bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 326: Aneuploidy-driven clonal diversification underlies tumor phenotype switching
Authors: Gao Chong-Feng , Su Yanli , Woude George Vande 
Published: August 2012

Abstract
The acquisition of an invasive phenotype and its reversion to a proliferative phenotype are crucial steps in tumor metastases. We have been able to reproduce these steps through a combination of in vitro and in vivo methods. We show that proliferative subclones isolated from human carcinoma cells can generate invasive subclones in vitro, which is associated with the epithelial-mesenchymal transition (EMT). Moreover, the invasive mesenchymal clones can reverse their phenotype (MET) through tumorigenesis in vivo. Phenotypic switching occurs with changes in karyotypes, which dictate changes in the chromosome transcriptome and in the expression of genes that account for the phenotypic switching. We conclude that chromosome instability generates the transcriptome diversity, which in the appropriate environment leads to the expansion of clonal variants responsible for malignant progression.
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 326. doi:1538-7445.AM2012-326
Abstract 3863: Aneuploid human colonic epithelial cells are sensitive to AICAR-induced growth inhibition through EGFR degradation
Authors: Ly Peter , Kim Sang B. , Wright Woodring E. , Amon Angelika , Shay Jerry W. 
Published: August 2012

Abstract
Trisomy for chromosome 7 is frequently observed as an initiating event in sporadic colorectal cancer. Although unstable chromosome numbers and recurrent aneuploidies drive a large fraction of human cancers, targeted therapies selective to pre-neoplastic trisomic cells are non-existent. We have previously characterized a trisomy 7 cell line (1CT+7) spontaneously derived from normal diploid human colonic epithelial cells that aberrantly express the epidermal growth factor receptor (EGFR, located on 7p11). Recent studies identified AICAR as a pharmacological inhibitor of aneuploid murine fibroblast proliferation. Here, we report that AICAR induces profound cytostatic and metabolic effects on 1CT+7 cells but not their isogenic diploid counterpart. Dose-response assays demonstrate that 1CT+7 cells are four-fold preferentially sensitive to AICAR compared to diploid cells. Unexpectedly, treatment of 1CT+7 cells with AICAR led to a reversible 3.5-fold reduction (p=0.0025) in EGFR overexpression. AICAR-induced depletion of EGFR protein can be abrogated through inhibition of the proteasome with MG132. AICAR also heavily promoted EGFR ubiquitination in cell-based immunoprecipitation assays, suggesting enhanced degradation of EGFR protein mediated by the proteasome. Moreover, treatment with AICAR reduced EGFR protein levels in a panel of human colorectal cancer cells in vitro and in xenograft tumors in vivo. Our data collectively supports the pharmacological compound AICAR as a novel inhibitor of EGFR protein abundance and as a potential therapeutic agent for aneuploidy-driven colorectal 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 3863. doi:1538-7445.AM2012-3863
Abstract 3904: Pyridylthiazole-based ureas as inhibitors of Rho-associated protein kinases
Authors: Pireddu Roberta , Forinash Kara , Sun Nan N. , Martin Mathew P. , Sung Shen-Shu , Alexander Brian , Zhu Jin-Yi , Guida Wayne C. , Schönbrunn Ernst , Sebti Saïd M. , Lawrence Nicholas J. 
Published: August 2012

Abstract
Rho GTPase is a small G-protein which plays a critical role in signaling pathways and controls cell growth and division. Rho-associated protein kinase (known as ROCK or Rho kinase) is a Ser/Thr protein kinase activated by GTP-bound Rho and phosphorylates target proteins involved in various signal transduction pathways. Rho and the Rho-kinase signalling pathways are implicated in cell morphology, motility, smooth muscle contraction, formation of stress fibres, focal adhesion and cell transformation. ROCKs have been subject to growing attention, having been implicated in a range of therapeutic areas including cardiovascular diseases, CNS disorders, and cancer. Further, the pharmacological inhibition of ROCKs has been suggested as a promising strategy in the prevention of cell invasion, a central event in the process of metastasis. Potent ROCK inhibitors of a new class of 1-benzyl-3-(4-pyridylthiazol-2-yl)ureas have been identified. Remarkable differences in activity were observed for ureas bearing a benzylic stereogenic center. Derivatives with hydroxy, methoxy and amino groups at the meta position of the phenyl ring give rise to the most potent inhibitors (low nM). Substitutions at the para position result in substantial loss of potency. Changes at the benzylic position are tolerated resulting in significant potency in the case of methyl and methylenehydroxy groups. X-ray crystallography was used to establish the binding mode of this class of inhibitors and provides an explanation for the observed differences of the enantiomer series. Potent inhibition of ROCK in human lung cancer cells was shown by suppression of the phosphorylation levels of the ROCK substrate MYPT-1. One of the series, RKI-1447 inhibits migration, invasion and anchorage-independent tumor growth of breast cancer cells and is discussed in an accompanying poster.
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 3904. doi:1538-7445.AM2012-3904
Abstract 3906: Design, synthesis and biological evaluation of 2nd generation ezrin inhibitors for metastatic osteosarcoma
Authors: Kosturko George W. , Bulut Gulay , Hong Sung-Hyeok , Rodriguez Veronica , Brown Milton , Toretsky Jeffrey , Khanna Chand , Paige Mikell , Uren Aykut 
Published: August 2012

Abstract
Though advancements in chemotherapy and surgical techniques have ameliorated treatment of primary osteosarcoma (OS), the metastatic phenotype remains a clinical challenge. Overall five-year survival rates for patients with localized OS have improved to 60-70%, yet survival rates of patients with metastasis remains at 20-30% with mortality linked to metastatis-induced respiratory failure. Therefore, targeting fundamental molecular events that lead to metastasis may yield significant benefit to patients with OS. Accumulating evidence from clinical samples and pre-clinical animal models suggests that ezrin is a key regulator in the metastasis of OS cells. Ezrin is a multifunctional protein that connects the actin cytoskeleton to extracellular matrix through transmembrane proteins and a critical component for cell motility, adhesion and shape. We have recently identified that a small molecule, NSC 668394 acts as a potent and selective inhibitor of ezrin function and inhibits migration in both in-vitro and in-vivo models. Moreover, suppression of ezrin phosphorylation by NSC 668394 significantly reduced the metastatic behavior in cellular and animal models and has thus emerged as an important lead inhibitor. Consequently, we conducted a series of structure-activity-relationship (SAR) studies that monitored direct binding; OS cell migration and HUVEC monolayer invasion in ‘real-time’ with surface-plasmon resonance and electrical impedance technology. From our 2nd generation library, we have designed novel candidate inhibitors which feature enhanced ezrin-binding affinity, and improved anti-migration and anti-invasion activities. In addition to their potency against the different stages of OS metastasis, these compounds possess other desirable attributes for development including good druggable physical-chemical characteristics and are currently undergoing further preclinical evaluation.
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 3906. doi:1538-7445.AM2012-3906
Abstract 3919: Novel model to study NFkB driven resistance to endocrine treatment in breast cancer
Authors: Sas Leen , Laere Steven Van , Peeters Dieter , Marsan Melike , van Schooneveld Eleni , Lardon Filip , van Dam Peter , Dirix Luc , Vermeulen Peter 
Published: August 2012

Abstract
Background: Patients with estrogen receptor (ER)-positive breast cancers are generally treated with endocrine therapy, but in a considerable fraction of patients resistance occurs. Previous research showed that nuclear factor kappa B (NFkB) may play a role in the development of resistance to hormonal therapy. In this study, we investigated the role of NFkB, and its interaction with ER in the development of endocrine resistance by studying breast cancer cell lines with variable ER and NFkB activity. Material and methods: Three gene expression data sets of breast cancer cell lines (GSE12777: Hoeflich et al, 2009; GSE16795: Hollestelle et al, 2009; E-TAM-157: Neve et al, 2005) were retrieved from Gene Expression Omnibus or ArrayExpress. The expression profiles were screened for ER and NFkB target genes to identify cell lines with strong and weak activation of ER and NFkB. Based on these activation profiles, 8 cell lines (MCF7, BT20, CAMA1, MDA-MB-361, MDA-MB-231, MDA-MB-134, MDA-MB-468 and MDA-MB-436) with high and low ER and NFkB activation profiles were selected. Using qRT-PCR on RNA from these cell lines, the expression of 6 biomarkers for endocrine resistance (ADAMDEC1, ITK, ABAT, CLEC7A, ETS1 and STC2) were profiled. 18S and beta-Actin were used as housekeeping genes. Relative expression levels were analyzed in function of ER and NFkB activation. Results: There is a significant lower expression of ADAMDEC1 (P=0.011), ITK (P=0.012) and ETS1 (P&lt;0.001) in the ER-positive cell lines compared to the ER-negative ones, while ABAT (P&lt;0.001) and STC2 (P=0.049) are significant higher expressed in ER-positive cell lines. Comparison of ER-positive/NFkB-negative with ER-positive/NFkB-positive cell lines revealed a difference in expression in 3 of the 6 genes, namely ADAMDEC1 (P=0.037), ITK (P=0.013) and ABAT (P=0.014), showing a higher expression in the double positive cell lines. Conclusion: The construction of a set of breast cancer cell lines with different patterns of combined ER-NFkB activity is a useful tool to unravel the mechanism of ER and NFkB interaction leading to endocrine resistance. In this context, the number of cell lines will be expended. With respect to our data, the expression profiles of ADAMDEC1 and ITK were in line with the expected attenuated responsiveness of the NFkB-positive breast cancer cells to endocrine therapy and therefore might play a role in NFkB-driven resistance to endocrine therapy.
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 3919. doi:1538-7445.AM2012-3919
Abstract 4344: Ionizing radiation induces adhesion of breast cancer cells to fibronectin through upregulation of integrin alpha5beta1
Authors: Lee Shinhee , Cheng Huiwen , Wu Shiyong 
Published: August 2012

Abstract
Metastatic cancer is marked by the loss of integrity of extracellular matrix (ECM). Adhesion of tumor cells to the ECM mediated by integrins on the surface of the tumor cells is a key step in the initial phase of metastasis. Since ionizing radiation (IR), which is commonly used for cancer therapy can induce alterations of the cell surface, we investigated the effect of IR on the adhesion of breast cancer cells to ECM proteins. Results showed that in MDA-MB-231 breast cancer cell line, IR induced significant increase in both integrin expression and integrin-mediated adhesion to fibronectin, laminin, collagen I and IV. Soluble Arg-Gly-Asp peptide fragments or function-blocking antibodies directed against integrin alpha5beta1 inhibited IR-induced adhesion of MDA-MB-231 cells to fibronectin, indicating that IR-induced adhesion is caused by up-regulation of alpha5beta1 integrin fibronectin receptors. In contrast to MDA-MB-231 cells harboring mutant p53 (R280K), MCF-7 cells (WT p53) were unable to increase adhesion and up-regulation of alpha5beta1 integrin. Interestingly, knockdown of mutant p53 abrogated IR-induced integrin alpha5 integrin expression and adhesion to fibronectin. Our results indicate that mutant p53 coordinates breast cancer cell adhesion through up-regulation of alpha5beta1 integrin. This study suggests that alpha5beta1 integrin might be an effective target to improve the efficacy of radiotherapy in mutant p53 expressing cancers.
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 4344. doi:1538-7445.AM2012-4344
Abstract 4783: Proteomic analysis of acute lymphoblastic leukemia: de novo versus relapse
Authors: Kang Kee R. , Park Eun S. , Kang Dawon 
Published: August 2012

Abstract
Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with distinct biological and prognostic grouping. The initial response to induction chemotherapy is the most important prognostic factor in patients with acute lymphoblastic leukemia. Patients with rapid early response (RER &lt; 5% of blast in bone marrow at day 7 after induction chemotherapy) have better event-free survival compared to slow early responders (SER ≤ 25% of blast). However, no predictive marker for relapse or treatment failure is currently available. This study aimed to find plausible biomarkers of drug sensitivity in bone marrow mononuclear cells (BMMNCs) of childhood ALL cases using 2-dimensional gel electrophoresis and subsequent MALDI-TOF/mass spectrometry. The 714 spots in RER and 555 spots in SER were visualized in gels. Of these 28 up-regulated and 25 down-regulated proteins in SER_as compared to RER_were identified. The detected proteins were 60-kDa heat shock protein, actin, lamin-B1, heterogeneous nuclear ribonucleoprotein (hnRNP) K, and so on. HnRNPK, down-regulated in SER was further verified by Western blot analysis. In future studies, the roles of HnRNPK in drug sensitivity/resistance are undergoing to elucidate as a potential biomarker for ALL therapy. [Funding source: NRF grant (R13-2005-012-01003-0)].
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 4783. doi:1538-7445.AM2012-4783
Abstract 4865: Pak1 links the Wnt/β-catenin pathway to ErbB2 signaling in breast cancer cells
Authors: Romero Luis E. Arias , Cruz Olga Villamar , Chernoff Jonathan 
Published: August 2012

Abstract
Several studies suggest that Pak1 plays an important role in the genesis of breast cancer, but despite the similarity in their sequences, the contribution of the closely related enzyme Pak2 to this disease remains unclear. To establish the function of Paks in ErbB2 driven transformation, we used a three-dimensional tissue culture system of human mammary epithelial cells that stably co-express a chemically-activatable form of ErbB2 and doxycycline (DOX) inducible shRNAs against Pak1 or Pak2. We observed that silencing of Pak1 but not of Pak2 has a dramatic effect in cell proliferation and apoptosis. As expected, activation of ErbB2 induced growth factor-independent proliferation and disruption of 3D acinar-like structures via ERK and Akt signaling. In contrast, silencing of Pak1 compromised activation of ERK, resulting in reversion of the malignant phenotype and restoration of normal acinar architecture. Surprisingly, silencing of Pak2 also compromised ERK activation, but cannot restore normal morphology. Further, we found that ErbB2-amplified breast cancer cells expressing a DOX inducible shRNA against Pak1 formed significantly smaller tumors than cells expressing either GFP or a DOX inducible shRNA against Pak2 in SCID mice as the result of the inhibition of ERK. A phosphoproteomic analysis showed that several signaling pathways, e.g. Wnt and Mdm2-p53, are down regulated in our Pak1 deficient cell line. We found that the shPak1 cell line, but not the shPak2 deficient cell line has a dramatic reduction in total β-catenin levels, and that blocking β-catenin with chemical inhibitors restored normal acinar architecture. Finally, we found that targeting Pak and/or β-catenin in combination with trastuzumab sensitized trastuzumab-resistant breast cancer cells to trastuzumab, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance.
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 4865. doi:1538-7445.AM2012-4865
Abstract 4890: Arsenic trioxide induces apoptosis through the activation of ASK1 and is enhanced by a thioredoxin reductase inhibitor
Authors: Kwan Stanley , Garnier Nicolas , Miller Wilson H. , Mann Koren K. 
Published: August 2012

Abstract
Arsenic trioxide (ATO) is an effective treatment for acute promyelocytic leukemia (APL). While it is undergoing clinical trials for numerous malignancies including multiple myeloma, myelodysplastic syndrome, lymphoma and solid tumors, it has demonstrated only limited efficacy as a single agent. However, it may hold promise as part of a combination therapy. Thus investigation to elucidate the mechanisms of action underlying these clinical responses may lead to generation of rational combination therapies to increase its therapeutic spectrum. Previous work has described a pathway required for ATO-induced apoptosis in APL cells involving the generation of reactive oxygen species (ROS), and the subsequent induction of a specific mitogen-activated protein kinase (MAPK) cascade that includes both stress-activated protein kinase (SAPK)/ERK kinase 1 (SEK1) and c-Jun N-terminal kinases (JNK) activation. However, the link between ROS production and activation of SEK1 remains to be elucidated. Apoptosis signaling kinase 1 (ASK1) is a MAP3K upstream of SEK1 and has been implicated in the induction of stress-induced signaling. Here, we show that ATO activates ASK1 in a dose- and time-dependent manner in an APL cell line. ASK1 activation is preceded by ATO-induced ROS accumulation, which is significantly reduced with N-acetyl-L-cysteine antioxidant co-treatment. Murine embryonic fibroblasts (MEFs) from ASK1 deficient mice are less susceptible to ATO-induced apoptosis and growth inhibition. Moreover, they exhibit markedly lower ATO-induced JNK activity compared to wild type cells. One model of ASK1 regulation suggests that ASK1 is kept in an inactive form by reduced thioredoxin-1 (Trx1). During oxidative stress, Trx1 is oxidized and releases ASK1 for activation. Immunoprecipitation of ASK1 followed by immuoblotting for Trx1 in APL cells shows a strong basal association that is lost with ATO treatment. Furthermore, the activity of thioredoxin reductase 1 (TrxR1), an enzyme that converts oxidized Trx1 into reduced Trx1, is significantly decreased following ATO treatment. This suggests that ATO activates ASK1 signaling by ROS-mediated oxidation of Trx1 and by inhibiting the restoration of reduced Trx1 by decreasing TrxR1 activity. In addition, we show that inhibition of TrxR1 with the TrxR1 inhibitor Au(III)Cl sensitizes APL cells to ATO-induced apoptosis. This suggests that regulation of ASK1 is dependent on Trx1 redox states. Overall, our results suggest that targeting Trx1 may enhance ASK1 signaling and ATO-induced apoptosis in a novel combination therapy.
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 4890. doi:1538-7445.AM2012-4890
Abstract 5226: Potential anti-tumor effect of a small molecule dipeptidyl peptidase inhibitor, 4175, in colorectal cancer
Authors: Zhang Jiping , MacFarlane Alexander W. , Jones Barry , Bachovchin William , Cambpell Kerry , Borghaei Hossein 
Published: August 2012

Abstract
Introduction: Cetuximab is an effective therapeutic agent in a number of malignancies. Current data indicates that about 30% of colorectal cancer patients bearing mutated K-ras do not benefit from this agent. A possible mechanism of the antitumor effect of cetuximab is mediated through antibody-dependent cell-mediated cytotoxicity (ADCC). The present study is aimed to investigate the potential activity of Ari-4175, a broad -spectrum inibitor of prolyl peptidases and a potent immune stimulator in the treatment of K-ras mutant colorectal cancer xenografts as a single agent or in combination with cetuximab. Methods: The effect of Ari-4175 alone or in combination with cetuximab was evaluated both in vitro and in vivo. In vitro, the proliferation of K-ras mutant colon cancer cell lines DLD-1 and HCT-116 was detected after three days of culture in the medium containing various concentrations of Ari-4175 or cetuximab. In vivo, nude mice bearing DLD-1 or HCT-116 xenograft tumors were randomly divided into four groups, control, Ari-4175 alone, cetuximab alone and Ari-4175 plus cetuximab. Ari-4175 was administered orally at 100 ug, q.d or b.i.d and cetuximab was injected i.p at 200 ug per week. Tumor measurements were conducted twice a week. Peripheral blood was collected from the mice before the treatment or after 7 to 14 days of the treatment. CD16 expression on NK cells was monitored by flow cytometry. Results: Ari-4175 (10 nM ∼ 200 uM) alone or in combination with cetuximab did not show significant cytotoxicity on either DLD-1 or HCT-116 in cell culture. However, the growth of both DLD-1 and HCT-116 tumors were significantly blocked by the application of Ari-4175 in a dose-dependent manner. The combination of Ari-4175 with cetuximab lead to a further decrease in tumor size although not statistically significant, probably due to lower number of animals. Cetuximab alone did not show any therapeutic effect on HCT-116 xenograft but did have moderate efficacy on DLD-1 tumors. Treatment with Ari-4175 also increased the level of CD16 on mouse NK cells. Conclusion: The prolyl peptidase inhibitor, Ari-4175, showed anti-tumor effect in K-ras mutant colorectal cancer xengrafts when given alone or in combination with cetuximab. The therapeutic effect of 4175 might partially be due to the augmentation of ADCC through elevating expression of CD16 (FcγRIIIA) on NK cells. Our study provides the basis of testing Ari-4175 in a clinical trial.
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 5226. doi:1538-7445.AM2012-5226