bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C201: Activity of the GlaxoSmithKline kinase inhibitor set on glioblastoma stem cells
Authors: Khagi Simon , Sengupta Sejuti , Tabtieng Tate , Cochran Brent H. 
Published: May 2016

Abstract
Despite significant advances in our understanding glioblastoma (GBM) in recent years, it remains a deadly cancer with a very poor prognosis. There is an urgent need for new therapies. Kinases are well known regulators of cellular growth and survival and there are many compounds available that are capable of inhibiting specific kinases. Recently, GlaxoSmithKline has made available a library of over 350 kinase inhibitors in a public-private partnership to facilitate the discovery of new drugs and targets in multiple disease settings (Nature Chemical Biology 9:3 (2013)). Together these compounds have been shown to inhibit over 100 different kinases by in vitro kinase assay at 1 uM. We have screened these compounds against 3 different GBM stem cell lines under normoxic and hypoxic conditions. Over 40 compounds were strongly inhibitory for least one cell line and condition. However, only 9 of these compounds were capable of inhibiting the growth all three cell lines by 90% at 1 uM in both conditions. Seven of the 9 common inhibitors had IC50's under 100 nM and 4 had IC50's under 10 nM in at least one oxygen condition. In vitro kinase assays indicate that these compounds each have multiple kinase targets. Based on an analysis of common targets, it is likely that one of the targets is PLK1 which is well known GBM inhibitor. Two compounds that don't inhibit PLK1 both inhibit CLK2 and KIT strongly. IC50 analysis demonstrated wide variability among cell lines and oxygen concentrations. The effectiveness of a single compound could vary more then tenfold between cell lines and more than fiftyfold between normoxia and hypoxia. Some compounds were more effective under hypoxia and some were less. These results strengthen the case for personalized therapies and indicate that hypoxia (which is prevalent in GBM) can significantly alter the effectiveness of inhibitors.
Citation Format: Simon Khagi, Sejuti Sengupta, Tate Tabtieng, Brent H. Cochran. Activity of the GlaxoSmithKline kinase inhibitor set on glioblastoma stem cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C201.
Abstract A22: Cell growth regulation of gain-of-function mutant p53 via miRNAs on metabolic inhibition
Authors: Jo Se-Young , Moon Hae-Min , Lee ChuHee , Jang Se Jin , Suh Young-Ah 
Published: May 2016

Abstract
There is growing evidence that tumor cells depend on unique metabolism for their continued growth and survival, and that cancer cells are peculiarly addicted to the rapacious uptake of glucose and glutamine. Due to the gain-of-function, mutant p53 protein contributes to tumor metastasis and shortening the latency of tumor progression, and thereby activated K-ras/mutant p53 mouse is preferentially used as lung adenocarcinoma preclinical model. Epigenetic regulation through histone modification or miRNA also plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we have investigated the involvement of miRNAs in cell growth regulation upon the treatment of metabolic inhibitors. We have generated different genotypes of mouse tumor cells derived from activated mutant p53 and/or K-ras mutant mice. We have tested whether inhibitors regulating metabolism induce adverse effect on cell growth and changes of miRNA expression through microarray analysis, with the hint of enormous demands for nutrients in fast growing tumor cells. We then analyzed affected genes and miRNAs via quantitative RT-PCR to confirm the involvement of miRNAs on cell growth when tumor metabolic environment were damaged.
Citation Format: Se-Young Jo, Hae-Min Moon, ChuHee Lee, Se Jin Jang, Young-Ah Suh. Cell growth regulation of gain-of-function mutant p53 via miRNAs on metabolic inhibition. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A22.
Abstract IA06: SWI/SNF chromatin remodeling complex mutations in cancer: Mechanisms and potential therapeutic insights
Authors: Roberts Charles W.M. 
Published: May 2016

Abstract
Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least eight SWI/SNF subunits have been identified in a variety of cancers. These include inactivating mutations of the gene encoding the ARID1A (BAF250a) subunit in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers; and of the BRG1 (SMARCA4) subunit in non-small cell lung cancers, medulloblastomas and ovarian small cell carcinomas. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription.
My laboratory began studying the SWI/SNF complex when the SNF5 (SMARCB1/INI1/BAF47) subunit was first identified as a tumor suppressor over a decade ago when it was found to be recurrently and specifically inactivated in a highly aggressive type of pediatric cancer called malignant rhabdoid tumor. We now study the complex using mouse models, cell lines and primary human tumor samples. Our goals are to elucidate the normal function of the complex, identify the mechanisms by which subunit mutations drive cancer formation, and utilize this insight to identify and develop novel therapeutic approaches. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented.
Citation Format: Charles W.M. Roberts. SWI/SNF chromatin remodeling complex mutations in cancer: Mechanisms and potential therapeutic insights. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA06.
Abstract A08: Telomerase inhibition brings metabolic compromises in glioblastoma multiforme (GBM)
Authors: Ahmad Fahim , Sen Ellora 
Published: May 2016

Abstract
Introduction: A defining characteristic of cancer cells is their ability to circumvent multiple regulatory mechanisms that normally restrict cell proliferation. Understanding the links between aberrant metabolic adaptation and prosurvival responses in glioma cells is crucial towards the development of new anti-glioma therapies. Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of the telomerase holoenzyme. The telomere maintenance or telomerase activity is mainly driven by hTERT and hTERC. A large number of reports suggest an ever increasing role of telomere maintenance in cancer progression. We sought to evaluate its involvement in the regulation of metabolic status in these cells.
Methods: Human glioma cell lines A172 and U87MG Cells were grown in DMEM supplemented with 10% FBS. On attaining semi confluence, cells were switched to SFM (serum free media) for 4 hrs and further treated with Telomerase inhibitor for 24hrs. Glioma cell lines were transiently transfected with lipofectamine 2000 and lipofectamine RNAi max reagents. Cells were harvested 48hrs post transfection. Heterotropic glioma xenografts were generated upon injecting U87MG cells subcutaneously in flank region of nude mice. After 20 days of injection, prominent tumor volume was visible. Thereafter, mice were grouped and administered either with PBS or Telomerase inhibitor for 20 days on every alternate day. Mice were sacrificed and tissues were processed for subsequent experiments. Histochemically identified TERT mutant and wild type human glioma samples were also used to unravel the ongoing signaling cascades.
Results: Inhibition of telomerase resulted in metabolic compromises. TERT was found to regulate the expression of an important transcription factor responsibe for maintenance of metabolic and antioxidant proteins. The expression of this transcription factor was concomitant with altered metabolic profile as characterized by decreased pentose phosphate pathway. TERT regulated expression of PPP genes seemed to have its effect on prosurvival and antioxidant molecules.
Conclusions: hTERT plays a key role in survival responses by modulating the metabolic status of glioma cells both in vitro and in vivo. By switching the signals under the control of a metabolic sensor (transcription factor) that modifies energy status to govern anti proliferative environment, hTERT regulates both survival responses and energy status.
Citation Format: Fahim Ahmad, Ellora Sen. Telomerase inhibition brings metabolic compromises in glioblastoma multiforme (GBM). [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A08.
Abstract A15: Different stem-like characteristics of diffuse and intestinal type gastric cancer spheroids
Authors: Lee Jong Won , Sung Jae Sook , Chung Seok , Kim Yeul Hong 
Published: May 2016

Abstract
Cancer Stem Cells (CSCs) have been hypothesized to drive the tumor initiation, metastasis and chemo-resistance. Identification of this subpopulation is important to understand the CSCs characteristics and the development of treatment strategy. Spheroid forming ability is the character of CSCs. Thus, sphere culture can be utilized for isolation of CSCs in cancer cell lines. Here, we applied Spheroid Film as a limiting dilution assay platform to isolate gastric CSCs from single cell sphere culture. Gastric cancer cell lines MKN28, MKN74, SNU484 and SNU638 was seeded as single cell in non-attached 361 micro-wells culture dish with serum free condition. After 2 weeks, each well was evaluated whether single cell formed spheroid or not. The population of spheroids was increased in sub-spheroid culture. The spheroids showed higher expression levels of stemness marker, such as OCT4, SOX2 and NANOG than parent cells. Moreover, they exhibited up-regulation of CSC related gene ALDH1A1 and CD44v8-10 compared with parent cells. Spheroids cell were more resistant to drug inducing apoptosis (5FU, Cisplatin and Paclitaxel) than parent cells. When spheroids injected in to skin of nude mice, it showed larger size of tumor than parent cells. Especially, the expression of stemness gene was higher in diffuse type (SNU484 and SNU638) than intestinal type (MKN28 and MKN74). Besides, diffuse type has lower IC50 value of anti-cancer drugs than intestinal type. In conclusion, cancer stem-like cells were isolated efficiently by single cell spheroid culture methods from gastric cancer cell lines. We have shown that different stem-like characteristics in spheroids cell, and it may be related with their histological type. Further investigation of difference between diffuse and intestinal type gastric cancer sphroids may provide novel insights to understand gastric cancer stem cells.
Citation Format: Jong Won Lee, Jae Sook Sung, Seok Chung, Yeul Hong Kim. Different stem-like characteristics of diffuse and intestinal type gastric cancer spheroids. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A15.
Abstract A30: Two faces of YAP: Oncogene in malignant progression but barrier for phenotypic transition in LKB1-deficient lung cancer
Authors: Zhang Wenjing , Gao Yijun , Han Xiangkun , Li Fuming , Ji Hongbin 
Published: May 2016

Abstract
Hippo signaling is actively involved in adult tissue homeostasis and cell fate determination. Previous studies have linked the activation of YAP (the major downstream effector of Hippo pathway) with LKB1 deficiency. Here, we characterize the function of YAP in the malignant progression and phenotypic plasticity of LKB1-deficient lung tumors.
Using various lung cancer mouse models, we show that YAP expression significantly accelerates lung adenocarcinoma (ADC) malignant progression in KrasG12D mice whereas YAP deletion dramatically delays the process in Lkb1L/L/KrasG12D mice, suggesting that YAP functions as an essential mediator of malignant progression of Lkb1-deficient lung ADC. Further mechanistic studies identified Survivin as the mediator downstream of YAP in promoting malignant progression of Lkb1-deficient lung ADC. Knockdown of Survivin mimics the inhibitory phenotype of YAP knockdown whereas ectopic expression of Survivin rescues the inhibitory function of YAP knockdown. Our previous work has shown LKB1 inactivation confers lung ADC with strong plasticity to progressively change the cell fate and transit to squamous cell carcinoma (SCC). We find that ectopic YAP expression dramatically inhibits ADC to SCC transdifferentiation whereas knockdown of YAP conversely accelerates the transition process. YAP is initially activated by LKB1 loss in ADC, leading to ZEB2 up-regulation in ADC cells, which binds to DNp63 gene promoter to repress DNp63 transcription. During the transition process, extracellular matrix (ECM) depletion in ADC inactivates YAP, thus relieves ZEB2 mediated default repression on DNp63 transcription in ADC, leading to the initiation of squamous differentiation program.
Together, these findings uncover the two faces of YAP in lung tumor malignant progression and phenotypic plasticity. YAP is an essential mediator of malignant progression of Lkb1-deficient lung ADC via regulating Survivin whereas an important barrier for lung cancer transdifferentiation through ZEB2 dependent DNp63 repression. Those works shed light on the fundamental role of YAP in regulating cancer progression and lineage phenotypic transition in LKB1 deficient lung tumors, which might help future development of better therapeutic strategies.
Citation Format: Wenjing Zhang, Yijun Gao, Xiangkun Han, Fuming Li, Hongbin Ji. Two faces of YAP: Oncogene in malignant progression but barrier for phenotypic transition in LKB1-deficient lung cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A30.
Abstract A31: Monitoring the activity of various classes of methylltransferases in vitro using a universal, homogenous and bioluminescent assay
Authors: Goueli Said A. 
Published: May 2016

Abstract
Post transcriptional modifications of proteins and nucleic acids are well-recognized to play major role in mediation of extensive and broad range of cellular functions. Such modifications that include phosphorylation, acetylation, methylation, etc. are known to be critical for normal and abnormal cell growth, and thus, the enzymes involved in these reactions have been validated as drug targets resulting in the development of several drugs. Recent biochemical and biological data suggest that the enzymatic activities of several of these enzymes have pathogenic roles in cancer, inflammation, and neurodegenerative diseases. Thus, pharmacological modulation of these enzymes by small molecules will be beneficial in the development of novel therapeutics for multiple unmet medical needs. Of these, methyltransferases are known to alter the epigenome by altering the methylation status of nucleic acids or proteins resulting in changes in cellular phenotypes. Towards this goal of searching for activators/inhibitors of these enzymes for the development of next generation of drugs, screening assays for these modulators are urgently needed. To address these unmet needs, we have developed a novel assay that monitors the activities of these enzymes and their modulation by small molecules. The assay is bioluminescent based, HTS formatted and highly sensitive. The assay is universal since it is based on monitoring the formation of the universal product S-adenosylhomocysteine (SAH), i.e., capable of detecting changes in activity of a broad range of methyltransferases such as DNA, protein, RNA, and small molecules methyltransferases. In addition, the assay has been validated for all classes of protein methyltransferases (Lysine and Arginine), and with different types of substrates (small peptides, large proteins, or even nucleosomes). This enables determining the specificity of these enzymes and their substrate requirements. The assay has high signal to background and low C.V. The assay is robust (Z’ value &gt; 0.7) and has been validated using various plate densities such as 96-, 384, and 1536-well plates. A strong feature of this assay is its utility with broad range of substrates with no limitations on the use of high concentrations of substrates or the composition of the substrates (short vs. long peptides), thus enabling the generation of kinetic data and determining the mechanism of action of various modulators of methyltransferases of interest.
Citation Format: Said A. Goueli. Monitoring the activity of various classes of methylltransferases in vitro using a universal, homogenous and bioluminescent assay. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A31.
Abstract B08: Inflammasome components caspase-1, IL1β, IL18 and NLRP3 (NOD-like receptor family, pyrin domain containing 3) are increased in a spontaneous model (chicken: Gallus gallus) of human ovarian cancer
Authors: Luborsky Judith , Edassery Seara , Edassery Seby L. , Barua Animesh , Bahr Janice M. 
Published: May 2016

Abstract
Chronic inflammation is associated with cancer risk and development. There is increasing evidence that a chronic, pro-inflammatory environment is mediated by multi-protein inflammasome complexes that promote activation of IL1β and IL18, which are apex cytokines for regulation of inflammation. The objective was to determine if the inflammasome components NLRP3, caspase-1, IL1β and IL18 were expressed in ovarian cancer and if the expression differed between normal ovary and ovarian tumors using the hen, an animal model of spontaneous ovarian cancer. mRNA was measured by qRT-PCR using primers based on chicken orthologs of human genes from the NCBI database as follows, NLRP3 XM_001233261.3; Caspase-1 XM_003642384.2; IL1β NM_204524.1; IL18 NM_204608; IL17 NM_204460.1. mRNA expression (mean fold change compared to normal ovary = mFC) was increased significantly (t -test) compared to normal ovaries for caspase-1 (mFC=14.6±12.6; p=0.01), IL1β (mFC=6.5±5.3 p=0.01) and IL18 (mean fold change=4.9±3.4; p=0.01) with a moderate increase in NLRP3 (mFC=1.7±0.98; p=0.04) in cancer (n=8) compared to normal ovary (n=6). Expression of the pro-inflammatory cytokine, IL17 was increased (mFC=4.0±6.0; p=0.1) but not significantly in this limited sample set. Moderate protein expression of the same components was evident by immunohistochemistry in groups of tumor cells but not in all tumor cells. Expression also occurred in tumor immune cells; the number of immunohistochemically reactive immune cells varied among tumors. Differences in invading immune cells with an activated inflammasome could account for the range of total mRNA values; differences among tumor expression of inflammasomes infers a potential basis for differences in response to immunotherapies. The results demonstrate expression of inflammasome components in a spontaneous model resembling human ovarian cancer and suggest a mechanism by which a chronic pro-inflammatory, pro-tumor environment is maintained. Improved understanding of the role of inflammasomes could lead to methods for management of the tumor immune environment and responses to immunotherapy.
Citation Format: Judith Luborsky, Seara Edassery, Seby L. Edassery, Animesh Barua, Janice M. Bahr. Inflammasome components caspase-1, IL1β, IL18 and NLRP3 (NOD-like receptor family, pyrin domain containing 3) are increased in a spontaneous model (chicken: Gallus gallus) of human ovarian cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B08.
Abstract B33: The oligoclonal antibody MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancer cells harboring EGFR extracellular domain mutations
Authors: Arena Sabrina , Siravegna Giulia , Mussolin Benedetta , Kearns Jeffrey D. , Wolf Beni B. , Misale Sandra , Lazzari Luca , Bertotti Andrea , Trusolino Livio , Adjei Alex , Montagut Clara , Nicolantonio Federica Di , Nering Rachel , Bardelli Alberto 
Published: May 2016

Abstract
The anti-EGFR antibodies cetuximab and panitumumab are used to treat ‘RAS’ wild type colorectal cancers (CRCs), but their efficacy is limited by development of drug resistance. At relapse, approximately 20% of tumors carry EGFR extracellular domain (ECD) mutations (S492R, R451C, S464L, G465R, G465E, K467T, I491M) that impair antibody binding. We find that these EGFR genetic variants are effectively targeted by the oligoclonal anti-EGFR antibody MM-151. Both EGFR mediated signaling and proliferation of colorectal cancer (CRC) cells carrying EGFR ECD mutations are impaired by MM-151. Notably, EGFR extracellular domain mutations, which are found in circulating free tumor DNA (ctDNA) of CRC patients who relapsed upon anti-EGFR antibodies treatment, decline during MM-151 therapy. In conclusion, MM-151 based therapy may be valuable for the treatment of secondary resistance to cetuximab and panitumumab driven by EGFR ECD mutations. Further prospective clinical evaluation is warranted.
Citation Format: Sabrina Arena, Giulia Siravegna, Benedetta Mussolin, Jeffrey D. Kearns, Beni B. Wolf, Sandra Misale, Luca Lazzari, Andrea Bertotti, Livio Trusolino, Alex Adjei, Clara Montagut, Federica Di Nicolantonio, Rachel Nering, Alberto Bardelli. The oligoclonal antibody MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancer cells harboring EGFR extracellular domain mutations. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B33.