bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3861: Fusion toxin BLyS-gelonin inhibits growth of B-NHL cell lines in vitro and in vivo
Authors: Luster Troy A. , Mukherjee Ipsita , Carrell Jeffrey A. , Cho Yun Hee , Gill Jeffrey , Garcia Andy , Ward Christopher , Ullrich Stephen , Migone Thi-Sau , Humphreys Robin 
Published: August 2012

Abstract
B lymphocyte stimulator (BLyS) is a member of the TNF superfamily of cytokines. BLyS is expressed by cells of myeloid origin and is one of many soluble factors that regulate human B-cell activation. The biological activity of BLyS is mediated by three cell surface receptors: B-cell-activating factor-receptor (BAFF-R/BR3), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA). These receptors are expressed by normal and malignant B-cells at various stages of development. To target malignant B cells expressing BLyS receptors, the recombinant plant-derived toxin gelonin was fused to the N-terminus of BLyS to generate the fusion toxin BLyS-gel. Gelonin is an N-glycosidase that removes a critical adenine from eukaryotic 28S rRNA, disrupting ribosome function and inhibiting protein synthesis. Importantly, gelonin is not toxic to cells unless coupled with a targeting moiety that can enter the cell. BLyS-gel was used to treat a panel of nearly 50 malignant non-Hodgkin lymphoma (NHL) cell lines expressing BLyS receptors. NHL subtypes mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL) and B cell precursor-acute lymphocytic leukemia (BCP-ALL) were preferentially sensitive to BLyS-gel mediated cytotoxicity, with EC50 values in the low picomolar range. BLyS-gel cytotoxicity was mediated primarily by BR3 and TACI in sensitive cell lines; however, cell surface expression of these BLyS receptors did not necessarily confer sensitivity to BLyS-gel. The internalization of BLyS-gel was confirmed in both sensitive and resistant cell lines, indicating resistance was not due to a lack of internalization. As expected, BLyS-gel treatment inhibited protein synthesis in sensitive, but not resistant cell lines. In most cell lines, cell death seemed to be mediated by the “ribotoxic stress response.” This response involves activation of p38 MAPK and JNK/SAPK, and BLyS-gel mediated cytotoxicity was inhibited by the p38/JNK inhibitor SB203580. Finally, BLyS-gel treatment significantly prolonged survival in three distinct disseminated xenograft models (BCP-ALL, DLBCL & MCL) in SCID mice, and BLyS-gel was shown to specifically localize to sites of disease. Together, these findings suggest BLyS has potential as a targeting ligand for the therapeutic delivery of toxins and/or drugs directly to malignant B 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 3861. doi:1538-7445.AM2012-3861
Abstract 3862: The potential role of CD44 in liver regeneration
Authors: Lam CT , Yang ZF , Ng MN , Wan T , Lau J , Ho DW , Fan ST , Poon RT 
Published: August 2012

Abstract
Background and Aim: Liver regeneration occurs after liver damage by ischaemia, hepatitis, or in hepatocellular carcinoma (HCC) patients receiving hepatic resection or liver transplantation. Understanding the molecular bases of this process will provide novel therapeutic approaches for patients with various liver diseases. Previous studies suggested the linkage between CD44, a multifunctional cell surface receptor, and liver regeneration. The detailed role of this receptor in liver regeneration, however, remained unclear. The present study aimed at elucidating the role of CD44 in liver regeneration. Materials and Methods: A mouse model of liver regeneration induced by partial hepatectomy (PH) was employed. Serum and liver tissues were collected at different time points after PH. ELISA was performed to measure hyaluronic acid (ligand for CD44) level in serum. Flow cytometry was done to characterize liver cell populations after PH. Liver regeneration was quantified by measurement of liver mass and by immunohistochemical staining for PCNA (a proliferation marker). Quantitative PCR was performed to compare gene expression pattern of 46 genes between CD45− CD44+ cells and their CD44− counterparts. Results: Firstly, serum hyaluronic acid level was elevated at the early stage of liver regeneration. Secondly, by flow cytometry, an increase in CD45− CD44+ cell population was found. Thirdly, immunohistochemical analysis revealed active hepatocyte proliferation during this period. Interestingly, the hepatectomy-induced cell proliferation was suppressed after treating mice with anti-CD44 antibody, suggesting a functional role of CD44 in liver regeneration. Lastly, dysregulation of genes involving in cell proliferation, angiogenesis, and metabolism of hyaluronic acid was disclosed in CD45− CD44+ cells. Conclusion: The present study indicated that CD44-mediated pathways are required for liver regeneration, which may have therapeutic implications in treating liver diseases, including 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 3862. doi:1538-7445.AM2012-3862
Abstract 3865: The rGel/BLyS fusion toxin enhances the therapeutic effects of bortezomib in in vitro and in vivo models of mantle cell lymphoma.
Authors: Lyu Mi-Ae , Pham Lan V. , Sung Bokyung , Tamayo Archito T. , Ahn Kwang Seok , Cheung Lawrence H. , Marks John W. , Ford Richard J. , Aggarwal Bharat B. , Rosenblum Michael G. 
Published: August 2012

Abstract
Mantle cell lymphoma (MCL) is an incurable, aggressive histo-type of B-cell non-Hodgkin lymphoma associated with both high relapse rates and relatively short survival. MCL is a therapeutic challenge and presents an opportunity for the application of novel, targeted agents. Because MCL over-expresses receptors for B lymphocyte stimulator (BLyS) and displays constitutively active NF-κB, agents targeting these pathways may be of therapeutic relevance in this disease. To explore the potential clinical use of the rGel/BLyS fusion toxin in combination with bortezomib in MCL, we evaluated this fusion toxin for its ability to inhibit MCL growth in a severe combined immunodeficiency (SCID) xenograft model. Compared with PBS-treated mice, mice treated with rGel/BLyS showed both prolonged median (84 d vs. 125 d) and overall survival (40%) (p=0.0027). Compared with bortezomib alone-treated mice, mice treated with rGel/BLyS plus bortezomib showed significant median (91d vs. 158d) and overall survival (20%) (p=0.0127). Histopathologic analysis of peritoneal intestinal mesentery from MCL-SCID mice showed no demonstrable microscopic lymphomatous involvement at 225 days after treatment with rGel/BLyS. Followup in vitro mechanistic studies demonstrated that the rGel/BLyS plus bortezomib combination resulted in an additive or a synergistic growth inhibition, reduction of NF-κB DNA-binding activity, inhibition of cyclin D1, Bcl-xL, p-Akt, and Akt and up-regulation of Bax. We additionally found that combination treatment caused induction of apoptosis associated with caspase-9, caspase-3 activation and PARP cleavage. rGel/BLyS is an effective therapeutic agent for both primary and savage treatment of aggressive MCL and may be an excellent candidate for clinical development. This research was conducted, in part, by the Clayton Foundation for Research and by a Translational Research Award (LLS 6234-07) from the Leukemia and Lymphoma Society.
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 3865. doi:1538-7445.AM2012-3865
Abstract 3869: Proteomics highlights which G-protein coupled receptors are candidates for ADC development
Authors: Kast Juergen , Boyd Robert , Ackroyd James , Allen Jason , Anderson Amanda , Barnes Martin , Bozhenok Ludmila , Dusanjh Palminder , Hudson Lindsey , Yu Xiaohong , Aud Dee , Awdew Rahel , Bisht Arnima , Pandya Deepal , Trang Michael , Terrett Jonathan , Rohlff Christian 
Published: August 2012

Abstract
Antibody-drug conjugates (ADCs) are a recent and exciting development for targeted therapy of cancer. Their efficacy is governed by ADC-intrinsic characteristics such as avidity, drug load and linker chemistry, and mechanisms of activation and action, which can be controlled or clarified in the early stages of ADC development. In contrast, the properties that define a promising ADC target are still somewhat unclear. OGAP is a unique proteomic database that integrates information at the tissue, disease and protein isoform level across diseases, indications, and normal tissues to clarify protein expression levels and profiles. Specifically, it currently holds information on ∼2,000,000 human protein peptide sequences, ∼16,000 human proteins sequenced, ∼7,000 cancer membrane proteins, ∼50 tissues/organs, and ∼60 diseases. Building on OGAP and a proprietary sample preparation and processing workflow that relies on state-of-the-art high-throughput mass spectrometry and data processing to provide quantitative information on over 4,000 membrane-enriched proteins from ∼ 15,000 unique peptide sequences per analysis, we have established a novel predictive tool to establish each protein's potential to serve as a target for ADC development. The tool considers proteomic and target-specific information on antigenicity, structure, function, expression level, regulation, and tissue distribution in order to highlight the most suitable candidates for ADC development. We will demonstrate the utility of this process for the protein family of G-protein coupled receptors (GPCRs), which according to a recent bioinformatics prediction encompasses 899 distinct members in the human genome. These cell surface receptors are the target of more than one third of conventional drugs, yet their potential for ADCs is largely unexplored. Here we show that proteomics in the context of the OGAP database can highlight which of this large family of receptors have the potential to become true ADC targets.
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 3869. doi:1538-7445.AM2012-3869
Abstract 387: PEDF binds to IL- 10 receptor in the absence of IL-10 and inhibits melanoma tumor growth
Authors: Khan Aslam A. 
Published: August 2012

Abstract
Macrophages exist within the tumor microenvironment and play an important role in influencing tumor cell growth, angiogenesis and cancer progression. The interaction between macrophages, tumor cells, and endothelial cells occurs largely through cytokine secretion and detection by tumor associated macrophages (TAM). In this study, we investigate the role of interleukin-10 (IL-10) and pigment epithelial derived factor (PEDF) in the macrophage-tumor interaction. In an explant model of melanoma, tumor growth was significantly reduced in IL-10 knockout mice. Media from IL-10 deficient macrophages significantly inhibited tumor cell proliferation when compared to media from wild-type macrophages. Interestingly, expression of the anti-tumor and anti-angiogenic cytokine PEDF was increased in IL-10 knockout macrophages. Media of IL-10 KO macrophages treated with recombinant IL-10 (rIL-10) and anti-PEDF failed to inhibit tumor cell proliferation. Neutralization of PEDF in IL-10 KO mice restored tumor growth in these mice. To further explore the molecular mechanisms of the interaction between PEDF, IL-10 and IL-10 receptor, IL-10 receptor binding of PEDF was evaluated in presence or absence of rIL-10. PEDF binds to IL-10 receptor only in the absence of competing rIL-10. Taken together these studies show a novel interaction between PEDF and the IL-10 receptor and suggest that the anti-tumor activity of PEDF can be significantly enhanced by reducing IL-10 levels.
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 387. doi:1538-7445.AM2012-387
Abstract 3870: Construction and characterization of completely human serine protease therapeutics targeting Her2/neu
Authors: Cao Yu , Mohamedali Khalid A. , Chueng Lawrence H. , Hittelman Walter N. , Rosenblum Michael G. 
Published: August 2012

Abstract
The serine protease granzyme B (GrB) is a powerful enzymatic inducer of apoptosis via a multi-modal intracellular mechanism including direct activation of the caspase cascade, damaging mitochondria resulting in the release of cytochrome C, and damaging nuclear matrix. We developed a novel recombinant immunotoxin linking GrB to a humanized Herceptin-derived scFv (4D5) specific for the Her2/neu cell-surface domain. The GrB/4D5 fusion constructs were efficiently expressed in HEK 293T mammalian cells as active glycosylated molecules and purified by immobilized cobalt affinity chromatography. In vitro studies demonstrated that GrB/4D5 retained the affinity and specificity of the original Herceptin antibody with a Kd of 0.24nM, as well as the biological activity of GrB (BAADT assay, enzymatic activity of 2.08×105U/µM, vs 1.39×105U/µM for free GrB). Target cell-specific activity was observed with IC50 of 10 to 50nM against a panel of Her2/neu positive tumor cells. In addition, the rapid induction of apoptosis in cells was confirmed by Annexin V staining and detection of activated caspase-3 in the cytosol. GrB/4D5 was active against BT474 M1 parental cells as well as Herceptin-resistant cells, despite the fact that these cells were more than 150 fold resistant to Herceptin. Addition of EGF or NRG-1 had no inhibitory effect on the cytotoxicity of the fusion construct against BT474 M1 cells. This is the first report of GrB-based immunotoxins having the potential to overcome Herceptin resistance arising in breast tumor cells. Further in vitro characterization against Her2/neu positive cancer cells expressing MDR or MRP-related proteins and in vivo xenograft model studies are ongoing. Research conducted, in part, by the Clayton Foundation for Research.
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 3870. doi:1538-7445.AM2012-3870
Abstract 3874: A novel human fusion protein composed of the serine protease Granzyme B and VEGF121 to target the vasculature of solid tumors
Authors: Mohamedali Khalid A. , Cheung Lawrence H. , Cao Yu , Rosenblum Michael G. 
Published: August 2012

Abstract
Targeting solid tumors and their metastases continue to be viewed as an essential aspect of therapeutic success to achieve long-term tumor control. Targeted therapy is a promising approach in this regard and the utilization of human proteins assures the potential for long-term therapy without immunological restrictions. VEGF121 is a naturally-occurring splice variant that binds to both VEGFR-1 and VEGFR-2 receptors over-expressed on the endothelium of tumor vasculature but not normal vasculature. The serine protease granzyme B (GrB) is capable of inducing intense cellular apoptosis through both caspase-dependent and caspase-independent multiple-cascade mechanisms. We expressed pro-GrB/VEGF121 in HEK293T cells and harvested the fusion protein under serum-free conditions. The purified protein expressed as a homodimer and Western blotting confirmed incorporation of both VEGF121 and GrB components into the construct. Comparison of GrB/VEGF121 with its expected molecular weight by SDS-PAGE suggests minimal (1-2 kDa) glycosylation. The enzymatic activity of GrB in GrB/VEGF121 was comparable to that of human GrB. The cytotoxicity of GrB/VEGF121 confirmed specific targeting and internalization into PAE/hVEGFR-2 (IC50 ∼ 10 nM), but not PAE/hVEGFR-1 cells (IC50 &gt; 300 nM). GrB/VEGF121 induced apoptosis in PAE/VEGFR-2, but not PAE/VEGFR-1 cells, as determined by Annexin V staining. The targeting efficacy of GrB/VEGF121 against a panel of cells expressing a range of VEGFR receptor levels is under study. Studies investigating GrB/VEGF121 signaling events and in vivo efficacy against various tumor models are currently ongoing and will be presented. Research conducted, in part, by the Clayton Foundation for Research.
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 3874. doi:1538-7445.AM2012-3874
Abstract 3876: Role of Stat3 transcriptional activation in a preclinical mouse model of prostate cancer and potential as a therapeutic target
Authors: De Velasco Marco A. , Tanaka Motoyoshi , Fujimoto-Ouchi Kaori , Moriya Yoichiro , Kura Yurie , Kobayashi Yasuki , Yamamoto Yutaka , Hatanaka Yuji , Kato Hiroyuki , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2012

Abstract
The transcription factor, Stat3, has been implicated in the growth and progression of several cancer types including lung skin, liver, ovarian, kidney, colon cancer and prostate. Stat3 has also been shown to induce the metastatic behavior of prostate cancer cells in vitro and in vivo. Activation of Stat3 occurs by the binding of various cytokines to its receptors leading to the activation of the JAK/Stat3 signaling pathway. Of these cytokines, interleukin-6 (IL-6) has been implicated in regulating growth of various malignant tumors and activated IL-6 has been shown to be elevated in the sera from patients with metastatic prostate cancer. In the present study we examined the IL6-induced Stat3 transcriptional activation in the development and progression of prostate cancer and its possible role as a target for the treatment of prostate cancer using the prostate-specific conditional targeting PTEN knockout mouse model. Homozygous PTEN-mutants develop prostate cancer in a stage-specific manner and have the ability to grow and develop castration-resistant prostate cancer after total androgen ablation by castration. ELISA assays revealed increased expression of soluble IL-6 receptor (IL-6R) in tissue lysates from prostate tumors in non-castrated and castrated mice (77.0 ± 6.17 vs 23.75 ± 5.17 ng/g of tissue, p&lt;0.001, respectively) at 32 wks of age. Immunohistochemical analysis revealed correlated expression of with Stat3 transcriptional activation, proliferation and androgen receptor in tumors from castrated mice. To determine the role of IL-6R induced transcriptional activation of Stat3, non-castrated and castrated tumor bearing mice were treated with an anti-mouse IL-6R antibody (MR-16). Mice treated with MR-16 showed downregulation of phosphorylated Stat3, however, treatment failed to inhibit tumor development and cellular proliferation. However, it was discovered that therapeutic doses of MR16 treatment resulted in increased phosphorylation of Erk1/2. Our data suggests that inhibition of IL-6R-induced Stat3 activation is insufficient to suppress tumor growth; however, further studies need to be conducted to evaluate the efficacy of horizontal combination strategies targeting Stat3 and MAP kinase signaling cascades.
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 3876. doi:1538-7445.AM2012-3876
Abstract 3877: ABT-737 synergizes with bortezomib to induce apoptosis: Activation of Bid, Bak, and Bax in the apoptotic response in malignant human glioma cells
Authors: Jane Esther P. , Premkumar Daniel , DiDomenico Joseph , Agostino Naomi , Vukmer Natalie , Pollack Ian 
Published: August 2012

Abstract
Glioblastomas are invasive tumors with poor prognosis despite current therapies. ABT-737 has monotherapeutic toxicity against leukemia, lymphoma and other malignancies, and we and others have noted some antiglioma activity, although insufficient to warrant use as monotherapy. We have recently demonstrated that proteasome inhibitors, such as bortezomib, dramatically sensitized highly resistant glioma cells to apoptosis induction, suggesting that proteasomal inhibition may be a promising combination strategy for glioma therapeutics. In this study, we examined whether bortezomib could enhance response to ABT-737 inhibition in glioma cells. Although primary cells from glioblastoma multiforme (GBM) patients and established glioma cell lines did not show significant induction of apoptosis with ABT-737 treatment alone, the combination of ABT-737 plus bortezomib, significantly enhanced apoptosis. The enhanced efficacy was due to proapoptotic mitochondrial injury and increased generation of reactive oxygen species. Our results also revealed that combination of bortezomib/ABT-73 enhanced apoptosis by increasing Bid cleavage, Noxa upregulation, Bak, Bax activation, and cytochrome c release. Further downregulation of Mcl-1 using shRNA enhanced cell killing by the bortezomib/ABT-737 combination. The significantly enhanced antitumor activity that results from the combination of bortezomib and ABT-737 offers promise as a novel treatment for glioma patients.
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 3877. doi:1538-7445.AM2012-3877