bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 663: YK-4-279 inhibits ERG and ETV1 mediated prostate cancer cell invasion
Authors: Rahim Said , Beauchamp Elspeth M. , Kong Yali , Brown Milton L. , Toretsky Jeffrey A. , Üren Aykut 
Published: June 2012

Abstract
Chromosomal translocations involving the ETS family of transcription factors are found in a majority of prostate cancers, including the most clinically aggressive forms. These translocations produce a chimeric gene, which fuses the promoter region of an androgen responsive gene, such as TMPRSS2, to the coding region of ETS factors, most frequently ETV1 or ERG. Over-expression of ETS factors in prostate cancer cells results in a more invasive phenotype. The high prevalence of these rearrangements, and their biological significance represents a novel therapeutic target for the treatment of prostate cancer. We recently reported the development of YK-4-279, a small molecule inhibitor of EWS-FLI1 oncoprotein in Ewing's Sarcoma. ERG and ETV1 belong to the same class of ETS factors as FLI1. Due to the close homology of FLI1 with ERG and ETV1, we tested the ability of YK-4-279 to inhibit ETS biological activity in prostate cell-lines such as VCaP and LNCaP that demonstrate androgen dependent ERG and ETV1 expression, respectively. YK-4-279 inhibited ERG and ETV1 mediated transcription of target genes such as PLAU, PLAT, ADAM19 and MMP-13, which are involved in breakdown of the extracellular matrix and metastasis. YK-4-279 reduced the motility and invasive phenotype of ETV1-fusion positive LNCaP cells and ERG fusion-positive VCaP cells in in vitro invasion assays. However, ETS fusion-negative PC-3 cells were unresponsive to YK-4-279. ERG knockdown in VCaP cells resulted in a loss of drug responsiveness. Transient ERG expression in PC-3 cells resulted in an increased invasive phenotype, which was reduced by YK-4-279. Our results demonstrate that YK-4-279 inhibits ERG and ETV1 biological activity in fusion-positive prostate cancer cells leading to decreased motility and invasion. Therefore, YK-4-279 may have an impact on metastasis in prostate cancer, which is a leading cause of death, and it may be further evaluated for its clinical applications in prostate cancer, in addition to Ewing's sarcoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 663. doi:10.1158/1538-7445.AM2011-663
Abstract 665: Targeting the MluI cell cycle box (MCB) sequence 5’-ACGCGT-3’ in the human Dbf4 promoter using the rationally designed polyamide formamido-imidazole-pyrrole-imidazole (f-IPI)
Authors: Lin Shicai , Kiakos Konstantinos , Lee Moses , Hochhauser Daniel , Hartley John A. 
Published: June 2012

Abstract
Dbf4 is the regulatory subunit of Cdc7 kinase, which is essential for the initiation of DNA replication throughout S-phase. The level of Dbf4 is critical for the activation of Cdc7. Human Cdc7/Dbf4 (HuCdc7/Dbf4) kinase activity is essential for cell proliferation by activating DNA replication. High levels of the Cdc7 kinase activity have been implicated with a large number of aggressive solid cancers. The MluI cell cycle box (MCB) sequence 5’-ACGCGT-3’ is the critical site for transcription factor binding that activates the expression of the HuCdc7/Dbf4 core gene in mammalian cells. HuDbf4 promoter activity has previously been shown to be significantly reduced by a point mutation within the MCB. We have previously shown that the rationally designed simple polyamide formamido-imidazole-pyrrole-imidazole (f-IPI) binds to its cognate sequence 5’-ACGCGT-3’ as a stacked dimer in an anti-parallel conformation (2:1 ligand/DNA complex) with exceptionally high affinity and selectivity, superior to the natural product distamycin A binding to its cognate sequence. DNAse I footprinting experiments indicated selective binding of f-IPI to the MCB sequence in the HuDbf4 promoter at 0.1µM. Eletrophoretic mobility shift assays using the MCB-containing sequence from the HuDbf4 promoter showed dose-dependent inhibition of protein binding by f-IPI which was complete at 0.5µM. RT-PCR showed decreased expression of HuDbf4 mRNA in response to incubation of exponentially growing MDA-MB231 cells with 10 μM f-IPI. Selective effects on protein expression, DNA replication and cell cycle are currently underway. These data demonstrate the potential of small molecule polyamides as modulators of gene expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 665. doi:10.1158/1538-7445.AM2011-665
Abstract 668: Second generation silicon derivatives of indomethacin: Synthesis of potent COX-2 selective agents with improved anticancer activity
Authors: Zakai Uzma I. , Gately Stephen , West Robert 
Published: June 2012

Abstract
Elevated tumor cyclooxygenase-2 is associated with poor overall survival in patients with a variety of cancers. Patients with elevated COX-2 that receive a COX-2 inhibitor have demonstrated improved survival. Indomethacin (IM) is a COX-non-selective inhibitor with demonstrated anticancer activity in patients. The anticancer effects of IM are related to inhibition of COX-2 as well as COX-independent targets. We now report the improved synthesis and activity of IM-sila- amide derivatives where strategic silicon addition results in COX-2 selective IM derivatives that demonstrate activity in mouse models of human cancers and are devoid of the COX-1 associated toxicities. The sila-IM compounds demonstrated improved inhibition of purified human COX-2, IC50 0.2 uM and limited inhibition of COX-1 up to 10 uM. Sila-IM derivatives were also found to be potent inhibitors of NF-κB transcription activating function at concentrations below 1.0 UM. A sila-IM derivative Silexsyn was tested in various animal models of human cancer following oral administration. Significant activity was observed in models of non-small cell lung cancer and pancreas cancer. Potent synergism was observed for Silexsyn in combination with EGFR inhibitors. A synthetic methodology incorporating a heteroatom in the amino-functional silane has been developed and used to generate second-generation sila-IM derivatives that could have improved pharmacological properties. The introduction of silicon into an approved scaffold represents an efficient strategy for the rapid production of biologically relevant therapeutics for the treatment of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 668. doi:10.1158/1538-7445.AM2011-668
Abstract 684: The difference between gefitinib and serum deprivation in cancer cells
Authors: Suenaga Mitsuhiro , Yamamoto Masatatsu , Furukawa Tatsuhiko , Tei Chuwa 
Published: June 2012

Abstract
Gefitinib is a selective inhibitor of epidermal growth factor receptor tyrosine kinase. The serum free condition could resemble to gefitinib exposure since it blocks EGF stimuli. In this study, we examined distinction between gefitinib exposure and serum deprivation in cultured cancer cells. At first, we verified that ERK phosphorylation was downregulated by gefitinib exposure in A431 and A549 cells. We examined the phosphorylation status of ERK under the serum deprivation condition. The phosphorylation of ERK in A431 cells was downregulated after 1hr culture in serum free medium, while after 3-6hr ERK was phosphorylated again. We hypothesized that an auto- or paracrine mechanism would work to phosphorylate ERK. In the cells cultured with the conditioned serum free medium from the dish in which A431 cultured for 24hr, the downregulation of ERK phosphorylation was weaker than with the fresh serum free medium. We confirmed that gefitinib could inhibit the ERK phosphorylation under the serum free condition. Exogenous EGF attenuated the inhibitory effect on ERK phosphorylation with serum free medium. These results suggest EGF may be one of the auto- or paracrine substance that induces ERK phosphorylation. Since the ERK phosphorylation status affects the stability of c-MYC, we also examined whether “gefitinib” and “serum deprivation” affect the expression of c-MYC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 684. doi:10.1158/1538-7445.AM2011-684
Abstract 690: Selection of resistance by anticancer drugs is not responsible for alterations in membrane micro-fluidity: A study by Fluorescence Correlation Micro-Spectroscopy
Authors: Winckler Pascale , Cailler Aurélie , Jaffiol Rodolphe , Royer Pascal , Jeannesson Pierre , Morjani Hamid 
Published: June 2012

Abstract
Expression of P-glycoprotein (P-gp), the multidrug resistance (MDR) 1 gene product, can lead to MDR in tumors. Previous studies on multidrug-resistant cells have suggested changes in membrane fluidity associated with P-gp expression in drug-selected resistant cells. However, Aleman and co-workers have shown that, in MDR1 transfected cells, expression of P-gp has little effect on membrane fluidity and the changes in this parameter observed in drug-selected cells must reflect other host adaptations to drug selection. In this study and the other reported on drug-selected resistant cells, membrane fluidity has been measured using fluorescent membrane probes and fluorescence anisotropy or electron spin resonance on cell population samples (Aleman et al. Cancer Res. 2003 63:3084-91).
Here, we propose to explore the plasma membrane microfluidity by using the fluorescent membrane probe DiA and fluorescence correlation micro-spectroscopy (FCM-S) on a single living cell and nanometer scale. By using the fluorescent membrane probe DiA and FCM-S to explore the plasma membrane micro-fluidity, we have previously shown a decrease in plasma membrane micro-fluidity in LR73R cells (the Chinese hamster ovarian LR73 cells transfected with MDR1 cDNA; Boutin et al., J Biomed Opt. 2009 14: 034030). Moreover, a strategy using flow cytometry and calcein-AM functional fluorescence-activated cell sorting permitted us to select two cell populations from LR73R cells expressing distinct levels of P-gp function. In this case, we were able to observe distinct level of membrane micro-fluidity in the two populations. Cells showing high level of calcein-AM uptake presented a higher membrane micro-fluidity. In contrast, the FCM-S yielded opposite data when we compared the membrane micro-fluidity of several parental cell lines (MCF7, KB3.1, LR73, ME-SSA) and their resistant counterparts which have been selected in the presence of anticancer drugs.
Our data are not in agreement with previous published data and demonstrates clearly that alterations that can affect drug-selected cells do not induce any changes in membrane fluidity. Moreover, micro-analysis of cell membrane could allow to more precise measurements of membrane fluidity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 690. doi:10.1158/1538-7445.AM2011-690
Abstract 700: ICAM-3 endows anti-cancer drug resistance against microtubule-damaging reagents via modulation of caspases activities and Bcl-2
Authors: So Kwangsup , Kang Sung Wook , Kim Jae-Sung , Hwang Sang-Gu , Um Hong-Duck , Park Jong Kuk 
Published: June 2012

Abstract
We have previously reported that intercellular adhesion molecule-3 (ICAM-3) is associated with various cancer cell physiologic responses including developing cellular radio-resistance. In this report, we studied whether ICAM-3 exerts an additional effect on development of resistance against anti-cancer drug because drug/radiation resistance of cancer usually displays cross-resistance. We treated several anti-cancer drugs including, paclitaxel (Ptxl), 5-fourouracil (5-FU), and etoposide (Eto), to an ICAM-3 over-expressing stable transfectant or empty vector- transfected control NCI-H1299 non-small cell lung cancer (NSCLC) cell line (p53 and PTEN null cell). Ratios of cell survival against each drug were detected with microculture tetrazolium (MTT) assay. ICAM-3 stable transfectants showed less cell death compared with empty vector-transfected cells by Ptxl treatment. The ICAM-3 stable transfectants also showed a resistance against cell death induced by vincristine (VCS), another microtubule-damaging reagent. In clonogenic assay and cell counting assay, we also observed significant drug-resistance against microtubule-damaging reagents in ICAM-3 stable transfectant cell line. Ptxl/VCS-treated control control transfectant cells showed more apoptotic cell death and activation of caspase-3/-8 than those of ICAM-3 stable transfectant cell line at 96 hour after drugs treatments. Blockage of p44/42 MAPkinase and PI3-kinase/Akt pathway by treatment of pharmaceutical inhibitors increased Ptxl/VCS-induced apoptotic cell death. However, in same condition, ICAM-3 stable transfectant cell line showed relatively less cell death. We also detected ICAM-3 inhibited Ptxl/VCS-induced degradation of mitochondrial anti-apoptotic molecules including Bcl-2, Bcl-XL, and Mcl-1 in dose-dependent manner. These results indicate that ICAM-3 endowed drug-resistance of cancer cells against microtubule-damaging reagent via modulation of apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 700. doi:10.1158/1538-7445.AM2011-700
Abstract 711: Understanding the mechanisms of resistance to BRAF inhibitors in melanoma
Authors: Villanueva Jessie , Krepler Clemens , Vultur Adina , Chen Yuhao , He Xu , Wubbenhorst Bradley , Nathanson Katherine L. , Herlyn Meenhard 
Published: June 2012

Abstract
The presence of activating BRAF mutations in approximately 50% of melanomas, the majority of which are BRAFV600E, has prompted the development of selective BRAF inhibitors for targeted therapy. Pre-clinical data using multiple BRAF inhibitors and results from recent clinical trials using PLX4032 validate the effectiveness of this treatment strategy and offers hope to patients suffering from this deadly disease. However, similar to other malignancies, therapy with BRAF inhibitors is effective in only a subset of patients and even if an initial effective response is observed, tumors eventually develop resistance and patients relapse. We recently reported that acquired resistance to BRAF inhibitors can be mediated by non-genetic mechanisms through rewiring of their signaling pathways and this is mediated by a RAF kinase switch and increased PI3K-dependent survival. However, as melanoma is a highly heterogeneous disease, we anticipate that multiple mechanisms can be associated with acquired resistance to BRAF and/or MEK inhibitors. Also, the mechanisms of intrinsic resistance can be different from those underlying acquired resistance.
Here we report that melanoma cells which harbor the BRAFV600E mutation and express PTEN have low levels of phospho-AKT and are sensitive to BRAF inhibitors. In contrast, BRAFV600E mutant melanoma cell lines that do not express PTEN have higher levels of phospho-AKT and are less sensitive to BRAF inhibitors. Co-targeting PI3K and mutant BRAF in melanoma cells that lack functional PTEN sensitizes them to the combination strategy. Our studies suggest that the presence or absence of functional PTEN can modulate response to inhibitors of the MAPK pathway and warrant further evaluation of combination strategies to treat melanomas refractory to BRAF inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 711. doi:10.1158/1538-7445.AM2011-711
Abstract 720: Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2 extracellular domain in human breast cancer cells
Authors: Yoshida Ryosuke , Tazawa Hiroshi , Hashimoto Yuuri , Uno Futoshi , Kagawa Shunsuke , Fujiwara Toshiyoshi 
Published: June 2012

Abstract
Human epidermal growth factor receptor 2 (HER2) is a member of a family of receptors associated with tumor cell proliferation, apoptosis, adhesion, migration, and differentiation. According to numerous preclinical and clinical studies, HER2 can be immunogenic and antibodies against this transmembrane receptor have become in use in individuals with HER2-overexpressing tumors. Trastuzumab, a monoclonal antibody that targets HER2, induces antibody-dependent cellular cytotoxicity (ADCC) and inhibits HER2-mediated signaling. Numerous randomized trials have confirmed the utility of trastuzumab in HER2-overexpressing breast cancer in various clinical scenarios; however, HER2-overexpression has been identified only in approximately 25-30% of primary breast cancers. Moreover, it has been reported that the majority of metastatic breast cancer patients treated with trastuzumab develop acquired resistance within a year. In this study, we analyzed the mechanism of resistance to trastuzumab and examined for molecular sensitization by exogenous expression of HER2 extracellular domain in human breast cancer cells. A long-term exposure to trastuzumab induced its resistance in HER2-positive breast cancer cells. We found that trastuzumab-resistant cells exhibited down-regulation of HER2 expression in cell surface and impaired ADCC activity, suggesting that trastuzumab-resistant cells could be re-sensitized to trastuzumab by exogenous induction of extracellular domain (ECD) of HER2.We constructed the expression vector with HER2-ECD and stably transfected into low HER2-expressing human breast cancer cell line, MCF7. HER2-ECD expression had no apparent effect on the growth and signaling pathway in MCF7 cells; however, ADCC activity was strongly enhanced in HER2-ECD-expressing MCF7 cells compared to parental MCF7 cells. These results suggest that exogenous expression of HER2-ECD might be an appropriate strategy to sensitize HER2-negative or trastuzumab-resistant human breast cancer cells to trastuzumab. The modification of the tumor-specific replication-competent adenovirus (OBP-301, Telomelysin) to contain the HER2-ECD gene for exogenous expression is currently under the investigation. We will further examine the antitumor effects of this virus in the combination with trastuzumab.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 720. doi:10.1158/1538-7445.AM2011-720
Abstract 742: Mechanisms of resistance to small molecule inhibition of anaplastic lymphoma kinase in human neuroblastoma
Authors: Carpenter Erica L. , Haglund Elizabeth A. , Chow Adrian K. , Christensen James G. , Maris John M. , Mosse Yael P. 
Published: June 2012

Abstract
The purpose of this study was to identify therapeutically targetable mechanisms of resistance to anaplastic lymphoma kinase (ALK) inhibition in neuroblastoma. ALK is a receptor tyrosine kinase (RTK) frequently activated in neuroblastoma, a malignancy of the autonomic nervous system representing almost 10% of pediatric cancers. ALK aberrations, including mutation and amplification, lead to increased autophosphorylation and activation in neuroblastoma. PF-02341066, an orally available small-molecule inhibitor of the ALK tyrosine kinase, has shown dramatic activity in non-small lung cancers harboring an ALK translocation, and is currently in phase 1 trials in pediatrics. Although pharmacological inhibition of kinases in diseases such as chronic myelogenous leukemia has significantly improved survival, resistance inevitably develops. Mechanisms of resistance to tyrosine kinase inhibitors have included mutation of the targeted receptor as well as up-regulation and dependence switch to other RTKs. We hypothesize that patients with neuroblastoma who successfully respond to ALK inhibition will eventually relapse and that in vitro models can be used to predict the underlying mechanisms of resistance. To mimic the development of resistance, we treated ALK-expressing human neuroblastoma-derived cell lines in vitro with PF-02341066 for several months. Once resistance was established, serial dilutions were used to generate clonal populations of PF-02341066-resistant cells. Western blotting was used to confirm inhibition of phospho-ALK and rule out drug efflux as a resistance mechanism. DNA analysis revealed no additional PF-02341066-induced mutations or copy number variations within ALK. We next used Western blot and phoshpho-array technology to evaluate changes in the activation state of a panel of RTKs as well as their downstream signaling molecules. Interestingly, in comparison to the untreated parental line, PF-02341066-resistant cells had up-regulated activated epidermal growth factor receptor (EGFR) as well as other downstream signaling molecules. Dependence of the PF-02341066-resistant cells on these pathways was verified by showing increased sensitivity of the resistant versus parental cell lines to inhibition of these up-regulated pathways. Taken together, these data suggest that ALK inhibition in neuroblastoma leads to a dependence switch to EGFR and implies the need to develop therapeutic strategies to target this receptor when ALK inhibition is used clinically.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 742. doi:10.1158/1538-7445.AM2011-742