bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5339: Inhibition of breast cancer cell proliferation and unique epitope recognition by EpCAM-specific human monoclonal antibody adecatumumab
Authors: Münz Markus , Murr Alexander , Kvesic Majk , Rau Doris , Mangold Susanne , Pflanz Stefan , Lumsden John , Volkland Jörg , Fagerberg Jan , Riethmüller Gert , Rüttinger Dominik , Kufer Peter , Baeuerle Patrick A. , Raum Tobias 
Published: February 2011

Abstract
Epithelial cell adhesion molecule (EpCAM; CD326) is frequently and highly expressed on a wide variety of human carcinomas. The emerging role of EpCAM as a signalling receptor and activator of the wnt pathway, and its expression on tumor-initiating cells, further add to its attractiveness as target for immunotherapy of cancer.
Thus far, five conventional monoclonal IgG antibodies have been tested in cancer patients for safety and anti-tumor activity. These are murine IgG2a edrecolomab and its murine/human chimeric IgG1 antibody version, and humanized, human-engineered and fully human IgG1 antibodies 3622W94, ING-1, and adecatumumab (MT201), respectively. We have recombinantly produced all antibodies but murine edrecolomab in Chinese hamster ovary cells and investigated all five antibodies for their binding affinity, EpCAM epitope recognition, antibody-dependent cellular (ADCC) and complement-dependent cytotoxicity (CDC), and inhibition of breast cancer cell proliferation.
ING-1 and 3622W94 bound to recombinant EpCAM with much higher affinity than adecatumumab and edrecolomab, which was largely determined by slower off-rates. Edrecolomab, ING-1, and 3622W94 all recognized epitopes in the exon 2-encoded, N-terminal domain of EpCAM, while adecatumumab recognized a more membrane proximal epitope encoded by exon 5. All antibodies induced lysis of EpCAM-expressing human cancer cell lines by both ADCC and CDC with potencies that correlated with their binding affinities for recombinant EpCAM. The chimeric version of edrecolomab with a human Fcγ1 domain was much more potent in ADCC with human effector cells than the murine IgG2a version of the antibody. Of the five antibodies, only adecatumumab showed a significant inhibition of MCF7 breast cancer cell proliferation in the absence of complement and immune cells.
A moderate binding affinity and recognition of a distinct domain of EpCAM may best explain why adecatumumab showed a larger therapeutic window in cancer patients than the two high-affinity IgG1 antibodies ING-1 and 3622W94, both of which caused acute pancreatitis. Adecatumumab emerges as an anti-EpCAM antibody with unique characteristics and biological activity.
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 5339.
Abstract 534: Invasive human prostate cancer and integrin cleavage: Potential role of uPAR contributed by macrophages
Authors: Cress Anne E. , Sandoval Cynthia P. , Gard Jaime M.C. , Pawar Sangita C. , Sroka Isis C. , Abril Edward R. , Nagle Raymond B. 
Published: February 2011

Abstract
Laminin binding integrins are major determinants of cancer cell migration, invasion and metastasis. Our previous work showed that integrin α6β1 is cleaved on the tumor cell surface by urokinase-type plasminogen activator (uPA), producing a structural variant, α6pβ1. Urokinase plasminogen activator receptor (uPAR) is a regulatory determinant for α6 integrin cleavage since uPAR interacts with integrin and activates uPA. Previous work by others has shown that both human tumor tissue and tumor infiltrating macrophages express uPAR . In the present study, we investigated the potential of uPAR to co-localize with α6β1 integrin in human prostate cancer cells (DU-145) and whether uPAR expressed on the macrophage cell surface mediates integrin α6β1 cleavage. The results indicated uPAR and integrin α6β1 were co-expressed in invasive human prostate carcinoma. Co-localization of uPAR and integrin α6β1 occurred in some tumor cells in vitro, consistent with reports indicating a variable distribution in human tumors. The culture of macrophages with tumor cells resulted in an increased cleavage of integrin α6 as detected by immuno precipitation followed by western blot analysis. Taken together, these data suggest that integrin α6 cleavage is directed by the receptor for uPA, uPAR, contributed either by the tumor cell itself or tumor cell contact with macrophages. (Supported in part by CA 56666, CA23752, T34 GM008718 and the TACMASS core service of the Arizona Cancer Center)
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 534.
Abstract 5340: Impact of binding epitope and antigen size on the cytotoxic activity of MCSP-specific BiTE antibodies for treatment of melanoma
Authors: Bluemel Claudia , Hausmann Susanne , Fluhr Petra , Sriskandaradja Mirna , Baeuerle Patrick , Kufer Peter 
Published: February 2011

Abstract
Melanoma chondroitin sulphate proteoglycan (MCSP; also called CSPG4, HMW-MAA, MSK16, MCSPG, MEL-CSPG, NG2, or gp240) is a surface antigen frequently expressed on human melanoma cells, which is involved in cell adhesion, invasion and spreading, angiogenesis, complement inhibition, and signalling. MCSP has therefore been frequently selected as target antigen for development of antibody- and vaccine-based therapeutic approaches. We have here used a large panel of monoclonal antibodies against human MCSP for generation of single-chain MCSP/CD3-bispecific antibodies of the BiTE (for bispecific T cell engager) class.
BiTE antibodies can transiently connect the T cell receptor subunit CD3 on T cells with a surface antigen on target cells leading to a highly efficient redirected lysis of target cells. This involves cytolytic synapse formation and delivery of perforin and granzymes. BiTE-engaged T cells are capable of serial target cell lysis, and are not affected by immune escape mechanisms interfering with peptide antigen processing and presentation, or clonal T cell differentiation.
Despite similar binding affinity to MCSP, respective BiTE antibodies greatly differed in their potency of redirected lysis of CHO target cells stably transfected with full-length human MCSP, MCSP deletion mutants or fusion proteins. BiTE antibodies binding to the membrane proximal domain D3 of MCSP were more potent than those binding to more distal domains. This epitope distance effect was corroborated with EpCAM/CD3-bispecific BiTE antibody MT110 by using MCSP/EpCAM fusion proteins as surface target antigens. Generally, CHO cells expressing small surface antigens were better lysed than those with large antigens, indicating that antigen size is also an important factor for BiTE potency. This is in line with the observation that target cell lysis by membrane proximally-binding BiTE antibodies improved upon omission of more distal MCSP domains.
The present study for the first time relates the size of surface antigens and positioning of binding domains to BiTE potency of target cell lysis via redirected cytotoxic T cells. In case of the MCSP antigen, this provides the basis for selection of a maximally potent BiTE antibody candidate for development of a novel melanoma 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 5340.
Abstract 5343: Development of novel anti-CD27 human antibodies with therapeutic potential
Authors: He Li-Zhen , Vitale Laura , O'Neill Tom , Crocker Andrea , Widger Jenifer , Storey Jim , Weidlick Jeff , Zhang Yan , Marsh Henry , Keler Tibor 
Published: February 2011

Abstract
The costimulatory molecule CD27 is a member of the tumor necrosis factor (TNF) receptor superfamily, and is constitutively expressed on the majority of mature T cells, memory B cells, and a portion of NK cells. The interaction of CD27 with its ligand CD70 plays key roles in T cell activation, proliferation, survival, maturation of effector capacity and memory; in clonal B cell expansion and germinal center formation; and in NK cell cytolytic activity. Previous reports have shown that antigen-specific CD8+ cytolytic T cell immunity can be augmented through CD27 activation in mice. Of particular relevance is the work by M. J. Glennie et al. demonstrating that an agonistic anti-mouse CD27 mAb given without a DC maturation signal has potent anti-tumor activity through boosting of T cell immunity. To explore the therapeutic potential of this target, a panel of fully human antibodies recognizing human CD27 was generated using human Ig transgenic mice immunized with recombinant human CD27. These human anti-CD27 mAbs showed specific and high affinity binding to CD27 and CD27-expressing lymphoma cells. We generated transgenic mice that express human CD27 (hCD27-Tg) to evaluate the anti-human CD27 mAbs in vivo. The expression profile and regulation of the human CD27 transgene driven by its own promoter were similar to that observed with endogenous mouse CD27. Administration of anti-human CD27 mAbs in combination with ovalbumin greatly enhanced antigen specific T cell responses compared to ovalbumin plus human IgG1 isotype control in the hCD27-Tg mice. The SIINFEKL-specific CD8+ T cell proliferation and activation were detected by pentamer staining and IFNγ ELISPOT analysis. These data support the further development of these novel human anti-CD27 antibodies and we are currently investigating their therapeutic activity using various in vivo tumor models.
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 5343.
Abstract 5347: Disruption of PDZ protein-protein interactions inhibits Tax transformation and HTLV-1 infection capacities
Authors: Twizere Jean-Claude , Dewulf Jean-François , Legros Sebastien , Boxus Mathieu , Zimmermann Pascale , Fujii Naoaki , Kettmann Richard 
Published: February 2011

Abstract
Approximately 15 to 25 million people worldwide are infected with human T-cell leukaemia virus type 1 (HTLV-1) or type 2 (HTLV-2). One of the viral regulatory proteins, Tax, is critical for viral transcription and replication and has been clearly implicated in T-lymphocyte transformation in vitro and oncogenesis in vivo. Elucidation of the metabolic processes involved in Tax activity is thus of prime importance for understanding the pathogenesis induce by HTLV.
Interactions between Tax and a selected group of PDZ containing proteins are associated with the transforming activities of Tax1 as well as persistent HTLV-1 infection. We demonstrate that the PDZ-containing protein syntenin-1 and −2, known to interact with Heparan sulfate proteoglycan receptor syndecan-1 and to connect cytoskeletal proteins, interact with HTLV-1 Tax and with the HTLV-1 receptor GLUT-1 but not with HTLV-2 Tax. Both PDZ1 and 2 domains of syntenins are required for Tax binding. We also show that syntenin-2 co-localizes with Tax in nuclear speckles. Furthermore, we demonstrate that an antagonist for PDZ protein- protein interaction suppresses Tax-induced transformation and prevents T cell infection by HTLV-1. Thus, disruption of PDZ protein-protein interaction may provide new therapeutic opportunities for HTLV-1 induced diseases.
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 5347.
Abstract 5349: Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type-I IFN production
Authors: Alain Tommy , Lun XueQing , Martineau Yvan , Sean Polen , Pulendran Bali , Petroulakis Emmanuel , Zemp Franz , Lemay Chantal G. , Roy Dominic , Bell John C. , Thomas George , Kozma Sara C. , Forsyth Peter A. , Costa-Mattioli Mauro , Sonenberg Nahum 
Published: February 2011

Abstract
Oncolytic viruses constitute a promising therapy against malignant gliomas (MGs). However, virus-induced type-I interferon (IFN) greatly limits its clinical application. The kinase mTOR (mammalian target of rapamycin) stimulates type-I IFN production via phosphorylation of its effector proteins, 4E-BPs and S6Ks. Here we show that both mouse embryonic fibroblasts (MEFs) and mice lacking S6K1 and S6K2, are susceptible to Vesicular Stomatitis Virus (VSV) infection due to an impaired type-I interferon response. We used this knowledge to employ a pharmacoviral approach to treat MGs. The highly specific inhibitor of mTOR, rapamycin, in combination with an IFN-sensitive VSV-mutant strain (VSVΔM51), dramatically increased the survival of immunocompetent rats bearing MGs. More importantly, VSVΔM51 selectively killed tumor, but not normal cells, in MG-bearing rats, which were treated with rapamycin. These results demonstrate that reducing type-I IFNs through inhibition of mTOR is an effective strategy to augment the therapeutic activity of VSVΔM51.
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 5349.
Abstract 535: Development of small-molecule hepsin inhibitors
Authors: Tang Xi , Vasioukhin Valeri 
Published: February 2011

Abstract
Hepsin is a cell-surface serine protease prominently overexpressed in the majority of human prostate tumors. We and others have previously demonstrated that hepsin promotes prostate cancer progression and metastasis in vivo. These findings identified hepsin as a very attractive therapeutic target in prostate cancer. To develop small molecule hepsin inhibitors, we have previously performed in vitro screenings of libraries of small drug-like molecules. These efforts resulted in identification of several lead compounds inhibiting hepsin proteolytic activity. We now identified and performed additional characterization of the derivatives of most potent hepsin lead inhibitors. We also developed a novel cell-based hepsin activity assay, which utilizes expressed on the cell-surface human hepsin and C-terminally HA-tagged pro-HGF, as its specific cleavage substrate. Overall, this study identified specific and potent small-molecule hepsin inhibitors that may be potentially used in the future as therapeutic agents to attenuate prostate cancer progression in the ‘watchful waiting’ cohort of prostate cancer patients.
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 535.
Abstract 5350: Does hepatitis C virus core protein promote liver cancer through androgen-receptor mediated signaling?
Authors: Ray Ratna B. , Steele Robert 
Published: February 2011

Abstract
Hepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinoma (HCC), which is one of the male dominant diseases. Androgen signaling in liver may be related to carcinogenesis. In this study, we investigated whether HCV proteins cross-talk with androgen receptor (AR) signaling pathway for promotion of liver cancer. We have demonstrated that HCV core protein alone or in context with other HCV proteins enhances AR-mediated transcriptional activity, and further augments in the presence of androgen. Subsequent study suggested that HCV core protein activates STAT3, which in turn enhances AR-mediated transcription. This activity was blocked by a pharmacological inhibitor of Jak/Stat signaling pathway, AG490. Vascular endothelial growth factor (VEGF) is a target gene of androgen receptor in liver, and plays an important role in angiogenesis. Therefore, we examined whether HCV infection modulates VEGF expression in hepatocytes. Our results demonstrated that HCV enhances VEGF expression and facilitates tube formation in human coronary microvascular endothelial cells in the presence of AR. We are in the process of evaluating the AR targets in the hepatocytes following HCV infection.
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 5350.
Abstract 5353: Identification of a subset of AIDS related lymphoma (ARL) containing HIV infected macrophages that is immunophenotypically distinct from EBV+ ARL
Authors: Huysentruyt Leanne C. , Bracci Paige M. , McGrath Michael S. 
Published: February 2011

Abstract
The risk of developing non-Hodgkin lymphoma is 60X greater in the HIV-infected population when compared to non-infected individuals despite the initiation of highly active antiretroviral therapy (HAART). The primary difference between lymphoma in non-infected individuals and those with AIDS related lymphoma (ARL) is that ARL is high-grade and metastatic. Since the introduction of HAART the incidence of ARL has decreased but not the same extent as other AIDS-related malignancies and there has been little change amongst the CD4 strata. Therefore, with the increase in life expectancy afforded by HAART, the overall number of ARL cases is expected to rise in the future. Preliminary reports have suggested that some ARLs contain HIV-infected macrophages that may contribute to ARL pathogenesis. A recent study evaluating HIV sequence evolution in the contest of metastatic ARL found lymphoma specific HIV compartmentalized within sites of lymphoma that was distinct from HIV present in non-lymphoma sites (Salemi et al, PLOSone Dec 3, 2009). These data suggested the existence of a lymphoma specific form of HIV evolving within individuals who develop ARL. The goal of this research was to determine the incidence of HIV infected lymphomas in the pre and post-HAART eras and if HIV-positive lymphomas have a specific immunophenotype. A tissue microarray containing ∼150 of ARLs (from 1982-2007) was obtained through the AIDS and Cancer Specimen Resource (ACSR) and was used for HIV p24 and macrophage CD68 immunohistochemistry. Double staining techniques confirmed that p24 expression was localized to tumor associated macrophages (TAM). There was a highly significant (p&lt;0.001) increase in the frequency of p24+ ARL cases post-HAART (after 1996; 49%) as compared to pre-HAART (before 1996; 26%). Using antigen expression data CD20, CD3, CD10, BCL6, BCL2, MUM1, Ki67, blimp, p53 and EBV, provided by the ACSR, we were able to determine that p24+ ARLs were generally of B cell origin but did not have a specific immunophenotype. In contrast, EBV+ ARLs were more likely to express MUM1 or blimp and less likely to express CD29, CD10 or BCL6. EBV status was not associated with a pre/post HAART diagnosis (44 vs. 40%). However, a subset of EBV-/p24+ tumors was identified. In the pre-HAART era, 13% of the tumors were EBV-/p24+ compared to 30% in the post-HAART era suggesting, that the incidence of this tumor type is increasing (p&lt;0.05). These data describe for the first time the existence of potentially tumor specific HIV in up to 1/3 of all post HAART ARLs, a class of tumor that is immunophenotypically distinct from EBV+ ARLs.
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 5353.
Abstract 5355: HPV-16 infection alters cellular microRNA expression in squamous cell carcinoma of the head and neck (SCCHN)
Authors: Wald Abigail I. , Wells Susanne I. , Ferris Robert L. , Khan Saleem A. 
Published: February 2011

Abstract
Up to 30% of squamous cell carcinoma of the head and neck (SCCHN) contain human papillomavirus (HPV) type 16 DNA. The presence of HPV DNA in these cancers is associated with a better disease outcome, and an understanding of the differences between HPV-positive and HPV-negative SCCHN has significant clinical importance. MicroRNAs (miRNAs) are approximately 22 nucleotides long, single-stranded RNAs that regulate gene expression at a posttranscriptional level. We hypothesize that HPV infection alters cellular miRNA expression which leads to changes in the expression of their target genes. We investigated the expression of cellular miRNAs using microarrays and quantitative Real Time RT-PCR. We found that 3 miRNAs were upregulated and 8 miRNAs were downregulated in HPV-positive SCCHN cell lines compared to HPV-negative SCCHN cell lines. MiR-363, miR-497, and miR-33 were upregulated, while miR-155, miR-181a, miR-181b, miR-29a, miR-218, miR-222, miR-221, and miR-142-5p were downregulated. We also analyzed miRNA expression in HPV-positive and HPV-negative SCCHN tumors and normal oral tissues. There were 17 up- and 1 downregulated miRNAs in SCCHN tumors compared to normal oral mucosa. These included several miRNAs that are known to be altered in many cancers, such as miR-21, miR-17-5p, and miR-145. MiR-363, the most upregulated miRNA in the HPV-positive cell lines, was also upregulated in HPV-positive tumors compared to HPV-negative tumors. Preliminary data using cell lines expressing HPV-16 E6 and/or E7 oncogene has shown that miR-363 expression increases with the expression of E6. These results suggest a possible role of HPV in altering the expression of specific cellular miRNAs, including miR-363. Studies are currently in progress to identify miR-363 gene targets by utilizing gene expression data and spectral counting proteomics. MiRNAs altered by the presence of HPV may identify specific pathways targeted by the virus, and may provide novel therapeutic targets for HPV-associated SCCHN.
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 5355.