimm. Interaction between mPGES-1 and iNOS promotes human melanoma progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4200. doi:10.1158/1538-7445.AM2014-4200
Abstract 4205: Mass-spectroscopy phosphorylation profiling identified differential activation of signaling molecules via spleen tyrosine kinase in B-cell receptor signaling and stromal cell stimulation in DLBCL and CLL cells that are inhibited by GS-9973
Authors: Paolo Julie A. Di , Clarke Astrid , Rong Hong , Rousseau Emma 
Published: May 2015

Abstract
Dysregulation of protein kinase activity leading to aberrant or excessive downstream signaling is widely believed to underlay the pathogenesis of multiple cancers. The purpose of this study was to identify the spleen tyrosine kinase (SYK)-dependent phosphoproteins that were activated in a diffuse large B-cell lymphoma (DLBCL) cell line, DHL4, and primary chronic lymphocytic leukemia (CLL) cells, upon either B-cell receptor (BCR) activation, stromal cell contact, or in a resting state and demonstrate inhibition with a selective SYK inhibitor, GS-9973. A commercial PTMScan Direct procedure from Cell Signaling Technology was utilized in this assessment. Cell lysates generated from resting, αIgG treatment or HS-5 human stromal cell line contact were digested with trypsin and the resultant peptides were enriched by immunoprecipitation with either an anti-phosphotyrosine or anti-phosphoserine/threonine antibody cocktail, and subjected to mass spectrometric analysis to identify and quantify phosphorylated peptides. The phosphorylated peptide profile was then compared to a similarly treated lysate after incubation with 1 μM GS-9973. Protein phosphorylations that were significantly changed by &lt; or &gt; 2.5-fold with GS-9973 treatment were identified and confirmed, where possible, by western blot of DHL-4 lysates or in primary CLL samples with antibodies specific for the identified sites. PTMScan Direct analysis showed overlapping, but not equivalent, patterns of phosphorylated peptides upon αIgG or stromal cell activation. A shared set of GS-9973 inhibited phosphoproteins were identified including pSyk, pAkt, pMek, pErk, pJnk2, pPKCδ, and pS6 kinase. Western blot analysis validated 13 out of 14 proteins as being modulated by 1 μM GS-9973 treatment. Furthermore, dose-response inhibition was demonstrated for pAkt-T473, pBCR-Y177, pBlnk-Y84, pMek-S217/221, and pErk-T202/Y204 with EC50s ranging from 23 to 50 nM. These data support the concept that Syk inhibition can block multiple signaling pathways known to be important in malignant B-cells function. Furthermore, identification of these sites elucidates possible pharmacodynamic signatures of GS-9973 inhibition that may be followed in clinical investigations of GS-9973 in oncology.
Citation Format: Julie A. Di Paolo, Astrid Clarke, Hong Rong, Emma Rousseau. Mass-spectroscopy phosphorylation profiling identified differential activation of signaling molecules via spleen tyrosine kinase in B-cell receptor signaling and stromal cell stimulation in DLBCL and CLL cells that are inhibited by GS-9973. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4205. doi:10.1158/1538-7445.AM2014-4205
Abstract 4223: Combined PI3K-AKT and MEK-ERK pathway inhibition provides broad antitumor efficacy in HER2+ breast tumor models
Authors: De Pradip , Sun Yuliang , Carlson Jennifer , Friedman Lori , Dey Nandini , Leyland-Jones Brian 
Published: May 2015

Abstract
Background: The PI3K-AKT-mTOR and the RAS-RAF-MEK-ERK pathways are thought to be the central transducers of oncogenic signals in cancer. Combined targeting of these two pathways may be necessary for optimal therapeutic activity in solid tumors. This study evaluated the PI3K inhibitor GDC-0941, the MEK1/2 inhibitor GDC-0973 and the combination of both in different HER2+ breast cancer cell lines. Methodology: Growth inhibition/survival, apoptosis, signal transduction and antitumor efficacy were examined using MTT assays, 3D-ON-TOP assays, annexinV staining and mouse xenografts respectively, in BT474 (trastuzumab sensitive), BT474HR (trastuzumab-resistant) and HCC1954 (PIK3CA mutated) breast cancer cell lines. Results: (1) GDC-0941 and GDC-0973 exhibited in vitro cell killing activity in MTT assays with IC50's ranging from 0.35 µM to 1 µm and from 8 µM to 20 µM respectively, (2) the initiation of apoptotic activity (annexin V) in GDC-0941 plus GDC-0973 was significantly superior to that of either drug alone, (3) inhibition of phosphorylation of AKT(S473, T308), P70S6K, S6RP, and 4EBP1(T37/46) was observed following GDC-0941 treatment, and the combination of GDC-0941 plus GDC-0973 more effectively blocked p-S6RP and p-4EBP1, especially in BT474HR and HCC1954 cells, (4) GDC-0973 abrogated activation of ERK, and this ERK inactivation was sustained when combined with GDC-0941, (5) a combination of GDC-0941 and GDC-0973 more effectively blocked 3D-ON-TOP clonogenic growth of HER2+ cells than either agent alone, and (6) xenograft data show that the combination of GDC-0941 and trastuzumab has an enhanced anti-tumor effect in both sensitive (almost 100%) and resistant models (85%), and tumor regression was observed in both sensitive and resistant models when mice were treated with GDC-0941 plus GDC-0973 plus trastuzumab. Conclusions: Therapy with dual PI3K and MEK combination is more efficient than with either drug alone in all three cell lines. Our data provide stronger evidence that the addition of MEK inhibitor along with pan-PI3K inhibitor to HER2-directed treatment could augment the clinical benefit in breast cancer patients.
Citation Format: Pradip De, Yuliang Sun, Jennifer Carlson, Lori Friedman, Nandini Dey, Brian Leyland-Jones. Combined PI3K-AKT and MEK-ERK pathway inhibition provides broad antitumor efficacy in HER2+ breast tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4223. doi:10.1158/1538-7445.AM2014-4223
Abstract 4227: The ribonucleotide reductase inhibitor Didox reverses tamoxifen resistance in breast cancer cells
Authors: Shah Khyati N. , Elford Howard L. , Faridi Jesika S. 
Published: May 2015

Abstract
Tamoxifen is the most prescribed endocrine therapy for estrogen receptor positive breast cancer patients. The emergence of endocrine resistance is a major hurdle in achieving a successful clinical outcome. Many advances have been made over the past few years to understand the biology of tamoxifen resistance. Activation of the AKT kinase is one of the primary mechanisms of intrinsic tamoxifen resistance. Previously, we reported that the Ribonucleotide Reductase M2 (RRM2) subunit is upregulated in AKT induced tamoxifen resistance and that inhibition of RRM2 by siRNA mediated interference reduces tamoxifen induced cell proliferation. In this study, we report that the inhibition of RRM2 by the small molecule inhibitor of ribonucleotide reductase activity Didox (3, 4-dihydroxybenzohydroxamic acid), significantly reduced tamoxifen induced cell proliferation in AKT overexpressing cells and tamoxifen resistant tumors generated by these cells. As well, Didox in combination with tamoxifen also inhibited cell proliferation in acquired tamoxifen resistant breast cancer cell lines. Employing comprehensive cell culture and in vivo models, we demonstrate that combining tamoxifen with Didox may reverse tamoxifen resistance in AKT expressing breast cancer cells.
Citation Format: Khyati N. Shah, Howard L. Elford, Jesika S. Faridi. The ribonucleotide reductase inhibitor Didox reverses tamoxifen resistance in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4227. doi:10.1158/1538-7445.AM2014-4227
Abstract 4236: Antitumor activity of a novel (-)-antofine analog in human lung cancer cells and paclitaxel-resistant lung cancer cells
Authors: Song Jayoung , Bae Song Yi , Shin Yoonho , Kim Won Kyung , Oh Jedo , Choi Tae Joon , Jeong Eun Ju , Park So Hyun , Jang Eun Jeong , Kang Ji In , Park Hyen Joo , Hong Ji-Young , Chung Hwa-Jin , Kwon Yongseok , Kim Sanghee , Lee Sang Kook 
Published: May 2015

Abstract
Our previous study revealed that (-)-antofine, a phenanthroindolizidine alkaloid from Cynanchum paniculatum Kitagawa (Asclepiadaceae), exhibited a potent growth inhibition activity against A549 human lung cancer cells. Based on the information several analogs were designed and synthesized to procure new entities. A novel (-)-antofine C-13a analog ((R)-4b) was found to be a potential growth inhibition and antitumor activities in A549 cells. Treatment with (R)-4b for 24 hours did not result in the induction of apoptotic cell death but moderately induced cell cycle arrest in the G0/G1 phase and inhibited the expression of cyclin D1, cyclin E, CDK4 and pRb. In addition, (R)-4b suppressed the phosphorylation of mTOR and its downstream effectors such as 4E-BP-1 and eIF4E. The paclitaxel-resistance was also overcome in human lung cancer cells (A549-Pa) via the suppression of p-glycoprotein expression. Furthermore, (R)-4b significantly inhibited the tumor growth of A549 and A549-Pa xenografts in a nude mouse model. Taken together, these findings suggest that (R)-4b might be a potential candidate for the development of cancer chemotherapeutic agents derived from natural products.
Citation Format: Jayoung Song, Song Yi Bae, Yoonho Shin, Won Kyung Kim, Jedo Oh, Tae Joon Choi, Eun Ju Jeong, So Hyun Park, Eun Jeong Jang, Ji In Kang, Hyen Joo Park, Ji-Young Hong, Hwa-Jin Chung, Yongseok Kwon, Sanghee Kim, Sang Kook Lee. Antitumor activity of a novel (-)-antofine analog in human lung cancer cells and paclitaxel-resistant lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4236. doi:10.1158/1538-7445.AM2014-4236
Abstract 4244: Inhibition of HER2 and IGF2 triggers cell death in trastuzumab-resistant HER2 positive JIMT1 cells
Authors: Helu Xousaen M. , Leon Daisy De 
Published: May 2015

Abstract
Breast cancer is the second leading cause of death in women. Overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) is detected in 20-30% of breast cancers. Increased levels of HER2 are linked to poor prognosis, more aggressive phenotype, and resistance to chemotherapy and hormonal treatment. HER2 is part of a four member family of cell surface receptors that are implicated in transmission of signals controlling cell growth and differentiation. HER2 has an intracellular domain with tyrosine kinase catalytic activity and dimerization of HER2 activates the MAP kinase and AKT pathways. HER2 receptor also heterodimerizes with the IGF1 receptor(IGF1R) in trastuzumab-resistant cell lines. The insulin-like growth factor 2 (IGF2) has an important role in fetal and cancer development signaling through the IGF1R, insulin receptor (InsR), and cross-talk with the estrogen receptor alpha and beta (ERα, ERß). Previous findings in our lab demonstrate an increased expression of IGF2 in trastuzumab-resistance cell line JIMT1 when compared to trastuzumab-sensitive cell lines BT474, SKBR3, and ZR75-30. We hypothesis that to overcome trastuzumab-resistance in JIMT1 cell lines, dual inhibition of HER2 and IGF2 is necessary to induce cell death. When JIMT1 cells were treated with resveratrol, both HER2 and IGF2 mRNA and protein levels were reduced and a decrease in cell viability was observed. We also analyzed the phosphorylation levels of HER2 and IGF1R. Our studies suggest that blocking both HER2 and IGF2 is necessary to decrease cell viability in trastuzumab-resistant JIMT1 cells.
Citation Format: Xousaen M. Helu, Daisy De Leon. Inhibition of HER2 and IGF2 triggers cell death in trastuzumab-resistant HER2 positive JIMT1 cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4244. doi:10.1158/1538-7445.AM2014-4244