bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4373: Targeting FGFR system in a model of HCC
Authors: Lang Sven A. , Scheller Tobias , Moser Christian , Mycielska Maria , Hellerbrand Claus , Schlitt Hans J. , Geissler Edward K. 
Published: August 2012

Abstract
Activation of the fibroblast growth factor receptor (FGF/FGFR) system has been reported in a large number of human cancers including human hepatocellular carcinoma (HCC). Furthermore, expression of FGFR2 has been associated with aggressive tumor growth and poor prognosis in this tumor entity. Moreover, HCC is known to be a hypervascularized tumor and activation of the FGF/FGFR system is a crucial event in tumor angiogenesis. Hence, we addressed the issue of targeting the FGFR system in HCC (Huh-7, HepG2) and stromal cells (endothelial cells (EC), vascular smooth muscle cells (VSMC), hepatic stellate cells (HSC)). The FGFR inhibitor BGJ398 (Novartis Oncology, Basel, Switzerland) was used to inhibit FGFR activation. Effects of targeting FGFR on growth of cells were determined by MTT assays. Inhibition of constitutive and growth factor induced cell motility was investigated in modified Boyden Chamber assays. Activation of signaling pathways upon treatment with BGJ398 was assessed by Western Blot analyses whereas effects on mediators of tumor angiogenesis (VEGF-A, PDGF-B) where measured by RT-PCR and ELISA, respectively. Results show that inhibition of the FGF/FGFR system with BGJ398 led to dose-dependent inhibition of growth in tumor cells and ECs whereas only minor effects were observed on VSMC and HSCs. Moreover, motility of tumor and stromal cells (ECs, VSMCs, HSCs) was significantly impaired upon constitutive conditions (P&lt;0.05 for all). In addition, FGFR inhibition led to decrease in HSC motility even when cell were incubated with conditioned media from cancer cells (P&lt;0.05). With regards to activation of signaling intermediates, FGFR inhibition impaired constitutive and growth factor induced phosphorylation of Akt and ERK in HCC cell lines, ECs and HSCs whereas only minor effect was observed in VSMCs. Moreover, treatment with BGJ398 led to inhibition of c-Myc expression and significantly reduced VEGF-A production from cancer cells, as determined by Western blotting and ELISA, respectively. Evaluation of effectiveness of BGJ398 in animal models is currently ongoing. However, results so far indicate that targeting FGFR impairs angiogenic signaling and motility in HCC cell lines and stromal cells. Therefore, inhibition of FGFR warrants further evaluation and might be an interesting novel approach for anti-neoplastic treatment protocols in human HCC.
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 4373. doi:1538-7445.AM2012-4373
Abstract 4379: Activating the prostaglandin I2-IP signaling suppresses metastasis in lung cancer
Authors: Minami Yoshinori , Endo Satoshi , Okumura Shunsuke , Shibukawa Kiyoko , Sasaki Takaaki , Ohsaki Yoshinobu 
Published: August 2012

Abstract
Background: The mechanism by which bone marrow (BM)-derived cells might contribute to tumor metastasis and angiogenesis is controversial. We have reported that bone marrow derived angiogenic progenitor cells (Lin- cKit+ Flk-1+ cells) express prostaglandin I2 (PGI2) specific receptor; IP, and the PGI2-IP system is necessary for vascular remodeling and angiogenesis. Additionally, we have reported that the specific knockdown of IP in bone marrow derived cells (BMDCs) increases tumor metastasis in mouse models. Objectives: The purpose of this study was to test the hypothesis that activating the PGI2-IP signaling suppresses tumor metastasis. Materials & Methods: We employed both a mouse lung metastatic model and a mouse bone marrow transplanted model. Mouse-derived Lewis lung carcinoma (LLC) cells labeled with DsRed were used for a mouse lung metastatic model to distinguish cancer cells from BMDCs. The LLCs were injected into the tail vein of mice (c57BL/6J), which bone marrow cells were transplanted from GFP-labeled mice. Beraprost sodium (BPS; IP receptor agonist) or PBS control was continuously administered for 3 weeks by subcutaneous osmotic pumps. Tumor metastasis to lung was assessed by using hematoxylin-eosin staining. The a-SMA as a pericyte marker and the CD31 as an endothelial cell marker were studied by immunofluorescence to evaluate angiogenesis in metastatic lung tumors. Results: The size and number of tumor metastasis were significantly decreased in BPS group compared with in PBS control group assessed by the mice lung metastasis model. Immunofluorescence analysis revealed that the pericytes derived from bone marrow were scattered within tumors in PBS control group, while those were observed along with tumor micro vessels by supporting the endothelial cells within tumors in BPS group. Conclusions: The present study demonstrated that activating the PGI2-IP signaling suppresses metastasis in lung cancer. These results also suggested that the maturation of tumor angiogenesis by pericytes may decrease tumor metastasis. Finally, we propose that PGI2-IP system would be a novel therapeutic target in lung metastasis.
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 4379. doi:1538-7445.AM2012-4379
Abstract 4388: Combination therapy with anti-CTLA-4 plus leuprolide acetate in the pre-surgical setting of patients with regional, high-risk prostate cancer
Authors: Gao Jianjun , Sun Jingjing , Ward John F. , Rao Priya , Troncoso Patricia , Araujo John C. , Tang Derek N. , Chen Hong , Thall Peter , Wen Sijin , Sharma Padmanee 
Published: August 2012

Abstract
Anti-CTLA-4 is a monoclonal antibody (Ipilimumab or Yervoy, Bristol-Myers Squibb) that was recently FDA-approved for the treatment of patients with metastatic melanoma. Since anti-CTLA-4 targets a T cell specific molecule, as opposed to a tumor-specific molecule, it is being tested for therapeutic efficacy in multiple malignancies, including prostate cancer. In addition, since anti-CTLA-4 enhances anti-tumor T cell responses by blocking an inhibitory signal on activated T cells, it has been postulated that traditional therapies that lead to tumor cell death, thereby releasing tumor antigens to prime and potentially activate T cell responses, can be used in combination with CTLA-4 blockade to sustain activated T cell responses and enhance anti-tumor immune responses. Pre-clinical mouse models have shown this to be true. To determine the impact of combination therapy on human immune responses, we designed a pre-surgical clinical trial with a hormonal agent consisting of leuprolide acetate, a standard agent that has therapeutic efficacy against prostate cancer, plus anti-CTLA-4 (ipilimumab), in the setting of patients with regional, high-risk prostate cancer. As of October 2011, we have treated 4 out of a planned 20 patients on trial. Patients receive one injection of leuprolide acetate (Lupron, Tap Pharmaceuticals) at a dose of 22.5 mg on week 0 and ipilimumab at 10 mg/kg/dose on weeks 1 and 4. Patients then undergo surgery at week 8. Tumor tissues are collected prior to any therapy and then at the time of surgery. Blood is collected throughout the study prior to each therapeutic intervention and after surgery. Immunologic analyses are ongoing on all collected patients’ samples. These data will be compared to those obtained from previously completed trials consisting of a trial whereby patients were treated with ipilimumab monotherapy and a trial whereby patients were treated with hormonal therapy prior to surgery. Our preliminary data indicate that combination therapy impacts T cell responses including a measurable increase in the frequency of T cells expressing the inducible costimulator (ICOS) molecule. In addition, four patients have completed the trial, including surgery, without any serious adverse events related to the 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 4388. doi:1538-7445.AM2012-4388
Abstract 4410: Neutralizing Endosialin antibody, MORAb-004, enhances efficacy of TAXOTERE in a metastatic melanoma model
Authors: Krauthauser Candice , Grasso Luigi , Nicolaides Nicholas , Lin JianMin 
Published: August 2012

Abstract
Endosialin/Tumor Endothelial Marker-1 (TEM1) is a cell surface glycoprotein that is expressed on cells involved in the development of tumor vasculature, primarily pericytes and stromal fibroblasts. Studies have found it to play a key role in tumor growth and neo-vessel formation in numerous cancer types. We are currently evaluating the safety and therapeutic potential of MORAb-004, a humanized monoclonal IgG targeting endosialin/TEM-1, in clinical trials. Because MORAb-004 only recognizes human antigen and has no cross-reactivity with rodent endosialin/TEM-1, we generated a human endosialin/TEM-1 knock-in mouse in order to assess its activity in vivo. Previously, in this transgenic model, we found that MORAb-004 significantly inhibited subcutaneous B16-F10 melanoma progression by ∼70% when administered intravenously for 5 consecutive days. Moreover, using the Lewis Lung Carcinoma model of metastatic disease our results showed that MORAb-004 had a significant inhibitory effect on the number of lung metastases. For these studies, supporting clinical trials for using MORAb-004 in combination with standard of care chemotherapeutics, we developed a B16-F10 melanoma lung colonization model. In this model, the human endosialin/TEM-1 knock-in mice were implanted intravenously with B16F10 cells adapted for in vivo lung colonization. These mice were treated with Docetaxel, MORAb-004, or the combination of the two agents, respectively. A group of the tumor-bearing mice receiving PBS served as control. At the end of the study, the lungs of each mouse were harvested. A ratio of the area of tumor nodules versus total lung surface area is calculated as tumor burden. MORAb-004, at 50 mg/kg three times weekly for a total of 7 i.v. injections reduced tumor burden by 45%. Treatment of Docetaxel, at 3mg/kg twice weekly for a total of 5 i.p. injections, reduced less than 20% of tumor burden in the lungs. When MORAb004 was added to Docetaxel treatment, a significant enhancement of efficacy was observed. The reduction of tumor nodules in the lungs was increased to approximately 70%. A similar trend is seen in combination therapy where MORAb-004 was added to gemcitabine regimen. Our results demonstrate the ability of MORAb-004 to inhibit tumor growth in a murine model. Moreover, when added to the chemotherapeutic regimen, it significantly enhances the therapeutic effect of traditional chemotherapy.
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 4410. doi:1538-7445.AM2012-4410
Abstract 4489: Clinical specimen-based investigatory study of biomarkers for gastric cancer
Authors: Oshima Takashi , Kunisaki Chikara , Hasegawa Shinichi , Ono Hidetaka , Fujii Shinichi , Sato Tsutomu , Yamada Roppei , Yukawa Norio , Rino Yasushi , Masuda Munetaka , Imada Toshio 
Published: August 2012

Abstract
Objectives: We have identified potential biomarkers for gastric cancer using a cDNA bank on the basis of mRNA extracted from frozen specimens of gastric cancer tissue and adjacent normal gastric mucosa. We report currently available results. Methods: The study group comprised 227 patients in whom 5 or more years had elapsed since gastrectomy. The disease stage was IB in 29 patients, II in 66, III in 103, and IV in 29. Among the 139 patients who postoperatively received fluoropyrimidines, 97 with stage II or III disease were given adjuvant chemotherapy with S-1. A total 104 genes were selected on the basis of the results of comprehensive DNA microarray analysis, extraction from serial analysis of gene expression (SAGE) libraries, and preclinical and other studies of potential targets for molecular-targeted therapy. The relative expression levels of these genes in gastric cancer tissue and adjacent normal mucosa from each patient were measured by a quantitative polymerase chain reaction assay using the cDNA bank described above, and the relations between clinicopathological factors and outcomes were examined. Results: In patients who underwent gastrectomy, high expression of matrix metalloproteinase-9 (MMP9), insulin-like growth factor receptor 1 (IGF-R1), and apolipoprotein E (APOE) genes were associated with significantly worse outcomes. In patients with stage II or III disease who received adjuvant chemotherapy with S-1, high expression of IGF-R1, thymidylate synthase (TS), and regenerating IV (Reg IV) genes were associated with significantly worse outcomes. Conclusions: MMP9, IGFR-1, and APOE gene expression levels were suggested to be useful prognostic factors in patients who underwent gastrectomy for gastric cancer. In patients with stage II or III disease who received adjuvant chemotherapy with S-1, IGF-1R, TS, and Reg IV gene expression levels were suggested to be useful prognostic factors.
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 4489. doi:1538-7445.AM2012-4489
Abstract 4621: EMP2 regulates the tumor microenvironment and is a novel therapeutic target for triple negative breast cancer
Authors: Goodglick Lee , Fu Maoyong , Braun Jonathan , Wadehra Madhuri 
Published: August 2012

Abstract
Breast cancer remains the most common malignancy in women, with the aggressive triple negative subtype accounting for nearly half of all breast cancer deaths. In this abstract, we describe a novel tetraspan protein, epithelial membrane protein-2 (EMP2) that is highly expressed in the majority of breast cancer tumors examined compared to healthy mammary epithelium. In particular, high levels of EMP2 were observed in over 70% of triple negative breast cancer cases examined. In tumor cells, EMP2 altered the integrin expression profile as well as promoted endothelial cell migration and tube formation through upregulation of VEGF. We produced a fully human intact IgG1 to test their effect on EMP2 expressing breast cancer cell lines. In vitro treatment with anti-EMP2 IgG1 decreased Src and FAK activation and resulted in cell death. Moreover, cultured supernatant from treated cells reduced endothelial cell migration and capillary-like tube formation. To determine the in vivo efficacy of EMP2 treatment, we first characterized potential toxicity from systemic administration. Anti-EMP2 IgG1 produced no observable toxicity (weight, CBC counts, tissue pathology) when administered at 10mg/kg over 7 weeks. Using similar conditions in preclinical xenograft and syngeneic mouse models, anti-EMP2 IgG1 decreased tumor growth with induction of necrosis. This effect was specific as no difference in tumor size was observed in EMP2 negative (Ramos) cell tumors. As in vitro and in vivo cytotoxicity was observed in both triple negative cell lines as well as cells expressing estrogen and progesterone receptors and/or Her-2/neu, these results present compelling evidence that EMP2 is a novel therapeutic target in triple negative breast cancers as well as other variants.
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 4621. doi:1538-7445.AM2012-4621
Abstract 4662: Shikonin causes cancer cell death by inducing mitochondrial dysfunction
Authors: Wiench Benjamin , Eichhorn Tolga , Efferth Thomas 
Published: August 2012

Abstract
Shikonin, a naturally occurring napthoquinone, has been used in herbal formulations for the treatment of several inflammatory diseases in Traditional Chinese Medicine since decades. In recent studies, shikonin revealed remarkable anticancer activities and thereby is a promising candidate for cancer chemotherapy. However, the underlying cellular mechanisms and targets of shikonin are still unknown. Here, we showed that shikonin indeed exhibits strong cytotoxic effects on a panel of 15 different cancer cell lines also containing multi-drug resistant cells. The strongest effects were obtained on U937 leukemia cells. To better understand the underlying mechanisms, we performed a whole genome expression analysis of these cells after shikonin treatment. Thereby novel molecular key players and genetic networks responsible for the effects of shikonin were identified. Induction of cell cycle arrest, apoptosis and increased levels of reactive oxygen species and DNA damage were revealed as striking cellular effects of shikonin. Furthermore, whole sets of genes responsible for cytoskeletal formation and mitochondrial energy metabolism were deregulated after shikonin treatment. Using cell based assays we showed that shikonin indeed induces G1/S phase cell cycle arrest and caspase 3/7 dependent apoptosis. Furthermore we confirmed the induction of reactive oxygen species and quantified the subsequent DNA damage. In addition shikonin significantly prevents cancer cell migration and cytoskeleton formation by inhibiting the dynamics of the microtubule system. The reason for all this secondary effects was revealed by real-time kinetic uptake experiments based on the intrinsic fluorescence of shikonin. Thereby a rapid cellular uptake and a direct accumulation of the drug in the mitochondria were observed. This caused a breakdown of the mitochondrial membrane potential within the same time range of drug uptake, resulting in a failure of the respiratory chain and the cellular energy production. As the mitochondrial structure and metabolism differs strongly between cancer and normal cells, targeting of mitochondria is a very recent and promising approach in cancer therapy. Our results showed that mitochondria are the primary targets of shikonin in cancer cells and thus we believe that shikonin has the potential in future clinical application.
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 4662. doi:1538-7445.AM2012-4662
Abstract 492: Identification of a novel complex MUC1/CIN85 involved in invasion and migration of breast cancer cells
Authors: Cascio Sandra , Finn Olivera 
Published: August 2012

Abstract
MUC1 is a transmembrane glycoprotein abnormally expressed in human adenocarcinoma. The extracellular domain of MUC1 contains a variable number of tandem repeats 20aa in length (VNTR region) which is fully glycosylated in normal epithelia and underglycosylated in tumor cells. We recently demonstrated that tumor form of MUC1 increases the accessibility of the VNTR peptide backbone to other proteins thus affecting protein-protein interactions and intracellular signaling. By using MALDI-TOF, we identified CIN85 as one of the proteins that bind the extracellular domain of MUC1. CIN85 is an adaptor protein involved in multiple cellular processes including signal transduction, vesicle-mediated transport, cytoskeleton remodelling, invasion and migration of cancer cells. Structurally, CIN85 contains three SH3 domains, a proline-rich region and a C-terminal coiled-coil region. The SH3 domain of CIN85 recognizes a specific sequence PXXAP that corresponds to the PDTRP sequence in the 20 amino acid tandem repeat in the MUC1 VNTR. Co-immunoprecipitation assay and confocal immunofluorescence confirmed that MUC1 and CIN85 co-localize in MUC1-transfected RMA (mouse T cell lymphoma) and IG10 (mouse ovarian carcinoma) cells and in human breast cancer cells MDA-MB-231 and MDA-MB-435 that express endogenous MUC1 and CIN85. Subcellular protein fractionation revealed that CIN85 and MUC1 co-localize mainly at plasma membrane but also in the cytosol. To better understand the function of CIN85/ MUC1 complex we analyzed their expression by immunohistochemistry and confocal immunofluorescence in human tissue microarray (TMA) composed of 31 breast cancer samples and 5 adjacent normal tissue. Hypoglycosylated MUC1 and CIN85 are over-expressed and co-localize in early and advanced clinical stage of breast cancer. Interestingly, CIN85 and MUC1 were localized to invadopodia-like structures suggesting a potential role in cancer cell invasion. siRNA-mediated silencing of CIN85 and/or MUC1 revealed that MUC1 enhances CIN85-dependent cell invasion and migration of breast cancer cells. In contrast, ectopic expression of MUC1 reduces the motility induced by CIN85. In conclusion, our finding suggest that the novel complex CIN85/MUC1 play a critical role in invadopodia formation and have control on invasive and metastatic potential of breast cancer cells.
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 492. doi:1538-7445.AM2012-492
Abstract 4945: Targeting ErbB3-addicted cancers across the HER2 spectrum
Authors: Onsum Matthew , Yarar Defne , Paragas Violette , Zhang Bo , Nguyen Stephanie , Schoeberl Birgit , McDonagh Charlotte , MacBeath Gavin , Nielsen Ulrik 
Published: August 2012

Abstract
ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in EGFR-, HER2-, and MET-addicted cancers, and ligand-driven activation of ErbB3 is a prominent method by which cancers become resistant to targeted inhibitors of ErbB signaling, as well as anti-hormonal and chemotherapeutic agents. With the goals of inhibiting survival signaling in cancer cells, delaying the onset of resistance to standard-of-care therapies, and re-sensitizing cancer cells to prior therapies, we developed an anti-ErbB3 monoclonal antibody, MM-121, that effectively blocks ligand-dependent activation of ErbB3 and induces internalization and degradation of the receptor. The activity of single-agent MM-121 was examined in xenograft models and a machine-learning algorithm was developed that accurately predicts which preclinical models of cancer will respond to MM-121 based on five protein-based biomarkers. By simulating ErbB3 inhibition using a computational model of ErbB signaling, we predicted that a bispecific molecule that docks onto HER2 and subsequently binds to ErbB3 would effectively block ErbB3-driven signaling in HER2-amplified tumors. We therefore developed a bispecific antibody comprising two human scFv antibodies linked by a modified form of human serum albumin. The resulting molecule, MM-111, forms a trimeric complex with HER2 and ErbB3, effectively inhibiting ErbB3 signaling and demonstrating antitumor activity in preclinical models that are dependent on HER2 overexpression. Both MM-121 and MM-111 are now in early stages of clinical development.
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 4945. doi:1538-7445.AM2012-4945