bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C44: Positive interaction between Lapatinib and Capecitabine in human breast cancer models: In vitro study of molecular determinants
Authors: Chefrour Mohamed , Fischel Jean-Louis , Giacometti Sarah , Formento Patricia , Renee Nicole , Milano Gerard , Ciccolini Joseph 
Published: June 2012

Abstract
Background: Lapatinib (Tykerb®) is an innovative small molecule with a dual-TKI inhibitory action against both HER1 and HER2. Lapatinib has demonstrated antiproliferative efficacy in various models, including breast tumors, thus heightening the expectations for new breast cancer therapies. The association of Lapatinib with Capecitabine (Xeloda®) has been recently approved, both in the USA and in Europe, in patients with HER2+ metastatic breast cancer, relapsing after trastuzumab treatment. However, little is known on the exact molecular mechanisms underlying the increase in efficacy expected when combining these drugs.
Methods: In the following preclinical study, we studied the molecular determinants of this new targeted drug / antimetabolite association on a panel of representative human breast cancer cell lines: BT474, MCF-7, MDA-MB-468, SK-BR-3, T47D and ZR-75. Effects of concomitant and sequential drug combinations on proliferation and apoptosis were measured, along with the study of the determinants of response/resistance to Capecitabine (e.g., dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), and thymidine phosphorylase (TP) levels), to Lapatinib, (e.g., members of the HER1/2 signaling pathway), and to proliferation (P21) and apoptosis (Bax, Bcl-2).
Results: Additive to moderate synergistic effects were demonstrated (Chou & Talalay combination indices, CI) with CI's ranging between 0.55 and 1.03. Further experiments were performed to identify the mechanisms underlying the efficacy of the combination. We observed that Lapatinib down-regulated thymidylate synthase (−30%), thus suggesting a better cytotoxic effect of Capecitabine when tumor cells were preliminary exposed to Lapatinib, but had not effect on DPD activity. Impact on TP levels was model-dependent, but could lead additionally to a better activation towards active metabolites eventually. Besides, adding Capecitabine to Lapatinib strongly down-regulated P-AKT (e.g., from −56 to −100%) and p-P42/44 (−78 to −100%), allowing a deeper inhibition of the HER1 and HER2 downstream signaling pathway. A +150 to +300% increase of the Bax/Bcl2 ratio in cells exposed to both drugs was observed, leading to the enhancement of apoptosis and cell death. Those findings were consistent with the observation that the association of Lapatinib and Capecitabine led to an increase of P21 protein expression and consequently to cell cycle arrest.
Conclusion: Taken together, these results suggest that the more-than-additive effects observed when associating Lapatinib and Capecitabine is mostly based both on TS modulation and HER1 and HER2 signaling pathways down-regulation, eventually resulting in apoptosis and cell death. In vivo experiments are ongoing to fully confirm these data.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C44.
Abstract C48: The role of the neuregulins and their receptors in the islets of Langerhans
Authors: South Jack C. M. , Gullick William J. 
Published: June 2012

Abstract
The Neuregulins are a sub-class of the Epidermal Growth Factor (EGF) family of mitogenic ligands. This research aims to investigate their expression in individual cell types within the Islets of Langerhans in order to determine whether they play a role in regulating islet cell growth or hormone secretion. This information may be useful in the future in treating diabetic patients or in rare instances of islet cell cancer.
An expression profile of all the EGF receptors and ligands, including the four NRG genes and some of their splice variants, was determined in rat islets using immunohistochemical staining with specific mouse monoclonal and rabbit polyclonal antibodies. Double immunofluorescent staining with antibodies to the ligands or receptors and to the main islet cell hormones, insulin, glucagon and somatastatin was used to identify which cell types were expressing each isoform. The rat islet tumor cell line CRI-G1 was selected as a model system to determine cellular responses to addition of the different ligands. Immunofluorescent staining and RT-PCR was used to construct a receptor and ligand expression profile.
Immunohistochemistry demonstrated that some ligands such as NRG3 or the alpha and beta isoforms of NRG1 were expressed in restricted regions of the islets. Through double immunofluorescence it was found that NRG-1α was present in β-cells and NRG-1β and NRG-3 were mainly present in α-cells. The same restricted pattern of expression was also found in human islets. In contrast, staining for HER-3 and HER-4 receptors in rat islets was much more homogenous. In using single immunofluorescence with the CRI-G1 cell line both HER-3 and HER-4 as well as with two of the NRG-4 splice variants were detected. PCR using cDNA from the cell line confirmed the expression of both NRG-1 and NRG-2 at the mRNA level.
Differential expression of NRG-1α and 1 in or cells due to alternative splicing may play a role in regulating cell proliferation, differentiation or hormone secretion in individual islet cell types across a range of species. Differences in localisation between the three Neuregulin forms and their two receptors suggests that both autocrine and paracrine neuregulin-mediated signalling occurs. The expression of NRG-1, NRG-2, NRG-4 and the receptors HER-3 and HER-4 within the CRI-G1 cell line provides a model system to explore the activity of this complex system in vitro.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C48.
Abstract C58: Causal Network™ Modeling identifies common and unique mechanisms for sensitivity to the PI3K inhibitor GSK1059615 and the AKT inhibitor GSK690693
Authors: Macoritto Michael P. , Laifenfeld Daphna , Catlett Natalie , Jorge Milena , Matthews Andrea , Auger Kurt R. , Kumar Rakesh 
Published: June 2012

Abstract
Background: Aberrant PI3K and AKT signaling play an important role in the development of some human tumors by promoting cell proliferation and survival. Inhibitors that target the kinase activity of PI3K or AKT may constitute an effective treatment for human malignancies that rely on these molecules for their growth. GlaxoSmithKline has developed a PI3K inhibitor, GSK1059615, and a pan-AKT inhibitor, GSK690693. Since AKT is activated by PI3K via generation of PIP3, and is a key effector of PI3K signaling, a high degree of overlap is expected in the effects of a PI3K and an AKT inhibitor. To determine whether the effects of the PI3K inhibitor are mediated solely through the AKT pathway, we compared the molecular response of BT474 human breast cancer cells to both GSK1059615 and GSK690693 as well as the sensitivity profile of 16 other human cancer cell lines.
Methods: The mechanisms of action of the PI3K inhibitor GSK1059615 and the AKT inhibitor GSK690693 were evaluated in BT474 human breast cancer cells using RNA expression and phosphoproteomic data. Causal Network™ Modeling was used to characterize these data sets to identify processes that contribute to the inhibition of proliferation observed in cells sensitive to these inhibitors, and processes that could explain differences in sensitivity to the two inhibitors. The sensitivity/resistance profile of 16 human cancer cell lines to GSK1059615 and GSK690693 was also determined.
Results: Four common processes were found in BT474 cells treated with either GSK690693 or GSK1059615: RB1-Mediated Cell Cycle Arrest
Increased FOXO Signaling
Decreased MYC and TFRC Signaling
Decreased Metabolism
We identified one process specific to the PI3K inhibitor GSK1059615-treated cells: Decreased MAPK Signaling
Conclusions: In BT474 cells, GSK690693 and GSK1059615 inhibit cell proliferation by increasing RB1-mediated cell cycle arrest, increasing FOXO signaling, decreasing MYC signaling, and decreasing cellular metabolism, as identified by Causal Network™ Modeling. In addition to these four shared mechanisms, the PI3K inhibitor GSK1059615 attenuates MAPK signaling. Five of 16 cell lines tested for sensitivity to the inhibitors were sensitive to GSK1059615 treatment only, and these five cell lines were the only ones that contained mutations activating MAPK signaling. Thus decreased MAPK signaling is likely an additional mechanism by which GSK1059615 inhibits cell proliferation, and may confer sensitivity to this PI3K inhibitor in cells resistant to the AKT inhibitor.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C58.
Abstract C77: In vivo anticancer activity of an aurora kinase inhibitor, VX-680, in gastric cancer
Authors: Kim Hyo Song , Yu Eun Jeong , Jeung Hei-Cheul , Kim Tae Soo , Chung Hyun Cheol , Roh Jae Kyung , Noh Sung Hoon , Jang Paul , Kim Minkyu , Rha Sun Young 
Published: June 2012

Abstract
Background: Aurora kinases (AK) constitute one family of seine/threonine kinases, whose activity is essential for mitotic progression. Expression of aurora kinase is greatest in G2-M phase, and their function includes spindle formation, centrosome maturation, chromosomal segregation, and cytokinesis. Over-expression of AK is related to aneuploidy and carcinogenesis. Herein, we investigated the in vitro and in vivo anticancer acvitivity of a novel AK inhibitor, VX-680 in gastric cancer.
Methods: AK protein expression and kinase activity were screened in gastric cancer cell lines using immunoblot and in vitro kinase assay, respectively. The anti-proliferative activity of VX-680 was measured using MTT assay. The changes of cell cycle by the treatment of VX-680 were analyzed by flow cytometry. YCC-16 cell line selected for tumor xenograft models. In vivo activity validation using mouse xenograft models and extract protein or tissue slide from each tumors.
Results: AK protein expression and its kinase activity were variable among cell lines. VX-680 showed anti-proliferative effect in vitro on a wide range of gastric cancer cell lines, and calculating the IC50 value, it was distributed from 0.04uM to 19.87uM. It was correlated with kinase activity, not with protein expression of AK. VX-680 induced the reduction of phosphor-histone H3 and the cell cycle defects that accumulated &gt;4N DNA. In vivo experiment, confirmed that AKI had an effect on tumor inhibition. Solid tumor formed with YCC-16 cell lines and VX-680 was injected twice a day for 5 days with a dose of 50mg/kg. Estimating the tumor volume for 21 days after VX-680 injection, the difference in tumor volume between the control and the treated mice were statistically significant. Kinase activity and phospho-histone H3 in VX-680 treated tumor was reduced in drug treatment samples compared to the control samples.
Conclusion: We demonstrated that VX-680 has anti-cancer activity in gastric cancer. Kinase activity of AK might be a predictor for sensitivity of VX-680.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C77.
Abstract C78: The mu opioid receptor regulates Lewis lung carcinoma tumor growth and metastasis
Authors: Mathew Biji , Lennon Frances E. , Siegler Jessica , Gerhold Lynnette , Mambetsariev Nurbek , Moreno-Vinasco Liliana , Garcia Joe G.N. , Salgia Ravi , Moss Jonathan , Singleton Patrick 
Published: June 2012

Abstract
Introduction: Expression of the mu opioid receptor (MOR) is increased in patients with non-small cell lung cancer (NSCLC), a disease with poor prognosis and limited therapies. Previous work by our laboratory and others suggested a role of opioids in several aspects of tumor growth (Anticancer Res 2009;29:3195–3205, Mol Cancer Ther 2008;7:1669–1679, Cancer Res 2002;62:4491–4498). In this study, we investigated MOR as a potential therapeutic target for lung carcinoma.
Methods: Lewis lung carcinoma (LLC) cells were treated with MOR siRNA or the peripheral MOR antagonist, methylnaltrexone (MNTX, 250 nM), prior to the addition of EGF (10 ng/ml), IGF (10 ng/ml), DAMGO (1 nM), morphine (1 nM) or serum (1, 5 or 10%). In vitro functional (cell proliferation and invasion) and biochemical studies (immunoblotting) were then conducted. For in vivo assays, C57BL/6J mice were injected intravenously with dual color (GFP-RFP labeled) LLC cells, with or without MOR siRNA treatment. In another experiment, MOR knockout as well as wildtype control mice were injected with LLC cells (subcutaneously into the flank) and followed for 12 weeks. In a parallel experiment, LLC tumor bearing C57BL/6J mice received continuous infusion of MNTX (10 mg/kg/day) for 2 weeks. Tumor growth and lung metastasis were evaluated using tumor volume measurements and/or in vivo fluorescent microscopy (Olympus OV-100) with or without intravenous injection of ProSense and/or MMP Sense probes.
Results: Our data indicate that LLC cells have ∼5 fold increased expression of MOR (compared to primary lung epithelial or BEAS-2B cells). Inhibition of MOR with siRNA or MNTX treatment reduced in vitro LLC proliferation (90%) and invasion (50–75%). In vivo lung metastasis was reduced by ∼75% in wildtype C57BL/6J mice with LLC lacking MOR (siRNA) versus control siRNA-treated LLC (3 weeks post-i.v. injection, quantitated with OV-100). In addition, primary LLC tumor volume was substantially reduced (&gt;90%) in MOR knockout mice compared to wildtype mice (flank injection). Finally, we observed that continuous infusion of MNTX (10 mg/kg/day) in mice with pre-existing LLC primary tumors attenuates further tumor growth.
Conclusion: We have shown that MOR is a potential therapeutic target for inhibition of LLC proliferation, invasion and metastasis. In addition, MNTX can attenuate LLC primary tumor growth. Further study of MNTX as a potential therapeutic agent is warranted.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C78.
Abstract C83: The proliferation marker Ki-67 as novel molecular target in cancer therapy
Authors: Rahmanzadeh Ramtin , Rai Prakash , Rizvi Imran , Celli Jonathan , Abu-Yousif Adnan , Baron-Luehr Bettina , Gerdes Johannes , Hasan Tayyaba 
Published: June 2012

Abstract
Introduction: For patients with advanced ovarian cancer there are no effective therapies. The need for alternative treatments with high specificity but with low systemic toxicity can be achieved by targeting key molecular markers associated with cancer cells. Here, we show an innovative proof-of-principle approach for efficient killing of proliferating ovarian cancer cells by inactivating a protein associated with cell proliferation namely, the nuclear Ki-67 protein (pKi-67), using nanotechnology-based photodynamic therapy (PDT). pKi-67 is highly expressed in all proliferating cells and antibodies against this protein are widely used as prognostic tools in tumor diagnosis.
Materials and Methods: Anti pKi-67 antibodies were first conjugated to fluorescein isothiocyanate (FITC) and then encapsulated inside liposomes. The liposomes encapsulating antibodies were characterized by dynamic light scattering and transmission electron microscopy. We then evaluated the efficacy of Ki-67 targeting using two in vitro ovarian cancer models - monolayer cultures as well as 3D cultures established in our lab. Cell viability after irradiation with laserlight at 488 nm was assessed using MTT viability assay for monolayer cultures while a Live/Dead assay kit was used for analyzing 3D cultures.
Results: After incubation of OVCAR-5 ovarian cancer cells with the liposomal constructs, we used confocal microscopy to image localization of the antibodies to the nucleoli of the cells. Irradiation of these cells with a 488 nm laser led to a significant loss of viability. The efficacy of this approach was further demonstrated in a 3D culture model of OVCAR-5 cells. Incubation of 3D cultures with the liposomal constructs followed by light irradiation led to destruction of their acinar structures over 72 h following treatment. Using two different anti pKi-67 antibodies, where one targets the “active” form of pKi-67 while the other binds to the “inactive” form of the protein; we show that cell killing is specific after inactivation of the “active” Ki-67 protein. Further, the specificity of this approach for pKi-67 positive cells is demonstrated in confluent human lung fibroblasts (MRC-5) where minimal cell death was observed. This is in agreement with the flow cytometry results which show that only small populations of confluent MRC-5 cells express pKi-67.
Conclusions: Taken together, our findings suggest that pKi-67 is an attractive therapeutic target in cancer and this approach holds promise as an effective alternative cancer therapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C83.
Abstract A108: LY2606368, a second generation Chk1 inhibitor, inhibits growth of ovarian carcinoma xenografts either as monotherapy or in combination with standard-of-care agents.
Authors: McNeely Samuel C. , Burke Teresa F. , DurlandBusbice Sara , Barnard Darlene S. , Marshall Mark S. , Bence Aimee K. , Beckmann Richard P. 
Published: June 2012

Abstract
Chk1 is a key component of the cellular response to DNA damage resulting from exposure to various genotoxic agents. When damaged DNA is present, Chk1 maintains genomic integrity by stalling cell cycle progression thereby providing time for the appropriate repair to occur. Inhibition of Chk1 kinase activity leads to a loss in the regulation of this damage response and results in abrogation of cell cycle arrest and ultimately to cell death as cells with damaged DNA proceed inappropriately into mitosis. Thus first generation small molecule inhibitors of Chk1 kinase were developed to act as companion compounds that would be used together with established standard -of-care (SoC) cancer treatments that target DNA to enhance the effectiveness of such treatments. As a second generation inhibitor, LY2606368 distinguishes itself from other molecules in this class in that it has been shown to inhibit tumor growth when used either as monotherapy or in combination with SoC agents. The single agent activity of LY2606368 is likely related to the ability of this molecule to potently inhibit Chk1 thereby effectively interfering with its function to support normal DNA replication via regulation of origin firing and/or aspects of chromosomal dynamics during mitosis which are thought to be dependent upon Chk1 kinase activity. The studies presented here have evaluated the potential of LY2606368 to inhibit ovarian tumor growth both as monotherapy and in combination with cisplatin or paclitaxel. Treatment of tumor-bearing animals on a BID X 3 schedule with LY2606368 alone resulted in profound growth inhibition such that greater than 80% inhibition was observed at doses of 12mg/kg in both subcutaneous and orthotopic models. Moreover, the studies in the orthotopic SKOV3 model demonstrated that treatment with LY2606368 not only robustly inhibited growth of the primary tumor but also significantly reduced the incidence of metastases and accumulation of ascites fluid. Subsequent studies in SKOV3 subcutaneous xenografts revealed that significant growth inhibition could be achieved with various combination strategies which include agents that are commonly used in the treatment of ovarian cancer. In particular, the extent of growth inhibition that could be achieved with cisplatin or paclitaxel alone was augmented by combining these agents with LY2606368. Overall these animal studies indicate the potential therapeutic benefit in ovarian cancer that could be achieved with LY2606368 either as monotherapy or in combination with SoC agents.
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 A108.
Abstract A123: TEL is a dual anticancer agent that targets Stat3 and HIF-1α.
Authors: Chen Han , Guan Yongli , Gu Yuan , Tweardy David , Jing Naijie 
Published: June 2012

Abstract
We recently developed a dual anti-cancer agent, TEL (a perylence derivative) that independently targets both Stat3 and HIF-1α. Stat3 and HIF-1 have been demonstrated to be important targets for cancer therapy. Stat3 participates in oncogenesis through the up-regulation of genes encoding anti-apoptosis, cell-cycle regulators, and inducers of angiogenesis. Also, Stat3 suppresses anti-tumor immune responses and promotes inflammation-induced cancer, making it an attractive target. HIF-1 mediates the cellular response to hypoxia and activates the transcription of genes that are involved in angiogenesis, cell survival, glucose metabolism and invasion. HIF-1α was demonstrated to be overexpressed in many human cancers. Overexpression of HIF-1α, which results from intratumoral hypoxia and genetic alternations, has been associated with poor prognosis and treatment failure in a number of cancers. Our previous results demonstrated that targeting both Stat3 and HIF-1α together could improve tumor response, compared to either single agent alone, and reduce drug resistance and treatment failure.
Recently, we have isolated or derived more than 20 molecules from Chinese medicinal herbs. Based on drug screening, we found that TEL selectively targets both HIF-1α and Stat3, significantly inhibiting activation of HIF-1α and p-Stat3, and blocking the expression of both HIF-1α and Stat3 regulated oncogenes (e.g. Bcl2, VEGF, Glut1, and others) in cancer cells, showing that it has great potential to be an anti-cancer agent. Our results demonstrated that (1) TEL inhibits both p-Stat3 and HIF-1α; (2) TEL strongly interacts with the residues of E612, S613 and E638 in the SH2 domain of Stat3 and disrupts the interaction between Stat3 and the phosphotyrosine-stimulating receptor, blocking Stat3 phosphorylation; (3) TEL directly binds to HIF-1 protein and inhibits the interaction between N803 of HIF-1α and p300/CBP under hypoxia condition, inducing the proteasomal degradation and blocking its transcription; and (4) TEL greatly induces cancer cell apoptosis by targeting Stat3 and HIF-1α, but does not cause toxicity in normal cells under the same condition. TEL is likely to have a favorable safety profile, as do many Chinese herbed medicines. Therefore, TEL not only has broad drug activity for cancer therapy, but may be well tolerated in cancer 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 A123.