bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 598: EMT and nectin-1 mediate sensitivity to HSV-1 oncolysis in human HCC cell lines
Authors: Fuchs Bryan C. , Kuroda Toshihiko , Yamada Suguru , McGinn Christopher M. , Schmitt Anthony , Lanuti Michael , Tanabe Kenneth K. 
Published: February 2011

Abstract
Background: Oncolytic viral therapy mediated by herpes simplex virus 1 (HSV-1) is an emerging and promising cancer therapy. The entry of HSV-1 into cells is mediated in part by cell surface co-receptors. One of these co-receptors, nectin-1, is highly expressed in epithelial cells. Nectin-1 is localized to adherens junctions (AJs) where it interacts with E-cadherin through their respective peripheral membrane proteins, afadin and catenin. The loss of E-cadherin is a hallmark of epithelial-to-mesenchymal transition (EMT) and results in the disassembly of AJs. Here, we investigate the effects of EMT on cell surface nectin-1 expression, HSV infection and viral oncolysis. Methods: Western blot analysis was performed to determine E-cadherin expression in human HCC cell lines. Cytotoxicity to HSV-1 KOS strain was assessed by MTT analysis. KOS replication was assessed by a single-step burst assay, while viral infectivity was examined using the mutant bM24-BAC#3 virus which encodes GFP. Cell surface levels of nectin-1 and herpesvirus entry mediator (HVEM) were determined by flow cytometry and the role of nectin-1 in HSV-1 infectivity was further assessed using a nectin-1 neutralizing antibody. Results: Four of the human HCC cell lines were epithelial and four were mesenchymal. KOS oncolysis resulted in 50% cell death in the epithelial cell lines at multiplicities of infection (MOIs) 2-3 log orders less than the mesenchymal HCC cell lines. This difference was not attributed to cell growth rates as determined by population doubling times or to viral replication as assessed by burst assay. Instead, the epithelial cell lines had higher rates of infectivity which were attributed to greater cell surface expression of nectin-1 and not HVEM. Finally, blocking of nectin-1 with a neutralizing antibody inhibited viral oncolysis in all four epithelial HCC cell lines. Conclusions: EMT in human HCC cells results in the loss of nectin-1 cell surface expression and resistance to HSV-1 oncolysis. E-cadherin and nectin-1 are markers of sensitivity to HSV-1 oncolysis in human HCC cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 598.
Abstract 601: In vitro and in vivo inhibition of β-catenin by two novel β-catenin RNA antagonists, EZN-3889 and 3892
Authors: Zhang Yixian , Kim Steven , Shi Victoria , Qu Zhengxing , Castaneda Stephen , Wang Maoliang , Zhu Peifang , Filpula David , Greenberger Lee M. , Horak Ivan D. 
Published: February 2011

Abstract
Background: β-Catenin is a subunit of the cadherin protein complex and a key integral component in the Wnt signaling pathway. Therefore, it not only plays an important role in cell-cell adhesion but also in tumorgenesis. β-catenin is activated in most colon cancers due to either mutations in APC or activating mutations in β-catenin itself. Furthermore, activating β-catenin mutations have been found in a variety of other tumors such as melanomas, hepatocellular carcinomas, breast, and prostate cancer, whereas β-catenin is not activated in most normal tissues. Therefore, inhibition of β-catenin is likely to have therapeutic effects in many cancers. Unfortunately, because β-catenin is devoid of any enzymatic activity, the development of inhibitors of β-catenin has been slow. We present here both in vitro and in vivo evidence that the lack of specificity of small-molecule inhibitors may be overcome by two novel β-catenin LNA-based mRNA antagonists, EZN-3889 and EZN-3892. Material and Methods: In vitro, the ability of the compounds to inhibit mRNA, cell growth, and reporter gene were evaluated by qRT-PCR, MTS, and luciferase assays respectively, in multiple cell lines. In vivo, β-catenin mRNA down-modulation in liver and human tumors, which were grown on the flank of nude mice, was evaluated after intravenous administration of the compounds. Results: Without lipofection, we found that these two antagonists could specifically down modulate β-catenin mRNA and protein effectively in multiple cell lines with a long-lasting effect. Additionally, these two molecules effectively inhibited β-catenin transcriptional activity in SW480 colorectal and H1581 lung cancer cells stably expressing a TCF/LEF luciferase reporter gene, resulting in growth inhibition. Combination of EZN-3889 or 3892 with sulindac demonstrated improved activities in both growth and reporter assay. Moreover, EZN-3889 and 3892 inhibited the spontaneous growth of spheroids in SW480 culture and convert SW480 spheroids to monolayers. Preliminary data suggest that these spheroids were more tumorgenic than the monolayer cells. In mice, both molecules significantly down modulated β-catenin mRNA in the liver. Conclusions: Without lipofection, β-catenin antagonists potently and specifically inhibited β-catenin mRNA expression both in vitro and in vivo after intravenous injection. Target inhibition correlated with growth inhibition and phenotypical change of SW480 spheroids. Further studies will examine the significance of the inhibition of the spheroids and the effect of these antagonists on tumor growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 601.
Abstract 602: Silencing of the androgen receptor (AR) with a novel mRNA antisense oligonucleotide causes antitumor effects in xenograft models of prostate cancer
Authors: Zhang Yixian , Castaneda Stephen , Kim Steven , Kraft Patricia , Bandaru Raj , Filpula David , Greenberger Lee M. , Horak Ivan D. 
Published: February 2011

Abstract
Background: The AR is a ligand-activated transcriptional factor that plays an important role in prostate cancer. While androgen-deprivation therapies typically inhibit tumor growth, tumor recurrence due to the castration resistant form of the disease frequently occurs and leads to mortality. Nevertheless, castration-resistant tumors are still dependent on a functional (AR). Therefore, inhibition of AR expression, rather than systemic androgen deprivation, may provide a novel strategy for treatment of advanced prostate cancer. We have developed a novel locked nucleic acid (LNA)-based antisense oligonucleotide (ON), EZN-4176, which down-modulated AR and inhibited tumor growth. Methods: The target mRNA down-modulation, growth inhibition, luciferase activity, protein inhibition, and reduction of prostate specific antigen (PSA; an AR downstream target and biomarker of prostate cancer) were evaluated by qRT-PCR, MTS, SteadyGlo, western blot analysis, and ELISA assay, respectively, in LNCaP cancer cell lines. A mismatched LNA antisense oligo (EZN-4176MM) and an AR negative cell line (PC-3 prostate cancer) served as controls. Additionally, the effect of EZN-4176 on DHT-induced AR transcriptional activity was evaluated in LNCaP cells containing an AR-responsive luciferase reporter. In vivo, therapeutic efficacy of EZN-4176 was evaluated in the AR-positive CWR22 (androgen dependent). Results: In vitro, in the absence of any transfection reagent, EZN-4176 but not the mismatched control (EZN-4176MM) inhibited the growth of DHT-induced LNCaP cells. The growth reduction correlated with AR down-modulation and its down-stream target gene expression and AR-responsive luciferase activity. In vivo, EZN-4176, prepared in the absence of a delivery vehicle, demonstrated dose-dependent inhibition of mRNA of AR, PSA, and TMPRSS2 as well as protein level of AR in androgen-sensitive CWR22 tumor xenografts, resulting in significant tumor growth inhibition (TGI) (∼55%) (similar to high-dose Casodex® [bicalutamide] treatment). Cy5.5-labeled EZN-4176 was shown to localize in subcutaneous CWR22 or LNCaP tumor xenografts using xenogen imaging system. In castration-resistant tumor cells, EZN-4176 potently and specifically inhibited the growth of C4-2b cells as well as down-regulated AR-luciferase reporter systems. More importantly, AR and PSA mRNA were inhibited in both castration-resistant C4-2b and 22RV1 tumor xenografts. Conclusions: Our data suggest that AR mRNA down modulation by EZN-4176 inhibits prostate tumor growth and provides a novel strategy to treat advanced prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 602.
Abstract 603: Adenoviral mediated expression of Omomyc induced growth inhibition and apoptosis in lung cancer expressing Myc
Authors: Fukazawa Takuya , Matsuoka Junji , Yamatsuji Tomoki , Maeda Yutaka , Durbin Mary , Naomoto Yoshio 
Published: February 2011

Abstract
The Myc basic helix-loop-helix zipper domain determines dimerization with the constitutively expressed bHLH-Zip protein, Max, and also binding to the DNA E-box. Both of these functions play a critical role in the Myc regulation of growth, proliferation, tumorigenesis, and apoptosis. It has been reported that Myc recognition specificity is encoded in a short region within the leucine zipper. Mutation of four amino acids (E57T, E64I, R70Q, and R71N) generates a protein, Omomyc, that homodimerizes efficiently and can still heterodimerize with wild type Myc and Max. As a consequence, Omomyc suppresses activation of artificial E-box promoter elements by Myc/Max and strongly potentiates Myc-induced apoptosis in a manner dependent on Myc expression levels. Furthermore, Omomyc prevents initiation of K-RasG12D-induced lung tumors (Soucek L et al. Oncogene. 17: 2463-72. 1998, Nature. 455:679-83. 2008). In this study we have constructed an adenoviral vector (Ad-Omomyc) for use as a novel therapy for Myc or K-Ras mutated cancer. Ad-Omomyc expresses Omomyc and is driven by the CMV promoter. MTS assay and flowcytometric analysis demonstrated that Ad-Omomyc significantly suppressed cell viability and induced apoptosis in A549 pulmonary adenocarcinoma cells, which express Myc and harbor K-Ras mutations. Moreover, the combination treatment of Ad-Myc and Ad-Omomyc increased apoptosis in H441 pulmonary adenocarcinoma cells harboring a K-Ras mutation as compared to administering Ad-Omomyc alone. Ad-Omomyc induced little apoptosis in normal human lung fibroblasts (NHLF). Here, we describe a novel strategy to target Myc or K-Ras for the treatment of lung cancer using a Myc derivative: Omomyc.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 603.
Abstract 609: Paradoxical actions of a c-Src inhibitor on estradiol-induced apoptosis in long-term estrogen deprivation breast cancer cells
Authors: Fan Ping , Kim Helen R. , Jordan V. Craig 
Published: February 2011

Abstract
Resistance to aromatase inhibitors used for the treatment of estrogen receptor (ER) positive breast cancer is an increasing problem clinically. We have demonstrated in the laboratory that long term estrogen-deprived MCF-7 breast cancer cells referred to as MCF-7:5C (Lewis et al, JNCI 2005, 97:1746-1759), respond to physiological estrogen by triggering apoptosis. This scientific observation is now in clinical trial, but only 30% of patients receive clinical benefit (Ellis et al, JAMA 2009, 302:774-780). A goal of translational research is to increase the therapeutic responsiveness of antihormone resistant breast cancer. c-Src inhibitors are currently of interest, as they inhibit survival pathways in breast cancer. We have evaluated the potential of the c-Src inhibitor, PP2, alone (5 µM), and compared results of cell survival with estradiol (1 nM E2) alone, or in combination with PP2. The MCF-7:5C cells have increased levels of phosphorylation c-Src, compared to wild type MCF-7 cells. Long term treatment (at least 2 months) with PP2 initially decreased growth rates of MCF-7:5C cells, but then growth recovered. Long term treatment of MCF-7:5C cells with E2 initially causes massive apoptosis, but a population of surviving cells subsequently regrew, but these ER-positive cells were refractory to estrogen action. In contrast, a combination of PP2 + E2 actually retarded apoptosis and the resulting cell line (MCF-7:PF) is unique, as they grew vigorously in culture with physiological levels of estradiol, but remarkably are also stimulated in vitro by a panel of selective estrogen receptor modulators (SERMs). This is the first description of a Phase I (Jordan, Cancer Cell 2004, 5:207-213) resistant breast cancer cell line in vitro. These data illustrate that caution must be exercised when considering the evaluation of c-Src inhibitors in clinical trial following the development of acquired resistance to aromatase inhibitors. A combination with therapeutic estrogen treatment or indeed endogenous estrogen may impair therapeutic effectiveness of c-Src in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 609.
Abstract 612: FOXO1A is a target for HER2 overexpressing breast tumors
Authors: Wu Yanyuan , Shang Xiying , Sarkissyan Marianna , Slamon Dennis , Vadgama Jaydutt V. 
Published: February 2011

Abstract
Trastuzumab treatment has improved the overall survival of HER2 overexpressing breast cancer patients. However, many of these patients will eventually become resistant to treatment. It is unclear what mechanisms may contribute to resistance to Trastuzumab. In this study we have tested the hypothesis that targeting of the FKHR transcription factor FOXO1A in HER2 overexpressing breast tumor cells, can overcome the Trastuzumab resistance in vitro. We have demonstrated that overexpression of HER2 leads to activation of PI3K/Akt pathway and subsequent inactivation of FOXO1A in HER2 overexpressing breast cancer cells, SKBR3. In wildtype SKBR3 cells, Trastuzumab downregulates active Akt (pAkt) and increases FOXO1A expression that leads to increase in p27kip1, and decrease in cyclin D1, and finally inhibits SKBR3 cell proliferation. In contrast, the effect of Trastuzumab was eliminated by the reduction of FOXO1A in HER2 overexpressing cells with constitutively active Akt1 (Clone SKBR3/AA28). The down-regulation of FOXO1A in SKBR3/AA28 resulted in nuclear export of p27kip1. Blocking the constitutively active Akt by a specific Akt/protein kinase B signaling inhibitor-2 (API-2) significantly increased FOXO1A expression and rendered the SKBR3/AA28 cells more responsive to Trastuzumab induced growth inhibition. Re-activation of FOXO1A by stable transfection or transient transfection also restored the growth inhibitory effects of Trastuzumab in SKBR3/AA28 cells. In summary, Trastuzumab can inhibit proliferation of HER2 overexpressing breast cancer cells by re-activating FOXO1A through inhibition the PI3K/Akt pathway. FOXO1A may therefore serve as a target for HER2 overexpressing breast tumors, and its activation or increased expression may overcome resistance to Trastuzumab treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 612.
Abstract 613: Increased PI3K/AKT activity, which confers resistance to trastuzumab, can be overcome by lapatinib
Authors: O'Brien Neil A. , Wang YuHua , Chow Lucy , Wilcox Karen , Browne Brigid , Crown John , Arboleda Jane , Ginther Charles , Duffy Michael J. , O'Donovan Norma , Slamon Dennis J. 
Published: February 2011

Abstract
Trastuzumab and lapatinib provide clinical benefit to women with HER2 positive breast cancer. However, not all patients whose tumors contain the HER2 alteration respond. There are no clinically validated biomarkers of resistance to therapy. We evaluated responses to trastuzumab and lapatinib in a panel of 17 HER2-amplified cell lines in both two and three dimensional culture and investigated the role of receptor tyrosine kinase (RTK) signaling and PI3K/AKT pathway activation in resistance. We also conditioned four cell lines to acquire trastuzumab resistance, and two additional cell lines to acquire lapatinib resistance. The SUM-225, HCC-1419, HCC-1954, UACC-893, HCC-1569, UACC-732, JIMT-1 and MDA-453 cell lines are innately resistant to trastuzumab, whereas the MDA-361, MDA-453, HCC-1569, UACC-732, JIMT-1, HCC-202 and UACC-893 cells are innately lapatinib resistant. Lapatinib is active in both de novo (SUM-225, HCC-1419 and HCC-1954) and acquired trastuzumab resistant cell lines. Increased phosphorylation of HER2, EGFR, HER3 and IGF-1R correlated with response to lapatinib but not trastuzumab. p95HER2 levels correlated with response to lapatinib, however p95HER2 levels also correlated with levels of full length HER2, indicating that p95HER2 may not be an independent marker of lapatinib response. A decrease in AKT phosphorylation in response to trastuzumab or lapatinib treatment correlated significantly with response to either agent, indicating that loss of pAKT is a biomarker of response to both HER2-targeted therapeutics. Accordingly, trastuzumab treatment of trastuzumab resistant cells had little effect on AKT phosphorylation, whereas treatment of these cells by lapatinib significantly reduced pAKT levels. Thus, lapatinib retains its activity in trastuzumab resistance via continued dephosphorylation of AKT. We also observed that loss of PTEN or the presence of activating mutations in PI3K marked resistance to trastuzumab yet lapatinib response was independent of these factors. Thus, increased activation of the PI3K/AKT pathway confers resistance to trastuzumab which can be overcome by lapatinib. In conclusion, pharmacological targeting of the PI3K/AKT pathway may provide benefit to HER2 positive breast cancer patients who are resistant to trastuzumab therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 613.
Abstract 619: Dual targeted therapies to overcome tyrosin kinase inhibitors resistant in epidermal growth factor receptor (EGFR) expression of lung cancer
Authors: Huang Wen-Chien 
Published: February 2011

Abstract
Background: Non-small cell lung cancer (NSCLS) comprises about 80% of all lung cancers. The regular treatments for NSCLC are surgery, chemotherapy, radiotherapy and EGFR-targeted therapy. EGFR is frequently mutated and amplified in lung adenocarcinom as sensitive to EGFR inhibitors. The EGFR-targeted therapy, Gefitinib and Erlotinib, significantly improves disease free survival. However, it was not possible to predict super-responder of gefitinib degree of EGFR expression as a single agent. There is an imposing need for new rationally designed regimens to overcome Gefitinib resistance. The other tyrosine kinase inhibitor, Lapatinib, is a small-molecule inhibitor targeting both the HER2 and the epidermal growth factor receptor (EGFR) in solid tumors. We hypothesized that this aberrant activation of EGFR may contribute to Gefitinib resistance and dual blocking EGFR activation with EGFR and ERBB2 inhibitor will re-sensitize HER family in lung cancers.
Experimental Design: In the in vitro study, cancer cells with EGFR wild type or mutation type were treated with Tyrosine kinase inhibitor, Gefitinib, Lapatinib, or combined treatments. The responses of cells to Gefitinib or/and Lapatinib treatments were evaluated by MTS proliferation, apoptosis assay, soft agar colony formation assay and western blot. In the in vivo study, pulmonary xenograft tumors were established in ICR/SCID mouse and treated with vehicle control, Gefitinib, Lapatinib, or Gefitinib plus Lapatinib for 4 weeks. Tumor volume were monitored and further studied by immunohistochemistry on collected tumors.
Results: We selected multiple pairs of EGFR wild type and mutation type. The EGFR mutation cells have more effect under single tyrosine kinase inhibitor (Gefitinib) treatment compared with EGFR wild type cells. Dual inhibition of EGFR activation sensitized EGFR expression pulmonary cancer cells to Gefitinib treatment. Compared with single treatment, combined treatment led to a significantly more effective inhibition of cell proliferation and induced apoptosis. In a mouse pulmonary xenograft model, combination therapy with Gefitinib and Lapatinib dramatically inhibited EGFR wild type tumor growth.
Conclusions: Since the EGFR family inhibitor, Lapatinib is currently under Phase III clinical trial, combining Gefitinib with this Lapatinib, dual EGFR inhibitors is a clinically applicable strategy and a promising combinatory targeted anti-cancer therapy to overcome EGFR wild type mediated Gefitinib resistance.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 619.