bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B199: Identification of novel tubulin polymerization inhibitors by proteomic profiling.
Authors: Kawatani Makoto , Tomita Kouji , Muroi Makoto , Kazami Sayaka , Aono Harumi , Shimizu Takeshi , Osada Hiroyuki 
Published: June 2012

Abstract
Background: Every year huge numbers of compounds are screened for cancer cells proliferation inhibition. However, the mechanism of action and/or the molecular target as decisive factors in drug development often remain unknown. We recently developed a proteomic profiling technique to predict the mode of action of new drug leads. This method is based on recording the comprehensive patterns of variation in proteins in HeLa cells that are treated with compounds. The primary in vitro screening of the candidate anticancer compounds from the chemical library of RIKEN Natural Products Depository (NPDepo) revealed potentially active compounds with diverse chemical structures (NPD6689, NPD8617, and NPD8969). Here, we report on a rapid identification of a molecular target for these compounds by using the proteomic profiling system.
Materials and Methods: HeLa cells were treated with NPD6689, NPD8617, or NPD8969 for 18 h, and the cell lysates were subjected to 2-dimensional fluorescence differential gel electrophoresis (2D-DIGE). The proteome data were linked to our database, which contained proteome data that were generated by 47 compounds with well-established modes of action. Then, hierarchical cluster analysis was performed.
Results: NPD6689, NPD8617, and NPD8969 inhibited the growth of HeLa cells with the IC50 value of 615, 184, and 240 nM, respectively. The proteomic profiling of the effects induced in HeLa cells by 2D-DIGE revealed the NPD6689, NPD8617, and NPD8969 to belong to the same cluster as tubulin inhibitors, like vinblastine, paclitaxel, and colchicine. The predicted mode of action was confirmed by direct inhibition of tubulin polymerization, disruption of microtubule network in interphase cells, abnormal spindle morphology in mitotic cells, and cell cycle arrest at G2/M phase. The effects were time- and concentration-dependent.
Conclusion: These results indicate that NPD6689, NPD8617, and NPD8969 target tubulin and act as its polymerization inhibitors. Furthermore, our study shows that proteomics-based profiling will be very useful in rapid identification of mechanisms of action of anticancer compounds in future drug development and chemical genetic studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B199.
Abstract B2: Regorafenib, an oral multi-kinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases, potently inhibits tumor growth and angiogenesis in patient-derived xenograft models of gastric cancer.
Authors: Hung Huynh T. , Ong Richard , Soo Khee Chee , Politz Oliver , Zopf Dieter 
Published: June 2012

Abstract
Background: Gastric cancer (GC) is a prevalent and deadly disease. Because the VEGFR and PDGFR signaling cascade plays a critical role in the development and progression of gastric cancer and VEGF expression is correlated with angiogenesis, tumor progression and poor prognosis in patients with GC, blocking these signaling pathways could thus have therapeutic efficacy. This study aims to investigate the potential of a combined therapeutic approach to target these pathways in preclinical models of GC with regorafenib an oral multi-kinase inhibitor targeting VEGFR1–3, PDGFR, FGFR, TIE-2, RET and KIT.
Methods: Eight patient-derived GC xenograft models with different histotypes were treated orally with regorafenib or vehicle and tumor growth was monitored using caliper measurements. Tissue sections of vehicle- or regorafenib-treated xenografts were analyzed by immunohistochemistry for apoptosis, microvessel area, and cell proliferation using antibodies against cleaved PARP, CD31 and phospho-Histone3Ser10, respectively. Tumor lysates were analyzed by Western Blotting with respective antibodies for effects on marker proteins for proliferation, apoptosis and angiogenesis.
Results: Regorafenib demonstrated significant tumor growth inhibition of 81%, 85% and 88% in the GC09-0109 model after oral administration of 5, 10 and 15 mg/kg/d, respectively. In addition potent tumor growth inhibition ranging from 72–96% was observed in seven other GC models at a dose of 10 mg/kg/d. Regorafenib significantly inhibited angiogenesis in all models by 4–12 fold compared to the vehicle-treated group, independent of their degree of vascularization, as indicated by reduced CD31 staining. Furthermore inhibition of cell proliferation by 2–4 fold was observed by reduced staining for p-histone 3Ser10. Increased staining for caspase-cleaved p85 PARP by 2 to 20 fold was detected, indicating that regorafenib induced apoptosis. Finally, regorafenib also induced tumor necrosis as detected by histological staining. Inhibition of angiogenesis, reduced cell proliferation and induction of apoptosis and necrosis was associated with decreased levels of p-ERK1/2, p-cdk2Thr14/Tyr15, p-VEGFR2Tyr951, p-p70S6KThr421/Ser424, p-S6RSer235/236 and p-eIF4ESer209 and elevation of cleaved caspase-3 and cleaved PARP.
Conclusion: We show that regorafenib is an efficacious anti-tumor targeted agent in patient-derived gastric cancer preclinical models. Our findings support further investigation of regorafenib in the treatment of GC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B2.
Abstract B213: Isolation of muscle fatigue substance(s) with antitumor activities.
Authors: Munoz Ruben M. , Han Haiyong , Von Hoff Daniel D. , Hoffman Stanley 
Published: June 2012

Abstract
It has been scientifically established that regular physical exercise can reduce cancer risk by as much as 40% (Newton et al. 2008 Curr Treat. Options Oncol. 9:135). In early 1960's, Hoffman and colleagues reported that electric stimulation of rat femoris muscles caused the release of certain substance(s) that inhibited growth of transplanted rat tumors. The researchers called the substance “F-Substance” (fatigue substance) (Hoffman et al. 1961 Cancer Res. 22:597). However, the nature of the substance and the mechanism of its action are not known. In this study we sought to isolate and characterize the F-Substance. Femoris muscles freshly removed from 8–9 week old Wistar rats were electrically stimulated to induce contraction fatigue in a saline solution. Substances released to the saline solution were dialysed and lyophilized. Cell growth assays showed the substances isolated from the stimulated muscles had more significant inhibitory effect on the breast cancer cell line MCF-7 that those isolated from unstimulated muscles. To identify the molecule(s) responsible for the antitumor activity, we used a rat cytokine antibody array to profile the cytokines in the substances. Among the 29 different cytokines contained on the array, 3 showed greater than 3-fold difference between the substances isolated from the stimulated and unstimulated muscles. LIX (also known as CXCL5) is 6-fold higher in the substances isolated from stimulated muscles than those from the unstimulated muscles. TIMP-1 is 4.6 fold higher and sICAM-1 is 3.6 fold higher in the substances from the stimulated muscles. We are currently confirming the results by Western blotting and also evaluating the antitumor activity of these cytokines using cell based assays. Our results indicated that cytokines released from contracting muscles might be responsible for the antitumor effect of the “F-Substance”.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B213.
Abstract B22: Next-generation markers and targets in breast cancer: an integrative omics approach.
Authors: Barh Debmalya , Tiwari Sandeep , Bhat Dattatraya 
Published: June 2012

Abstract
Introduction: Although the complete human genome sequence and ultra high throughput screening (HTP) techniques have provided us a large number of Omics based potential molecular markers and drug targets, till date, most of these markers and targets fail to pass the initial phases of clinical trials (CTs) for any given cancer creating a big obstacle in developing personalized anticancer therapeutics. Therefore, a new strategy is required to analyze these Omics data and subsequent development of superior markers and targets. This study was aimed to explore molecular insights and to identify next-generation targets and targeted therapy in breast cancer (BC) based on an integrative omics approach.
Methods and Results: Using various Omics data for BC and an integrative bioinformatics strategy, we found that [1] there are more than one cross talking signalling pathways so the targets present in most BC cases. Therefore Herceptin like single targeting (HER2) drug alone cannot be 100% effective. [2] Four to five key transcription factors (TFs) directly regulate key tumorigenic pathways. [3] These TFs also regulate their targets through a number of key miRNAs. [4] Using feedback loop regulation, these miRNAs also regulate their regulatory TFs. [5] Such TFs and miRNAs can also regulate cancer stem cell micro-environment via onco-fetal oncogenes and pluripotent stem cell factors using similar feedback loop mechanism. [6] Identified TFs and miRNAs are differentially expressed in BC and may be used as early diagnostic and prognostic markers. [7] Upregulated TFs and miRNAs may be used as superior drug targets and [8] downregulated miRNAs may be considered as candidate therapeutics.
Discussion: Our integrative analysis demonstrates that heterogeneous signalling cross talks are prevalent in BC aetiology. Therefore, patient specific drug targets should be identified and multi-targeting approach must be recommended. Similarly, identified new markers and targets are required to be validated for their efficacy in CTs and in developing next generation targeted therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B22.
Abstract B224: Structure-based drug design of signal transducers and activator of transcription 5 inhibitors.
Authors: Cumaraswamy Abbarna A. , Gunning Patrick T. 
Published: June 2012

Abstract
Signal Transducer and Activator of Transcription 5 (Stat5) protein has gained notoriety for its aberrant role in many human cancers including breast, liver, prostate, skin, head and neck. Despite the significant evidence showing Stat5's role in cancers, there has been little progress in developing small molecule inhibitors of Stat5 function. In contrast, there has been significant advancements in identifying inhibitors for the Stat3 protein. As a result, several potent and direct small molecule and oligonucleotide-based inhibitors have entered pre-clinical trials as a Stat3 therapeutic. Unfortunately, there has not been progress towards the development of potent Stat5 inhibitors.
Stat5 is activated by ligand-receptor binding, which recruits Stat5 to intracellular receptor sites via their SH2 domain. Stat5 is then phosphorylated at conserved tyrosine (Y) residues Y694 and 699, which facilitates the formation of active Stat5 dimers via reciprocal pY-SH2 domain interactions. The dimers then translocate to the nucleus and induce target gene transcription. In cancer cells, Stat5 is constitutively phosphorylated leading to the aberrant expression of anti-apoptotic Stat5 target genes.
In an effort to identify direct inhibitors of Stat5, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against Stat5. Several potent (Ki &lt; 5 μM) and Stat5 selective (&gt;3-fold specificity for Stat5 cf. Stat1 and Stat3) inhibitors were identified which were then evaluated in K562 and MV-4–11 human leukemia cells which are known to harbour constitutively activated Stat5. BP-1–108 was identified as the most potent lead within these cell lines. The lead was further evaluated to show potent induction of apoptosis (IC50's ∼ 20 μM) which correlated with potent and selective suppression of Stat5 phosphorylation. In addition, it inhibited Stat5 target genes; Cyclin D1 & c-myc. BP-1–108 also showed no cytotoxicity against healthy bone marrow cells at concentrations up to 160 μM. These inhibitors represent the most potent and direct inhibitors of Stat5 function reported to date. An in silico docking analysis with BP-1–108 within the Stat5b crystal structure (pdb:1Y1U) revealed a tertrapodal projection of functionality facilitating access to a number of sub pockets within the Stat5 SH2 domain. Currently we are conducting a structure-activity relationship against Stat5's SH2 domain with one projection into the hydrophobic pocket using diverse heterocycles to delineate inhibitor binding to improve the potency of our inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B224.
Abstract B235: Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity.
Authors: Campbell Robert M. , Anderson Bryan D. , Chan Edward M. , De Dios Alfonso , Gilmour Raymond , Hatch Steven D. , Jambrina Enrique , Lee Paul , Mader Mary , Na Songqing , Neubauer Blake L. , Pratt Susan , Shih Chuan , Stancato Louis F. , Starling James J. , Velasco Juan A. , Watkins Scott A. , Wolos Jeffrey A. , Ye Xiang 
Published: June 2012

Abstract
p38α mitogen-activated protein kinase (MAPK) is activated by cancer cells in response to environmental factors, such as oncogenic stress, radiation, and chemotherapy. p38α MAPK phosphorylates a number of substrates, including MAPKAP-K2 (MK2), and regulates the production/message stability of cytokines produced in the tumor microenvironment, such as TNFα, IL1 β, IL-6 and IL-8. p38α MAPK is activated and highly expressed in human cancers and may play a role in tumor growth, invasion and metastasis. LY2228820 dimesylate is a tri-substituted imidazole derivative that is a potent and ATP-competitive inhibitor of the α and β isoforms of p38 MAPK in vitro (IC50 = 5.3 nM and 3.2 nM, respectively). This compound displays &gt; 1000-fold selectivity for p38α MAPK versus 179 other kinases tested (including p38δ and γ isoforms). In cell-based assays, LY2228820 dimesylate also potently and selectively inhibits phosphorylation of MK2 (Thr334) in TNFα-stimulated HeLa cells (IC50 = 8.1 nM) and anisomycin-induced mouse RAW264.7 macrophages (IC50 = 35.3 nM) with no changes in phosphorylation of p38α MAPK, JNK, ERK1/2, c-jun, ATF2 or cMyc at concentrations up to 10μM. LY2228820 dimesylate also reduces TNFα secretion by LPS/IFNγ-stimulated macrophages (IC50 = 6.3 nM). In mice transplanted with B16-F10 melanomas, phospho-MK2 was effectively inhibited by LY2228820 dimesylate in tumors in a dose-dependent manner (TMED70 = 19.4 mg/kg). Significant target inhibition (&gt;40% inhibition of phospho-MK2) was maintained for approx. 4–8hrs following a single 10mg/kg oral dose. In a broad range of xenograft models (A-549 NSCLC, SK-OV-3 Ovarian, U-87MG Glioma, MDA-MB-468 Breast), LY2228820 dimesylate demonstrates significant tumor growth delay. In summary, LY2228820 dimesylate is a novel, potent and selective inhibitor of p38 MAPK with anti-tumor activity. Further studies are ongoing to determine its molecular mechanism(s) of action, potential for combination with standard-of-care agents, and potential clinical activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B235.
Abstract B246: NVP-BGJ398: A potent and selective inhibitor of the fibroblast growth factor receptor family.
Authors: Guagnano Vito , Porta Diana Graus , Bordas Vincent , Douget Mickael Le , Stamm Christelle , Furet Pascal , Spanka Carsten , Wartmann Markus , Schmid Herbert , Brueggen Josef , Drueckes Peter , Bussiere Dirksen , Abrams Tinya , Rendahl Katherine , Bernard-Pierrot Isabelle , Radvanyi Francois 
Published: June 2012

Abstract
The mammalian fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) family comprises 22 FGF ligands, 18 of which exert their action through 4 highly conserved transmembrane tyrosine kinase receptors (FGFR1, FGFR2, FGFR3 and FGFR4). This highly complex signaling network regulates fundamental developmental pathways, physiological processes in the adult organism and a variety of cellular functions including proliferation, differentiation, and survival. Owing to such prominent roles, it is not surprising that different types of FGF/FGFR alterations, such as abnormal expression, mutations, and amplifications, have been found in diverse tumor types. A growing body of evidence linking deregulation of the FGF/FGFR system to the pathogenesis of cancer makes these receptors attractive targets for therapeutic intervention by a small molecular weight inhibitor approach.
We have established a new and non-conventional strategy to mimic documented lead compounds which consists in the replacement of real rings by stable pseudo six-membered rings resulting from the formation of an intramolecular hydrogen bond in a planar conjugated system. More recently, we have reported an example of the application of such strategy to the design of a new class of protein kinase inhibitors featuring a N-pyrimidin-4-yl-urea motif as an alternative to the pyrido[2,3-d]pyrimidin-7-one core structure of a well-known class of protein kinase inhibitors. In this context, we have described a prototype compound displaying submicromolar activity against several tyrosine kinases including FGFR1. In this communication we illustrate the process, guided by the use of molecular modeling and biochemical and cellular assays, that led to the identification of NVP-BGJ398, a potent and selective FGFR antagonist currently in phase I clinical trial.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B246.
Abstract B26: Expression of the KLF4 and SOX10 predicting for survival in colorectal cancer.
Authors: Lee Ha-young , Rha Sun Young , Roh Jae Kyung , Chung Hyun Cheol , Hong Soojung , Park Kyu Hyun , Kim Tae Soo , Baek Eun Sil , Park Han na , Shin Sang Joon 
Published: June 2012

Abstract
The zinc finger transcription factor Krüppel-like factor 4 (KLF4) is involved in many important cellular processes such as growth, development, differentiation, proliferation, and apoptosis. A loss of KLF4 expression has been observed in human tumors, particularly in the gastrointestinal tract. Sry box 10 (SOX10) is a transcription factor expressed in nerve cell and melanocytes. SOX10 is believed to be essential for neural crest fate determination and to maintain the multipotency of neural crest cells. Here, to investigate the roles of KLF4 and SOX10 in colorectal cancers (CRC), we examined the expression of KLF4 and SOX10 in tumor tissues and paired normal tissues in 125 CRC patients by real-time reverse transcription-polymerase chain (real-time RT-PCR). CRC had significantly lower KLF4 and SOX10 levels compared with matched normal tissues (KLF4: 2007±1531 Copies/ul in CRC, 6585±2833 Copies/ul in normal tissues, SOX10: 60±100 Copies/ul in CRC, 399±215 Copies/ul in normal tissues) (P&lt;0.0001). Statistically, KLF4 and SOX10 expression was not associated with age, sex, stage, lymph node metastasis, differentiation, tumor location. However, in univariate analyses, KLF4 and SOX10 were significant predictors of survival (P=0.002, P=0.039) and in multivariate analyses, KLF4 was significantly predictor of survival (P=0.045). Therefore, these findings suggest that KLF4 and SOX10 might have a potent oncogenic role in CRC tumorigenesis and prognostic value in predicting survival of CRC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B26.
Abstract B32: High-throughput solution for microRNA (miRNA) isolation from stabilized whole blood in a GLP setting: Development and comparison to established procedures.
Authors: Voss Thorsten , Kruhøffer Mogens , Nielsen Karsten Bork , Vial Alexander 
Published: June 2012

Abstract
Introduction: Beside the analysis of messenger RNA (mRNA) expression changes, profiling of miRNAs in human whole blood holds much promise for the development of genetic markers of disease. Many scientific groups in academia and in life science companies investigate the use of miRNAs as diagnostic tools at the moment. As these small RNAs become more and more important, effective and reliable isolation procedures are urgently needed. Especially standardization and exclusion of human errors require new automated solutions which are able to replace established manual processes without losing quality and quantity of the needed analytes. In this study we compare a newly developed and optimized procedure on QIAGEN's BioRobot platform to previously published automated (Kruhøffer et al., 2007, JMD 9: 452–458) as well as manual procedures.
Material & Methods: Whole blood from consented healthy adults was collected into PAXgene Blood RNA Tubes and subjected to RNA isolation. The RNA quality and quantity were determined by using a Beckman photometer and Agilent Bioanalyzer. miRNA yields were determined by quantitative RT-PCR using commercially available probe based (Life Technologies) assays on a BioMark (Fluidigm) instrument. Due to the small reaction volume of 9 nanoliters on the BioMark arrays a pre-amplification of the cDNA was performed. Therefore 14 amplification cycles were run with a 1:100 diluted primer set which was the same that was used in the following detection assays.
Results: Compared to the originally published partly automated method the workflow could be further streamlined resulting in a fully automated procedure. With this automation the time needed for manual steps could be reduced by more than 50%. In parallel, the quality and quantity of the isolated RNA (large and small RNA species) was not affected. This is demonstrated by high RIN values (&gt;7) and low DNA contamination levels &lt;0.1%. With respect to miRNA enrichment, the performance of the optimized protocol was at least comparable to the current manual or partly automated methods.
Conclusion: This comparison demonstrates the high efficiency of this optimized, fully automated isolation procedure for miRNAs from stabilized whole blood. The new procedure for purification of miRNAs provides the standardization required in a GLP setting.
All miRNA enrichment protocols, the PAXgene Blood miRNA Kit and the PAXgene Blood RNA MDx Kit are for research use only. Not for use in diagnostic procedures.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B32.