bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2939: Discovery and synthesis of highly potent and selective small molecule inhibitors of the histone methyltransferase EZH2
Authors: Verma Sharad K. , LaFrance Louis V. , Tian Xinrong , Newlander Ken , Duquenne Céline , Suarez Dominic , Knight Steven D. , Burgess Joelle , Brackley James , Johnson Neil W. , Graves Alan P. , Mellinger Mark , Romeril Stuart , Grant Seth W. , Scherzer Daryl , Shu Art , Creasy Caretha L. , Kruger Ryan , Diaz Elsie , Le Baochau , Thompson Christine , Morgan-Ott Heidi , McCabe Michael T. , McHugh Charles F. , Miller William H. , Tummino Peter , Dhanak Dash 
Published: August 2012

Abstract
The histone methyltransferases are a group of enzymes which catalyze the transfer of a methyl group from the co-factor S-Adenosylmethionine (SAM) to the lysine and arginine residues of histone tails. This post-translational modification is a key event in maintaining gene expression patterns. In recent years, the relationships between aberrant histone methylation patterns and cancer progression have been recognized. These developments, along with an improved understanding of the underlying structural biology, have made histone methyltransferases highly attractive targets for therapeutic intervention. The histone lysine methyltransferase EZH2 (Enhancer of Zeste Homolog 2) is frequently over-expressed in a wide variety of cancerous tissues. There is a strong correlation between overexpression of EZH2 and aberrant transcriptional signaling in cells, ultimately resulting in poor clinical prognosis. Inhibition of EZH2 is expected to alter transcriptional expression and ultimately lead to an improved clinical outcome. This presentation will describe medicinal chemistry efforts in the development of highly potent and selective small molecule inhibitors of EZH2. The synthesis, SAR, and identification of a clinical candidate will be discussed.
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 2939. doi:1538-7445.AM2012-2939
Abstract 2945: Antitumor activities of 2-fluorofucose, an orally active agent that inhibits cell-surface fucosylation
Authors: Okeley Nicole , Zhang Amy , Alley Stephen , Anderson Martha , Law Che-Leung , Senter Peter 
Published: August 2012

Abstract
Fucose is a component of many carbohydrates that are found on the outer membranes of cancer cells. There is evidence that loss of this sugar from cell-surface glycoproteins can change cancer cell behavior, including growth and metastasis. We have previously demonstrated that 2-fluorofucose (SGD-2083) blocks the fucosylation of antibodies in vitro and in vivo due to the depletion of GDP-activated fucose inside cells. These findings provide the basis for evaluating the antitumor activities of SGD-2083, since alterations of the fucose content on cell surfaces could potentially impact tumor growth and adhesion. To explore this, SGD-2083 was given orally to mice with carcinoma and hematologic tumor xenografts. Significant antitumor activities were obtained in prostate, renal cell and colorectal carcinomas, but not in the two hematologic cancer models tested. The doses used to achieve efficacy were well-tolerated. FACS analysis was used to detect alterations in tumor cell surface fucosylation in animals that responded to treatment with SGD-2083. Signal reduction was observed on E-selectin ligand and several other cell surface fucose linkages, while little or no response to the treatment was observed in the fucosylation of cell surface P-selectin ligand. These results show that oral administration of SGD-2083 leads to the alteration of tumor cell surface fucosylation in a well-defined manner, and this may account for the observed activities of this novel antitumor agent.
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 2945. doi:1538-7445.AM2012-2945
Abstract 2946: Post-transcriptional regulators of microRNA biogenesis regulate pathogenesis of cancer
Authors: Chung Wei-Jen , Sumazin Pavel , Yang Xuerui , Bansal Mukesh , Califano Andrea 
Published: August 2012

Abstract
MicroRNAs (miRs) have emerged as key regulators of both normal and pathologic phenotypes, including cancer. Fine grained regulation of their biogenesis, however, is still poorly understood and only a few of their key regulators have been characterized. In order to understand the extent and specificity of miR-biogenesis control, as well as the role of miR-biogenesis regulators in tumorigenesis and cancer progression, we set out to identify these regulators and profile their targets. We developed a genome-wide computational screening method that leverages miR and gene expression profiles in hundreds of samples to identify potential biogenesis regulators in glioma and ovarian cancer. In total, miRage predicted thirty miR-biogenesis regulators that are common to glioma and ovarian cancer tumors, and hundreds of glioma-specific and ovarian-cancer-specific regulators. Predicted regulators include known biogenesis regulators DGCR8, HNRNPA1, DDX5, LIN28 and SMAD family proteins. We validated selected regulators that are predicted to regulate miRs in both cancers and are differentially expressed across glioma prognosis. Differential expression of (1) mature miRs, (2) their host genes, (3) co-transcribed miRs, (4) miR precursors, and (5) pri-miRs were measured upon ectopic expression or RNAi-mediated silencing of the predicted regulators in a glioma cell line. DDX10 was predicted to up-regulate miR-218 biogenesis, and we showed that its ectopic expression up-regulates miR-218 at the pri-miRNA stage; up-regulation of DDX10 may account for miR-218 over-expression in poor-prognosis tumors. High-throughput screening by nanostring nCounter and fluidigm systems suggest that DDX10 regulation is broader effect than regulation by the known biogenesis regulator, DDX17. In total, we report on nearly a dozen validated miR-biogenesis regulators that were predicted by our computational screens. Our results suggest that miR biogenesis is a complex, context specific, and finely-regulated process, and that miR biogenesis regulators may influence tumor initiation and progression by altering the expression of specific tumor-suppressor and oncomirs or by modifying large miR programs.
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 2946. doi:1538-7445.AM2012-2946
Abstract 2949: miR-16 is an in vivo suppressor of gastrointestinal tumorigenesis
Authors: Moore Ashleigh E. , Young Lisa E. , Weiler Jan , Meisner-Kober Nicole , Dixon Dan A. 
Published: August 2012

Abstract
Commonly observed in colorectal cancer (CRC) is elevated expression of the prostaglandin synthase cyclooxygenase-2 (COX-2). In normal intestinal epithelium, the COX-2 mRNA is normally targeted for rapid decay through RNA elements present within its 3′-untranslated region (3′UTR), whereas in tumors rapid mRNA decay is compromised. To understand the mechanisms controlling COX-2 mRNA fate, we show that the COX-2 3′UTR can mediate mRNA degradation through microRNA-mediated regulation. MicroRNAs (miRNAs) are small non-coding RNAs that bind within the 3′UTR of target mRNAs and function as post-transcriptional regulators of gene expression. MiR-16 was identified to bind the COX-2 3′UTR and inhibit COX-2 expression by promoting rapid mRNA decay. Given the importance of miR-16 in cancer development, we examined miR-16 expression in CRC tumor specimens and cancer cells and observed a 2-fold decrease in miR-16 levels. Additionally, expression of miR-16 in cancer cells attenuated COX-2 expression and prostaglandin synthesis. The in vivo role of miR-16 in the initiation and development of colorectal cancer was examined using ApcMin/+ mice, a mouse model of intestinal neoplasia. To accomplish this, endogenous miR-16 was inhibited in the GI tract using an anti-miR oligonucleotide (AMO) against miR-16 containing 2′-O-(2-Methoxyethyl) modification with unmodified PO backbone. 50 mg/kg of AMO-16 or control AMO containing 4 nucleotide-mismatch of the AMO miR-16 sequence were administered by oral gavage to 8 week old ApcMin/+ and C57Bl/6 control mice twice a week over a 3-week period. Specific inhibition of miR-16 in intestinal tissue was observed. Over the treatment course, control mice displayed normal growth characteristics. Gross and histological analysis did not reveal any morphological changes in the GI tract of AMO-16-treated C57Bl/6 mice. In contrast, a significant 2-fold increase in small intestinal tumor burden was observed in ApcMin/+ mice treated with AMO-16 compared to control AMO (55.7 +/− 5.0 vs. 99.1 +/− 7.9, P = 0.0001). Gene expression analysis showed increased COX-2 and several miR-16 target cell cycle regulatory genes including cyclin D1, cyclin D3, cyclin E1, and CDK6 in AMO-16-treated small intestinal tissue from ApcMin/+ mice compared with AMO control treated mice, with the greatest level of altered expression observed in the proximal portion of the small intestine. These results identify miR-16 as a central post-transcriptional regulator of COX-2 along with other transcripts associated with promoting cancer cell proliferation, and reveal miR-16 to have tumor-suppressor properties in GI tumorigenesis downstream of a tumor-initiating event.
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 2949. doi:1538-7445.AM2012-2949
Abstract 295: IDO drives tumor-promoting, pathogenic inflammation in lung
Authors: Smith Courtney , Chang Mee-Young , Flick Hollie , DuHadaway James , Mandik-Nayak Laura , Laury-Kleintop Lisa , Parker Katherine , Beury Daniel , Ostrand-Rosenberg Suzanne , Prendergast George C. , Muller Alexander J. 
Published: August 2012

Abstract
First identified as a mediator of acquired immune tolerance of the ‘foreign’ fetus from maternal immunity, the tryptophan-catabolizing enzyme IDO (indoleamine 2,3-dioxygenase) has since been implicated in tumor escape from the host immune system. Insight into the intricate role of IDO in the classical DMBA/TPA skin carcinogenesis model suggested that inflammatory tumor environments can induce IDO production resulting in de novo tumor development. In the genetically deficient model of IDO, mice show resistance to tumor formation. This provided a basis for our current studies exploring the importance of IDO in the microenvironment of the lung. To this end, we have investigated both primary tumor formation and metastatic disease in the lungs of IDO-deficient mice using the KRAS-induced lung adenocarcinoma and the metastatic 4T1 breast cancer models. Elevation of the inflammatory cytokine IL6 was associated with tumor outgrowth in the lungs in both models but was greatly attenuated with the loss of IDO, consistent with the in vitro demonstration that IDO activity markedly potentiates IL6 production. MDSCs (myeloid derived suppressor cells) exhibited reduced T cell suppressive activity when isolated from tumor-bearing, IDO-deficient animals that could be rescued by ectopic production of IL6 in the tumor. IL6 production could likewise reverse the pulmonary metastasis resistance exhibited by IDO-deficient mice. Interestingly, while there is a clear role of the immune system in lung tumor and metastatic outgrowth, IDO-deficient mice appear to have reduced vascularization in the lung which may partly contribute to reduced tumor formation. Together, these findings genetically validate IDO as a therapeutic target in the settings of pulmonary cancer and metastasis and establish the importance of IDO as a driver of IL6 production and MDSC function. Furthermore, the correlation of IDO to angiogenesis may be a new insight into the role of this enzyme in cancer.
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 295. doi:1538-7445.AM2012-295
Abstract 2950: miR-34 prevents in vivo lung tumor initiation and progression in the therapeutically resistant Kras;p53 mouse model
Authors: Kasinski Andrea L. , Slack Frank J. 
Published: August 2012

Abstract
Lung cancer represents the leading cause of cancers deaths in men and women worldwide, and current therapies fail to treat this disease in the overwhelming majority of cases. The RAS and p53 pathways are two of the most frequently genetically modified pathways in lung cancers. Alterations in both result in loss of responsiveness to current therapies leading to decreased overall patient survival. Because the microRNA, mir-34 is a downstream transcriptional target of p53, which is reduced in its expression in p53 null tumors, we hypothesized that targeting Kras;p53 tumors with miR-34 would represent a novel yet powerful therapeutic to suppress lung tumorigenesis. To this end we have made use of the therapeutically resistant KrasLSL-G12D/+;p53LSL-R172H/+ mouse model of lung cancer. In this work we characterized the tumor progression in these mice following transgene activation specifically in the lung through intratracheal administration of adenoviral particles expressing cre recombinase. We note that adenocarcinomas are evident as early as 10 weeks following cre-recombination with severe lung inflammation presenting at 22 weeks. Epithelial cells from these tumors were harvested and cultured in vitro where they remain propagating, currently at passage 45. All three lines generated support growth in soft agar assays and are invasive based on transwell migration assays. Because of the pro-apoptotic effects of miR-34, we transduced the cells with miR-34-expressing lentivirus. Transduced cells responded with reduced proliferation and decreased migration. Based on these promising results we began two series of in vivo experiments. We first assessed the contribution of miR-34 to prevent tumor formation in KrasLSL-G12D/+;p53LSL-R172H/+ mice. Animals that were treated with miR-34 at the same time as cre-induced recombination of transgenes show little to no evidence of tumorigenesis at 19 weeks, while control animals had multiple nodules that represented ∼8% of the total lung area. The second series of in vivo experiments evaluated the ability of miR-34 to act as a treatment in pre-formed tumors. While miR-34 was unable to reduce the preformed tumors in these animals it was able to prevent further tumor growth. These data support the use of miR-34 as a tumor preventive mechanism and suggest that miR-34 may be useful in sensitizing tumors to other conventional therapeutics.
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 2950. doi:1538-7445.AM2012-2950
Abstract 2959: p53 as a guardian of genomic junk: A novel role for p53 in epigenetic silencing of retroelements
Authors: Leonova Katerina , Lipchick Brittany , Brodsky Leonid , Komarova Elena , Gudkov Andrei V. 
Published: August 2012

Abstract
Demethylating agents have been reported to be more toxic to p53-deficient cells than wild type (WT) cells in several models. To elucidate the mechanism underlying this phenomenon, we performed microarray-based global gene expression profiling of mouse embryo fibroblasts (MEFs) from p53-WT and p53-null mice with or without 5-aza-2′-deoxycytidine (5-aza-dC) treatment. This analysis revealed two major findings. First, all protein-coding transcripts induced by 5-aza-dC treatment in WT cells were highly expressed and irresponsive to the demethylating agent in untreated p53-deficient cells. This observation defines p53 as a major driver of DNA methylation-dependent gene silencing. Second, death of p53-null cells treated with 5-aza-dC is preceded by strong activation of transcription of interferon (IFN)-responsive genes driven by IFNα induction. Since no obvious candidates for the role of IFN-inducing factors were found among the genes represented on the microarray, we carried out high-throughput sequencing (HTS) of the entire transcriptome of p53-WT and p53-null MEFs, treated or untreated with 5-aza-dC. The HTS results revealed striking transcriptional upregulation of numerous genetic elements belonging to various classes of retrotransposons and non-coding RNAs in p53-null, but not in p53-WT cells, treated with 5-aza-dC. We named this phenomenon of massive induction of transcription of retroelements, which are normally repressed by p53, RETROSIS. Retrosis is likely to be the trigger of the observed IFN response and the mediator of toxicity in p53-null cells treated with 5-aza-dC. These findings define a novel role for p53, acting along with DNA methylation, in regulation of epigenetic silencing of the large proportion of the genome that consists of retroelements and suggest a new evolutionary role for this tumor suppressor. The impact of retrosis in tumor cells deficient in p53 and implications of this phenomenon for the tumor suppressor function of p53 will be discussed.
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 2959. doi:1538-7445.AM2012-2959
Abstract 2961: Reactivation of EWS-FLI1 suppressed FOXO1 expression as a novel therapeutic strategy for Ewing's sarcoma
Authors: Niedan Stephan , Kauer Max , Jug Gunhild , Walker Robert L. , Meltzer Paul S. , Kontny Udo , Kovar Heinrich 
Published: August 2012

Abstract
The EWS-FLI1 chimeric protein, characterizing Ewing's sarcoma (ESFT), is prototypic for an aberrant oncogenic ETS transcription factor. The mechanisms of transcriptional regulation leading to ETS-driven tumorigenesis are poorly understood. In-silico analysis of time-resolved expression data revealed enrichment of recognition motifs for forkhead box (FOX) proteins in EWS-FLI1 repressed promoters. Several FOX genes were found to be bound by EWS-FLI1 in ChIP-seq and transcriptionally affected by EWS-FLI1 knockdown. We therefore hypothesized that EWS-FLI1 exerts an important part of its repressive activity via inhibiting FOX proteins. Upon silencing of EWS-FLI1, both FOXO1 and FOXO3 proteins were strongly induced in ESFT cells consistent with this hypothesis, but only FOXO1 translocated to the nucleus. However, in the presence of EWS-FLI1, FOXO1 is excluded from the nucleus as a consequence of phosphorylation. Nuclear translocation was restored by either inhibition of CDK2, augmented by chemical inhibition of PI3K, or by mutation of CDK2 or AKT phosphorylation sites. Furthermore, ChIP experiments revealed that EWS-FLI1 directly binds the promoter of FOXO1 in vitro suggesting a multi-layered regulation of FOXO1 expression by transcriptional repression and post-translational modification. Functional restoration of nuclear FOXO1 expression in ESFT cells resulted in impaired proliferation and significantly reduced soft agar colony formation ability. A significant overlap between EWS-FLI1 repressed and FOXO1 activated genes was observed. Treatment of ESFT cell lines with Methyl-Seleninic-Acid (MSA) led to re-activation of endogenous FOXO1 in the presence of EWS-FLI1 in a dose- and time-dependent manner, and induced massive cell death, which we found to be at least partially FOXO1-dependent. Taken together, these data confirm our hypothesis that a repressive sub-signature of EWS-FLI1 regulated genes is due to suppression of FOXO1. FOXO1 re-activation by small molecules may constitute a novel therapeutic strategy in the treatment of ESFT. This study was supported by grant 22328-B09 from the Austrian Science Fund FWF.
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 2961. doi:1538-7445.AM2012-2961
Abstract 2963: ALK is a MYCN target gene and contributes to cell growth, migration and invasion in neuroblastoma
Authors: Hasan Md. Kamrul , Takatori Atsushi , Kishida Satoshi , Ohira Miki , Hossain Md. Shamim , Akter Jesmin , Ogura Atsushi , Nakamura Yohko , Kadomatsu Kenji , Nakagawara Akira 
Published: August 2012

Abstract
Neuroblastoma (NBL), the most common solid tumor of childhood, is an embryonal malignancy of the developing sympathetic nervous system. Human Anaplastic lymphoma kinase (ALK) has been identified as an oncogene mutated or amplified in NBLs. However, the role of wild-type ALK in NBL is still largely unknown. For better understanding a molecular event associated with ALK in the pathogenesis of NBL, it is necessary to clarify how ALK gene contributes to NBL progression. Previously in the analysis of NBL clinical samples, we have found that ALK expression is significantly high in MYCN amplified group. Consistent with this evidence, the developing tumors with NBL characteristics in MYCN-transgenic mice possess a high expression of ALK. In the present study, we have found that overexpression of MYCN induced ALK expression and siRNA-mediated knockdown of MYCN resulted in the downregulation of ALK expression in NBL and non-NBL cell lines. We have identified the promoter region of ALK, to which MYCN binds, in the upstream of the first exon from +30 to −350 bp and Luciferase reporter assay showed that MYCN overexpression enhanced the promoter activity of ALK. The site-specific deletion at MYCN binding site of ALK promoter region downregulated its promoter activity and chromatin immunoprecipitation (ChIP) assay indicated that MYCN can be recruited to the ALK promoter region, suggesting that ALK is directly regulated by MYCN. In general, high expression of MYCN is a well-known prognostic marker for aggressive progression and increases growth rate of NBL cells. However, the role of MYCN in enhancing cell migration and invasion has not yet been fully understood. We have further examined an effect of ALK expression in MYCN-induced cell migration. Functional assay revealed that overexpression of ALK enhanced NBL cell growth, migration as well as invasion. Moreover, these activities were suppressed by siRNA-mediated knockdown of ALK, indicating that ALK might be involved in the metastatic phenotype of NBLs. On the other hand, the forced expression of MYCN enhanced cell migration in MYCN-single copy cell line, SK-N-AS cells. Of interest, the increased migration by MYCN expression was suppressed by siRNA-mediated knockdown of ALK, suggesting that the cell migration induced by MYCN is at least partly regulated by ALK expression. Our present findings explore the fundamental understanding of ALK and help a future development of novel therapeutic tools by targeting ALK for aggressive NBLs.
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 2963. doi:1538-7445.AM2012-2963